dopamine interaction in learning

G. Di Giovanni, V. Di Matteo & E. Esposito (Eds.) Progress in Brain Research, Vol. 172 ISSN 0079-6123 Copyright r 2008 Elsevier B.V. All rights reserved

CHAPTER 27

Serotonin/dopamine interaction in learning Marı´ a Esther Olvera-Corte´s1,3,, Patricia Anguiano-Rodrı´ guez1, Miguel A´ngel Lo´pez-Va´zquez2 and Jose´ Miguel Cervantes Alfaro3 1

Laboratorio de Neurofisiologı´a Experimental, Centro de Investigacio´n Biome´dica de Michoaca´n, Instituto Mexicano del Seguro Social, Morelia, Mich., Me´xico 2 Laboratorio de Neuroplasticidad de los Procesos Cognitivos, Centro de Investigacio´n Biome´dica de Michoaca´n, Instituto Mexicano del Seguro Social, Morelia, Mich., Me´xico 3 Laboratorio de Neurociencias, Divisio´n de Estudios de Posgrado, Facultad de Ciencias Me´dicas y Biolo´gicas ‘‘Dr. Ignacio Cha´vez’’, Universidad Michoacana de San Nicola´s de Hidalgo, Morelia Mich., Me´xico

Abstract: Dopamine (DA)–serotonin interactions dealing with learning and memory functions have been apparent from experimental approaches over the past decade. However, since the former evidence showing that these cerebral neurotransmitter systems are involved in the regulation of the same cognitive processes, few experimental studies have been done to further clarify the nature of DA–serotonin interactions for cognitive processes sharing common brain structures. Nevertheless, a regulatory role of 5-HT/DA interactions in cognition and the prefrontal cortex (PFC) and the striatum as a neuroanatomical substrate for these DA/5-HT interactions, are now recognized. Experimental evidence indicates that pharmacological disruption of serotonin neurotransmission results in a facilitative effect on the processing of mnemonic information by cerebral regions under strong, functional DA modulation, such as the striatum and the PFC; on the other hand, increased serotonin neurotransmission appears to have a detrimental effect on cognitive functions integrated in these structures. These effects seem to occur through the interaction of different pre- and postsynaptic DA and serotonin receptor subtypes acting as opposite systems underlying cognitive abilities. Some studies, focused on DA–serotonin interactions underlying the pathophysiology of neurological and psychiatric diseases, which evolve with cognitive dysfunctions in human beings, have shown that drugs that are able to modify DA or serotonin neurotransmission may exert beneficial effects on cognitive functions, even though improvement of motor, mood and behavioural disturbances are the main objectives of pharmacological treatment of these diseases. The complete significance of DA–serotonin interactions in cognitive functions could be addressed by future experimental and clinical studies. Keywords: serotonin; cognition; striatum; prefrontal cortex; Parkinson’s disease; dopamine receptors; learning Introduction

different hormonal and neurotransmitter systems in cognitive processes. However, interaction between neurotransmitters in the performance of cognitive tasks is a less developed issue. It has been established that many of the complex actions of the central nervous system (CNS) are determined by the properties of particular neurotransmitter

Over recent decades, there has been mounting evidence for the participation of a number of Corresponding author. Tel.: +52 4433 241610; Fax: +52 4433 241610; E-mail: [email protected]

DOI: 10.1016/S0079-6123(08)00927-8

567

568

systems, and by the interactions between them (Trimmer, 1999). Neuromodulation is a term that consistently describes non-classical effects of neurotransmitters on neurons. Thus, neuromodulation occurs when a substance released from one neuron alters the cellular or synaptic properties of another neuron (Kupfermann, 1979; Kaczmarek and Levitan, 1987). There are centres in the brain responsible for producing neuromodulatory effects and between these centres are the raphe nuclei (RN) and substantia nigra (SN), which are small clusters of neurons located in the brain stem with diffuse projections to all other areas of the brain. Their divergent projection pattern suggests that these neurons modulate activity in other areas of the brain, and practically all neuronal circuits in the mammalian brain are subject to neuromodulation arising from these centres (Katz, 1999). There are three major dopaminergic (DArgic) systems in the brain (Wolf et al., 1987): the mesostriatal system originating in the SN pars compacta, the mesolimbic system originating in the ventral tegmental area (VTA) and terminating in the accumbens nucleus (AN) and the mesocortical system originating in the VTA, but terminating in the prefrontal cortex (PFC). The cell bodies and terminal regions of all three DArgic pathways are innervated by serotonergic (5-HTergic) neurons originating in the medial and dorsal raphe nucleus (DRN) (Geyer et al., 1976; Parent et al., 1981; Beart and McDonald, 1982; Nedergaard et al., 1988). Neurons in the DRN make connections with areas innervated by the DArgic system (amygdala, striatum and PFC), whereas medial raphe nucleus (MRN) neurons make connections to the hippocampus and septal nuclei, which are not major DArgic targets (Azmitia and Segal, 1978). The dopamine (DA) and serotonin (5-hydroxytryptamine, 5-HT) neurotransmitter system activities are independently related to each other in the modulation of diverse cognitive abilities. However, little is known about the interaction between these two systems in the modulation of cognition. Nevertheless, a neuroanatomical substrate for DA/5-HT interaction exists, and the distribution of DA and 5-HT receptors allows us to deduce the possible interactions between these neurotransmission systems.

We will emphasize the DA/5-HT interactions in those cerebral regions implicated in cognition that receive both DA and 5-HT innervation, and where it has been shown that the participation of these neurotransmitters causes modulation of cognitive performance. For this reason, the focus of the present chapter will analyse the participation of 5-HT and DA in cognition separately and then, we will analyse the mesostriatal and mesocortical target areas, their participation in cognitive processes and the regulatory role of 5-HT/DA interactions in cognition sustained by processes principally underlying the PFC and striatum.

The serotonergic system and cognition Serotonergic systems have been implicated in diverse behavioural processes including motor function, motivation, timing behaviour, behavioural inhibition and response to stress and threat (Iversen, 1984; Fletcher et al., 1999; Misane and O¨gren, 2000). Experimental work over recent decades has led to the general notion that experimental pharmacological and neurotoxic manipulations that reduce central 5-HTergic transmission increase the retention, or facilitate the acquisition, of information, whereas manipulations that increase the 5-HTergic function produce deficiencies in learning and retention of certain tasks (Asin and Fibiger, 1984; Altman et al., 1990; Fletcher et al., 1999). Cerebral 5-HT manipulation Early experimental works studied the effect of cerebral 5-HTergic depletion on diverse learning and memory abilities. The principal strategies used to deplete brain 5-HT were the intracerebroventricular (ICV) or intra raphe application of 5,7-dihydroxytryptamine (5,7-DHT) and the intraperitoneal application of para-chlorophenylalanine (PCPA). Early results indicated that 5-HT depletion produced impairments, improved or did not affect memory and learning, depending on pharmacological approach, doses and behavioural tests used, and depending on what type of information was used by the animals and the nature of the

569

associations established. Regarding human studies, the principal strategy used consisted of the modification of cerebral 5-HT levels through the manipulation of tryptophan (Trp) availability, because this essential amino acid is the precursor of 5-HT synthesis, and it has been extensively shown that modifications in dietary availability of Trp causes modifications in cerebral 5-HT content (Biggio et al., 1974). However, a recent study directed at validating the use of acute Trp depletion (ATD) to effect a reduction in 5-HT and DA efflux, found that despite the plasma reduction being similar to that reported after experimental ATD, no effect on efflux of DA and 5-HT was observed in the PFC (Plasse et al., 2007). Thus, behavioural effects observed after ATD must be interpreted cautiously, because they could be the result of compensatory changes in synaptic process and neurotransmitter systems, rather than being directly related to a reduction of serotonergic function. We will now provide a summary of experimental findings related to serotonergic manipulation and its effects on cognitive ability, including a limited number of works that show general outcomes obtained through similar work, and some relevant aspects will be highlighted. Frequently in cognitive tasks, individual processes are intermixed, for example, working memory is not dissociated from spatial processing, and short-term memory (STM) is not well-differentiated from working memory. Thus, neurotransmitter participation in the processing of different information can be interpreted from a single experiment, and for this reason, an experimental finding can be relevant to more than one cognitive process. Early works indicated that a behavioural test implicating spatial management was not affected by cerebral or hippocampal 5-HT depletion. Experimental ICV 5,7-DHT application producing cerebral 5-HT depletion had no effect on the performance of rats in a radial arm test or in a water maze (Richter-Levin and Segal, 1989; Altman et al., 1990; Murtha and Pappas, 1994), whereas this same pharmacological strategy resulted in better performance in active avoidance tests (Carli et al., 1995). In more recent work, it was reported that the ICV injection of 5,7-DHT (150 mg in 4.5 ml/ventricle) significantly diminished

spontaneous alternation in a Y-maze when the reduction of 5-HT in the PFC was about 85% (Hritcu et al., 2007). This could be related to the effect of increased perseveration reported after prefrontal 5-HT, because several findings indicate that 5-HT is more involved in the reversal of learning ability than working memory per se, and that prefrontal 5-HT depletion results in a deficiency in reversal learning, but only in the reversion of acquired rules without affecting working memory (Robbins and Roberts, 2007). Whereas it has been shown that 5-HT depletion alone does not cause alterations in place of learning ability, a double lesion of acetylcholine and 5-HT caused a more profound deficit than that observed after cholinergic lesions alone (Richter-Levin and Segal, 1989). However, a deficit in reference spatial memory assessed in a water maze, spatial working memory assessed in radial arm maze and reduction in spontaneous alternation in T-maze produced by cholinergic denervation induced by the intraseptal application of 192IgG-saporin were attenuated by hippocampal 5-HT depletion through injections of 5,7-DHT into the fimbria fornix and cingulate bundle, despite hippocampal 5-HT depletion alone (about 55% depletion) not affecting the performance of any test (Lehmann et al., 2002). Thus, 5-HT depletion can reverse cognitive deficits produced by acetylcholine depletion. However, in other cognitive tests, 5-HT depletion resulted in a facilitation of performance. For example, 5-HT depletion after application of p-chloroamphetamine (PCA) alone, or combined with bilateral ibotenic acid-mediated lesions of nucleus basalis magnocellularis (NBM), was induced in rats and later evaluated in a 14-unit Stone maze, which was a complex, positively reinforced spatial discrimination task. Cerebral serotonergic depletion produced enhanced learning in the task that was completely prevented by a basal magnocellularis nucleus lesion (Normile et al., 1990), implicating a 5-HT/cholinergic interaction. The same investigators (Altman et al., 1990) trained rats in the 14-unit Stone T-maze after selective hippocampal 5-HT depletion induced by deafferentation with 5,7DHT infused into the fimbria fornix and cingulate bundle. The lesioned rats reached the learning

570

criteria in significantly fewer trials, than the control rats did, and made significantly fewer errors throughout the training. Thus, both cerebral or hippocampal 5-HT depletion resulted in facilitation in this spatial tests. However, considering that the hypothesis regarding the participation of different memory systems in place- or egocentriclearning that could have cooperative or competitive interactions (McDonald and White, 1993), and because the Stone test has a strong egocentric component, raises questions regarding whether the egocentric component of the task influences the better performance. Moreover, STM was evaluated using Trprestricted rats using Biel’s maze, which consists of a series of T disjunctions with a longer final corridor in which the animal finds a reward, and the animals had to choose the correct pathway based on left–right turns, but could also make use of spatial information. Using this task, Gonza´lezBurgos et al. (1998) observed a facilitation of STM, which was expressed as an early significant reduction in errors made by the animals during single-session training, such that the animals reduced the number of errors made after the second training trial compared to control animals that made it to the fourth trial. The same authors performed an evaluation of STM after prefrontal 5-HT depletion through application of 5,7-DHT into DRN (1 mg/1 ml), and observed the same facilitatory effect in the performance of the rats (Pe´rez-Vega et al., 2000). However, more recently, it has been reported that ICV injection of 5,7-DHT (150 mg in 4.5 ml per ventricle) produced deficiencies in working memory in a radial arm maze, which was interpreted as a result of a deficiency in STM, because no effects were observed in reference memory in a radial arm tests (Hritcu et al., 2007). A test of the step-through latency in a multi-trial passive avoidance (PA) task was used to evaluate long-term memory (LTM), and no effect was observed after 5-HT. Moreover, the administration of PCPA neither altered the PA performance. The investigators only measured 5-HT depletion in the PFC, and observed a depletion of approximately 85% after 5,7-DHT treatment and 80% after PCPA treatment (Hritcu et al., 2007). An important difference between these

two experimental approaches is the use of different behavioural tests. Biel’s maze evaluates STM (not working memory), and posses a strong egocentric component, in such a manner that to solve this test the animals can make use of a series of left–right turns without using spatial information, or they can use a spatial mapping strategy, as required for radial arm maze resolution. To assess the possibility that an egocentric component of behavioural tests could account for the facilitating effect observed after 5-HT depletion, spatial egocentric learning ability was tested to cerebral 5-HT depleted rats using a Morris water maze. The rats received a unique intracisternal injection of 5,7-DHT at 21-days old, and were evaluated in a Morris maze at 60-days old, using a behavioural task designed to avoid the use of allocentric spatial cues to solve the Morris maze task. With this aim, a black curtain was used to surround the maze, and the starting point and the platform position, although relatively constant, were rotated in the maze. Cerebral 5-HT depletion produced a facilitatory effect on egocentric learning, which was evident in reduced escape latencies. The performance of experimental rats on the first day of training and in all six training days was compared with the control animals that were unable to learn the task (Olvera-Corte´s et al., 2001). From the experimental findings described above, the proposition that the nature of the information used by experimental subjects is an important determinant of the consequences of 5-HT manipulations emerges, in a manner that suggests that spatial information processing is not affected by 5-HT depletion, but rather, the processing of egocentric information (or tests with a strong egocentric component) is favoured by 5-HT depletion. McDonald and White (1993) proposed a dissociation between memory systems in which the hippocampus forms part of a system engaged in the processing of stimulus–stimulus associations (or configural associations), such as those used in the establishment of cognitive maps, whereas stimulus–response associations (such as those used in egocentric learning) are directed by the activity of a memory system, including the striatum as its principal component. Cooperative and competitive interactions can occur between

571

these systems. From this perspective, if egocentric processing, which implies striatal activity, is favoured by 5-HT depletion, other striatal-dependent cognitive processes must show a facilitating effect after 5-HT depletion. Conditioned tests involve the acquisition of stimulus–response associations, and have been extensively shown to require the participation of striatal activity (Kirkby and Polgar, 1974; McDonald and White, 1993). The effect of a reduction in 5-HT after the application of 5,7-DHT in DRN and MRN in thirsty rats trained to associate a conditioned stimulus with water delivery were tested by Fletcher et al. (1999). A reduction in 5HT, both in the hippocampus and striatum, was associated with an enhancement in the conditioned response, so the authors suggested that a reduction in 5-HT removes the inhibitory influence on the mesolimbic DArgic system, resulting in an increase in conditioned responses (Fletcher et al., 1999). However, 5-HT depletion in the neocortex, hippocampus and striatum of more than 90%, induced by the ICV application of 5,7-DHT in rats, led to the 5-HT depleted animals failing to acquire conditional visual discrimination in a go/no-go task. This deficiency was probably due to an inability to withhold responses, and thus, correctly complete the no-go trials. The depleted rats responded faster, but correctly, during the go trials, and incorrectly during the no-go trials (Harrison et al., 1999). Thus, the possibility exists that impulsivity can account for the errors in the no-go trials. However, when the investigators used trained rats with their conditioning established, and then effected 5-HT depletion, these animals showed a similar, although less severe effect, on the performance in the no-go trials, showing an increase in response. Therefore, although the animals were able to perform discriminative learning before the lesions, 5-HT depletion produced a more deficient response during the no-go trials associated with an increased impulsivity more than the response to acquisition deficiencies (Harrison et al., 1999). However, forebrain 5-HT depletion after ICV 5,7-DHT administration caused a facilitation in acquisition of the discrimination that occurred earlier than in the controls in a task involving simple conditional visual

discrimination. A similar facilitating effect was observed in rats after the infusion of 8-hydroxy-2(di-n-propylamino)tetralin (8-OH-DPAT) into the RN (reducing 5-HT release through 5-HT1A autoreceptors) (Ward et al., 1999). Ward et al. (1999) evaluated the acquisition and performance of conditional visual discrimination after forebrain 5-HT depletion in a task requiring the acquisition of a ‘stimulus–response’ rule or habit (Mishkin et al., 1984). The animals were required to learn the following rules to obtain a sucrose solution: ‘if fast go left’ and ‘if slow go right’ (‘fast’ corresponded to 0.1 s light pulses at a frequency of 5 Hz, and ‘slow’ corresponded to light pulses with a duration of 2.4 s at a frequency of 0.83 Hz). ICV infusion of 5,7-DHT was made in order to the lesion 5-HTergic cells, whereas cannulation of the RN was performed to infuse the 5-HT1 receptor agonist 8-OH-DPAT into the dorsal raphe of other group of rats. The rats injected with 5,7-DHT had reductions in 5-HT in the hippocampus and cortex (80%), as well as in the striatum (greater than 90%), with a less substantial reduction in the hypothalamus. The 5-HT depletion did not affect post-operative re-acquisition of lever pressing under a continuous reinforcement schedule, but in the visual discrimination task, the depleted rats reached the most stringent criteria of acquisition (85%) in fewer sessions than the sham animals did, although the facilitation occurred in the first part of the acquisition (when the criterion was moved from 59% to 67%). 5-HT-depleted rats also showed a tendency to make fewer errors of commission. Thus, in no-go tasks, 5-HT depletion caused a deficiency attributed to a perseverative response, but in this work, two rules implying a go-task were favoured by 5-HT depletion. Together, these findings indicate that 5-HT facilitates conditioned visual discrimination, whereas it produces deficiencies in tasks that include a component of inhibitory response, as found in no-go trials. Moreover, the effect of systemic PCA application on the performance of a one-way active avoidance task by rats was examined, and it was observed that an increase in 5-HT produced impairments in the acquisition and retention of a task, depending on the temporal effects of the drug on 5-HT release. The effect was blocked by the

572

application of PCPA, but not by catecholamine depletion (through a-methyl-p-tyrosine or by application of the selective noradrenergic toxin, N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP4)) (O¨gren, 1985). Moreover, the systemic application of the 5-HT receptor agonist 8-OHDPAT reduced the escape latency in PA tests (Misane and O¨gren, 2002). Findings such as these support a role for 5-HT in the regulation of aversive learning, and the view that 5-HT regulation predominates in cognitive processes organized by cortico-striatal activity, which is relevant, because of the preponderant participation of DA in regulation of these cerebral structures. Table 1 summarizes the principal findings described, and highlights important insights obtained from the data. Firstly, the behavioural tests that possess egocentric components are favoured by 5-HT depletion. Secondly, conditioning tasks, such as PA or instrumental tasks, are frequently favoured by 5-HT depletion (with the exception of no-go tests in which a component of impulsivity is primarily related to deficient learning). Thirdly, in general, these tasks are dependent on striatal function (or cortico-striatal processing) as part of a memory system that is under strong

DArgic modulation and is also extensively innervated by 5-HTergic terminals. Electrophysiological studies have demonstrated that systemic or local application of 5-HT receptor agonists and antagonists onto DArgic neurons in the VTA or SN modulate the spontaneous activity of DArgic neurons (Kelland et al., 1990). 5-HT normally inhibits the cell firing of DArgic nigral neurons, and thereby, may modulate DA-dependent cognitive processes. A review of prominent findings regarding DA regulation of cognition will allow us to see an integrative view of the roles of 5-HT and DA in cognition.

The dopaminergic system and cognition DA plays a significant role in memory processes, especially through the interconnection of two brain regions: the striatum and the PFC (Jay, 2003). Extensive clinical and experimental findings involve the DArgic system with working memory organization. Parkinson’s disease (PD) patients, whose diminished DA release in basal ganglia caused by DArgic nigral cell death, presents a deficit in working memory that is attenuated by

Table 1. Behavioural consequence of serotonergic modifications on learning and memory tests in rat studies Pharmacological approach

5,7-DHT

8-OHDPAT Trp

PCA PCPA Fluoxetine

Administration via/effect

ICV/CD HC-FF/HD WMPL ¼ SM+ IC/CD Raphe/CD Raphe/PFCD Raphe/CD Diet restriction/ CD Ip./CI Ip./CD Ip./CD Ip./CI

Spatial learning

WMPL=

STM/LTM

RAM=/=

Cognitive process Working memory

Spontaneous alternation

Avoidance

Conditioning

RAM

TM

PA+

S+

DeA

YM

WMEL + Go+/no-go

BM+/ Go+ TM (+) +/+ SM+ WMCL

AA DNMPT

Symbols: =, no changes; +, facilitation effect; —, detrimental effect. Abbreviations: CD, cerebral depletion; CI, cerebral increase; HD, hippocampal depletion; PFCD, prefrontal cortex depletion; ICV, intracerebroventricular; HIPP, hippocampal; BM, Biel’s maze; WM, water maze; RAM, radial arm maze; ST, Stone’s maze; TM, T maze; YM, Y maze; DeA, delayed alternation; DNMPT, delayed non-matching to position tests; S, simple conditioning; Go, Go tests; No-go, no-go tests; PA, passive avoidance; AA, active avoidance; WMCL, water maze cue learning; WMEL, water maze egocentric learning. Chemical compounds, see abbreviations list.

573

levodopa (L-dopa) administration (Lewis et al., 2005). Similarly, DA loss in the PFC causes profound working memory deficit in monkeys and rats (Simon et al., 1980). Experimentally, exposure to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP, 30 mg/kg73 c/12 h, i.p.) produced a depletion of 60% in striatal DA in rats. The performance of animals with this degree of DA reduction in a T maze delayed alternation test was impaired, but only under conditions of delayed response (20 s and 120 s), and this is indicative of spatial working memory impairment (Tanila et al., 1998). This effect was apparently mediated by the effect of DA depletion on the PFC, because similar results were obtained after specific prefrontal DA depletion induced by 6-hydroxydopamine (6-OHDA) without causing 5-HTergic or catecholaminergic alterations. Using this approach, Bubser and Schmidt (1990) observed deficiencies in a T maze-delayed alternation task and deficiencies in a radial arm maze, whereas in continuous tasks, no deficiencies were observed. However, the PFC and the striatum work as a system in the organization of the different aspects of working memory. For example, it has been reported that in mice, a transient increase in D2 receptor expression restricted to the striatum causes a selective cognitive impairment in a working memory task, and a behavioural flexibility that was associated with alterations in DArgic function in the PFC, including DA turnover and the activity of D1 prefrontal receptors (Kellendon et al., 2006). Improvement in spatial working memory has been observed after administration of pergolide, a mixed agonist of D1 and D2 DA receptors, to healthy subjects evaluated using a visuospatialdelayed matching test, whereas bromocriptine, a D2 receptor agonist, did not have an effect on the same task (Mu¨ller et al., 1998). DA participation in working memory organization is welldocumented, and implies DA actions, principally in the PFC. Experimental findings have implicated DA as a major participant in brain-reward circuitry, not as a mediator of the hedonic aspect of reward, but rather being involved in anticipatory aspects of rewards and the incentive value for motivated behaviours (Salomone et al., 1997; Ikemoto and

Panksepp, 1999; Wightman and Robinson, 2002). According to Ikemoto and Panksepp (1999), ‘Incentive motivation is a process in which approach or avoidance responses are generated by stimuli that predict the proximity or availability of unconditioned stimuli (positive or negative)’. When a reward is presented to a monkey, its DArgic neurons increase their firing rate within a period of a few milliseconds of delivery of the reward. If the animals are trained to anticipate the reward, pairing its presentation with a conditional cue, then the DArgic neurons respond to the cue more than to the reward itself (Mirenowicz and Schultz, 1994). Schultz (1998) proposed that these phasic changes in DArgic cell activity, which have been associated with large and transient increases in extracellular DA levels in terminal regions, could interact with remote receptors and act as an alerting signal for salient stimuli (Rebec et al., 1997; Robinson et al., 2001). Slower tonic changes in DA may regulate other aspects of reward (Wightman and Robinson, 2002). Recently, Pizzagalli et al. (2008) administered healthy volunteers with low doses of the D2/D3 receptor agonist pramipexole (0.5 mg/kg) to decrease the phasic DA release through actions on autoreceptors. The subjects showed a decreased response to a rewarded stimulus, which was independent of motor adverse effects, confirming that in humans, phasic DA release is required to reinforce actions (stimulus–response establishment) leading to reward. It is important to recapitulate at this point that 5-HT depletion is related to enhancement of conditioned responses, because of the probable relevance of DA in conditioning 5-HT/DA interactions in the organization of conditioning. In this sense, a hypothesis developed by Daw et al. (2002) based on indirect evidence, places 5-HT acting as an aversive system in opposition to a DA system acting as an appetitive system, constituting motivational opponency. DA depletion also participates in the organization of procedural learning, and evidence had been obtained from tests of motor sequential learning that depend on the integrity of corticostriatal functioning (Tinaz et al., 2006), and are also dependent on the DArgic system (Matsumoto et al., 1999; Carbon et al., 2004; Badgaiyan

574

et al., 2007). Impairment in sequential motor learning, evaluated in a radial arm maze, has been observed as a general consequence of monoamine depletion, and is particularly related to the degree of DA depletion in the dorsal striatum (Daberkow et al., 2005). In humans, sequential learning is impaired in DA-deficient patients (Carbon et al., 2004). Badgaiyan et al. (2007) used a dynamic molecular imaging technique that located regions where the DA receptor ligand 11 C-raclopride was displaced from receptors by DA released endogenously during the performance of a sequential motor learning task. Their findings indicate DA release from the posterior two-thirds of the dorsomedial aspect of the putamen and the caudate anterior, suggesting that striatal DArgic mechanisms are involved in human sequential learning. Similarly, in experimental studies, it has been observed that the striatum is a key nucleus in cognitive functions underlying basal ganglia activity (Matsumoto et al., 1999). For example, lesions or inactivation of striatum impairs the acquisition of instrumental tasks, stimulus–responselearning and temporal expectation in rats (McDonald and White, 1993; Florio et al., 1999; Hudzik et al., 2000). Thus, it is evident that those cognitive abilities that are facilitated by 5-HT depletion correspond to cognitive processes underlying the function of the cerebral system in relaying in the cortico-striatal activity, and are tightly subject to DA modulation. In previous experimental findings regarding both 5-HT and DA participation in cognitive processes, the pharmacological approach consisted of the application of neurotoxins that cerebrally deplete 5-HT or DA. The application of 5-HT reuptake inhibitors, which increase cerebral serotonergic activity, allows the entire 5-HT system to be manipulated using these global strategies. The availability of pharmacologically selective compounds for different subtypes of receptors has permitted the study of the different contributions of receptor subtypes on cognitive processing. However, the behavioural consequences after the increase or decrease in extracellular neurotransmitter levels caused by neurotoxins, or by the application of reuptake inhibitors, agonist and antagonists affecting global cerebral systems or

structures must be different to physiological changes in availability and release of neurotransmitter from afferent terminals into defined circuits and their effect on specific behavioural demands also changes. The diverse physiological actions of DA are mediated through two receptor populations: D1-like DA receptors and D2-like DA receptors. D1-type receptors include the subtypes D1 and D5, and are stimulators of adenylate cyclase, while D2-type receptors include subtypes D2, D3 and D4, which are inhibitors of adenylate cyclase (Kebabian et al., 1984). DA receptors and cognition It has been proposed that DA modulates spatial functions through the innervation arising in the SN and VTA to hippocampus (mainly into its ventral part), principally through D2 DA receptors with minor participation of D1 receptors (Wilkerson and Levin, 1999). However, evidence regarding the participation of D1 and D2 receptors in modulating spatial ability has not yet been well defined. For example, both place- and cue-learning were evaluated using a Morris maze after the administration of the D1-like receptor antagonist SCH23390, and D2-like receptor antagonist sulpiride, in rats. High doses of SCH23390 had an adverse effect on cue learning, whereas sulpiride in high doses impaired performance in the hidden platform test in the Morris maze (Stuchlik et al., 2007), apparently showing a dissociation of D1and D2-like receptors in striatal- and hippocampal-dependent navigation tests (McDonald and White, 1993) in a manner where D1 antagonism affected cue learning, but not place learning, whereas D2 antagonism impaired place learning. However, in tests on place conditioning, the systemic administration of SKF 82958, a D1 receptor agonist, induced place preference in rats (Abrahams et al., 1998). This is consistent with evidence that D1 receptors are critical for longterm potentiation (LTP) and spatial learning in hippocampus, and are also related to the acquisition of new information through hippocampal LTP and long-term depression (LTD) (Lemon and Manahan-Vaughan, 2006). Moreover, in place

575

avoidance tasks that were developed to evaluate the organization of behaviour and spatial cognition (Cimadevilla et al., 2001; Vales and Struchlik, 2005), a recently established testing paradigm, the active allothetic place avoidance task (AAPA), which requires rats to actively avoid a roomframe-fixed shock sector in a continuously rotating arena (Stuchlik et al., 2004), was used to evaluate the participation of a D1 receptor agonist and antagonist in the modulation of spatial cognition in rats. Application of the D1 receptor antagonist SCH23390 (0.02 and 0.05 mg/kg i.p.) produced a deficit in the solution of a task, as evident from the higher number of entrances to the shocking (punishment) zone, as well as the shorter time that elapsed without entrance into the punishment zone. In contrast, application of lower doses of the D1 receptor agonist (1R-cis-)-1-(aminomethyl)-3, 4-dihydro-3-tricyclo[3.3.1.13.7]dec-1-yl-[1H]-2benzopyran-5,6-diol hydrochloride (A77636) produced an enhancement of efficiency, as measured by the small number of errors (Stuchlik and Vales, 2006). Similarly, other authors observed spatial navigation deficits after systemic administration of SCH23390 to rats solving a radial maze (Liao et al., 2002), supporting the more important role of D1 receptors in spatial hippocampal-dependent tasks. However, when pretrained animals were evaluated in an AAPA task for reinforced retention under the influence of drugs after learning the test, no effect was observed for low doses of A77636 or SCH23390 in AAPA, but high doses of SCH23390 caused a motor deficit in the retention tests. From these observations, the investigators concluded that the effect observed on D1 antagonist application was due to a non-spatial aspect of the task, and that this affected procedural aspects of the task (Stuchlik, 2007). This is very important, because only the procedural components of the task were affected in the tests once the spatial information was acquired, and thus, this effect may be principally dependent on striatal function, which as was previously mentioned, is preponderant in the organization of procedural learning (McDonald and White, 1993). Thus, place navigation, working memory, conditioning and procedural learning are all processes organized principally or partially by a cerebral

system that is under the modulating influence of the DArgic system. Starting from this point of view, the effect of serotonergic modulation on these same cognitive abilities will be explored and related directly (when experimental evidence permits it) or indirectly from neurochemical data with the DArgic system in an integrative effort. Serotonergic receptors and cognition 5-HT1 receptor functions in 5-HT organized cerebral processes have been evaluated using 8-OH-DPAT, which initially considered the 5-HT1A receptor agonist, and which has later been found to have a combined effect as an agonist of 5-HT1A/7 receptors (Eglen et al., 1997). The consequences of 5-HT1A receptor activation were examined in different studies to evaluate spatial working memory. Deficiencies in working memory were observed after the systemic application of 8-OH-DPAT at doses of 0.2 and 0.5 mg/kg in pretrained rats. Briefly, the authors measured re-entry into baited or unbaited arms previously visited (working memory error) by rats that were trained to eat in four baited arms of a radial maze until they reached a criteria of three or more correct responses over five consecutive days. The number of working memory errors increased on agonist application, while no effect on the reference memory was observed (Carli et al., 1999; Isayama et al., 2001). The mediation of the effect of 5-HT1A receptors was investigated by Egashira et al. (2006), who evaluated spatial working memory ability in an eight-arm radial maze after systemic 8-OH-DPAT administration or bilateral infusion into the dorsal hippocampus. The spatial working memory was impaired, and this impairment was blocked by the application of 5-HT1A antagonists (NAN-190 and WAY-100635), while the administration of SB269970, a specific 5-HT7 receptor antagonist, had no effect on the impairment caused by 8-OH-DPAT. In a delayed non-matching to position task, which was used to evaluate working memory, Ruotsalainen et al. (1998) found that cerebral 5-HT depletion by 5,7-DHT application did not produce an effect, while 8-OH-DPAT application (100 mg/kg) reduced the probability of responding

576

to a sample lever without affect the choice accuracy. However, in a more recent study, Ferna´ndez-Pe´rez et al. (2005) who used a delayed non-matching to position task, to evaluate the effect of 8-OH-DPAT (0.3 mg/kg), the antagonist WAY-100635 and the 5-HT reuptake inhibitor fluoxetine, observed an effect on the accuracy of the response. 8-OH-DPAT and fluoxetine produced delay-dependent deficiencies in the response accuracy, and WAY-100635, which has no effect when applied alone, not only reversed the impairment caused by 8-OH-DPAT and fluoxetine, but improved the response accuracy in rats treated with fluoxetine. Thus, increased 5-HTergic activity through the administration of the 5-HT reuptake inhibitor fluoxetine or activation of the 5-HT1A receptors, caused the deficiencies in the conditioned tests evaluating working memory (through response delay), and the effect was mediated through the 5HT1A receptors. Meneses and co-workers have extensively evaluated the manipulation of 5-HTergic receptors activity in an autoshaping test. Briefly, rats were trained to press a lever (presentation of the lever for a period of eight seconds), followed by administration of a food pellet if the animal pressed the lever (conditioned response). The trial was shortened, and the food pellet was delivered immediately, thus, the learning produced an increase in conditioned response that could be evaluated for STM (1.5 h after) and LTM (24 h after). Using this task, the authors evaluated the effect of post-training systemic administration of 8-OH-DPAT (dosages ¼ 0.25 and 0.50 mg/kg), which produced impairments in STM and LTM (Meneses, 2007; Meneses et al., 2008). 5-HT1A receptors have been implicated in the regulation of spatial information processing. Latgen et al. (2005) evaluated the role of 5-HT1A in spatial learning in rats using a water maze task. Pretraining administration of 8-OH-DPAT impaired water maze performance both at low doses (0.01 and 0.03 mg/kg) and high doses (0.1 and 1.0 mg/kg). The impairment was blocked by the 5-HT1A receptor agonist NAD-299. An adverse effect of the activation of 5-HT1A receptors has been observed in spatial information acquisition, whereas 5-HT1B receptor activation,

through the application of the specific agonist CP 93129, preferentially impairs reference memory (Buhot et al., 1995). Thus, spatial working and reference memory are adversely modulated by 5-HT through 5-HT1A/B receptors. As described previously, antagonists to D1 and D2 receptors can interfere with hippocampalspatial processing. Moreover, 5-HT1A agonists administered systemically stimulate midbrain DArgic neurons, increasing DA release. Furthermore, 5-HT1A receptors are located post-synaptically in corticolimbic areas innervated by DArgic cells including the PFC, amygdala and hippocampus (Pompeiano et al., 1992). Each area is related to spatial working memory processing. In the PFC, the application of 5-HT1A receptors agonists in high doses decreases DA release (Alex and Pehek, 2007), in accordance with the effect of DA receptor antagonists causing deficiencies in spatial working tests. Moreover, Ferna´ndez-Pe´rez et al. (2005) have shown that in rats, the co-administration of fluoxetine and the 5-HT1A receptor antagonist WAY100635 produces memory improvement in a delayed non-matching to position task. This provides evidence that the cognitive deficits caused by 5-HT1A receptor agonism could be the result of their indirect actions on other neurotransmitter systems as DArgic system. However, no data exists that relates the 5-HT/DA interaction to deficits produced by 5-HT1A receptor agonists on place learning. Rather, the effect on spatial function has been related to 5-HT/Ach interactive effects. However, a substrate for interaction between 5-HT and DA in modulation of spatial processing exists. In associative learning, it has been reported that 8-OH-DPAT does not effect or retard acquisition (Harvey, 1996), while Misane and O¨gren (2000) have consistently shown that 8-OH-DPAT impairs 24-h PA retention when systemically administered before training or retention, whereas no effect is seen after immediate post-training administration (O¨gren, 1985, 1986; Misane et al., 1988). However, these authors indicate that no apparent effect on DA systems by 8-OH-DPAT exists (Misane and O¨gren, 2000). Other receptors participating in cognitive processes include the 5-HT2C receptor that has principally been involved in the modulation

577

of associative learning. 5-HT2A/C receptors are expressed post-synaptically in the neocortex, including the limbic cortex, the hippocampus, thalamus and basal ganglia. Several studies, including those on agonists of 5-HT2A/C receptors 4-methyl-2,5-dimethoxyamphetamine (DOM), 3,4methylenedioxyamphetamine (MDA) and 3,4methylenedioxymethamphetamine (MDMA) have shown an enhanced acquisition of conditioned responses. Moreover, the capability of 5-HT2A/C receptor antagonists to retard learning and to block the enhancement produced by agonists indicates that these receptors are needed for normal associative learning (Harvey, 1996). 5-HT2A receptors have been proposed as regulators of DA neuron activity through the regulation of corticotegmental projections, which in turn, regulate the activity of DArgic neurons (Pehek et al., 2006). Moreover, 5-HT2A receptor agonists increase the activity in the nigrostriatal DArgic pathway, while their antagonism decreases the evoked release of DA (Alex and Pehek, 2007). Evidence exists that 5-HT2C receptors inhibit DA release in striatum, AN and the PFC. In accordance with this, Boulougouris et al. observed an effect of the 5-HT2A receptor antagonist M100907 and the 5-HT2C receptor antagonist SB242084 in a serial spatial reversal learning task. Any of these antagonists altered the discrimination or retention of the response previously acquired, but only the 5-HT2A antagonist impaired reversal learning, manifested in an increase in perseverative responses, whereas the 5-HT2C receptor antagonist improved reversal learning, as measured by a decrease in the number of trials required to attain the criteria, and by a reduction in perseverative responses (Boulougouris et al., 2008). Thus, the activity of 5-HT through these receptors could account, at least partially, for the detrimental effect of 5-HT depletion on reversal learning. Because of the participation of the PFC in reversal learning, the effect of this compound could be occurring at this level under prominent DArgic control, for which DA/5-HT interactions could be occurring, since the 5-HT1A antagonists could mediate their effect through a reduction in DA release, whereas the 5-HT2C antagonists block the inhibitory effect of 5-HT through these receptors on release of DA.

PA is affected by manipulation of 5-HT4 receptors, the highest density of which, occur in the hippocampus, frontal cortex and amygdala, which are all regions related to cognitive processes (Eglen et al., 1995). The application of the partial 5-HT4 receptor agonist SL65.0155 (1 mg/kg/day), 7 days before a test of PA in mice showed an enhancement of the PA response, as evidenced by an increase in the latency of re-entry to the apparatus compared to vehicle-treated animals, after 1 day of the training trial. Moreover, this agonist is able to reverse amnesic effects caused by the administration of galanin (Micale et al., 2006), a compound that, when administrated in the lateral ventricles, inhibits acetylcholine release and produces deficits in learning and memory (Kinney et al., 2003). In PA tests in mice, the application of 5-HT4 receptor antagonists immediately after training produced an amnesic effect, which was prevented by 5-HT4 receptor agonists (Galeotti et al., 1998). Moreover, 5-HT4 receptor partial agonists facilitated both STM and LTM (5.0 and 10.0 mg/kg, respectively) in an autoshaping test (Meneses, 2007). Biochemical evidence indicates that 5-HT4 receptor stimulation is able to increase the release of striatal DA in vivo. Moreover, other evidence indicates that this receptor modulates impulse-mediated DA release, whereas it does not affect tonic release. The modulatory effect appears to occur through the action of 5-HT4 receptors located on SN neurons as well as by direct action on striatal elements (Alex and Pehek, 2007). Thus, it is possible to propose that the facilitating effect observed after stimulation of 5-HT4 receptors can be mediated by an increase in DA activity. However, despite the indirect evidence, it has not been evaluated whether changes produced by 5-HT4 receptor stimulation on PA are mediated by changes in DA. 5-HT3 receptors are related to cognition, although the principal effects observed regarding their participation concern the amelioration of deficits caused by acetylcholine depletion (Barnes et al., 1990). However, an effect of these receptors on learning and memory has been reported. Posttraining intraperitoneal administration of the agonist mCPBG impaired retention in autoshaping tests, whereas the antagonists tropisetron

578

and ondansetron improved retention (Hong and Meneses, 1996; Meneses, 2007). Granisetron, another 5-HT3 receptor antagonist, induced deficiencies in spatial learning in a Morris water maze when it was infused intra-hippocampally 20 min before daily training without having any effect on visual discrimination (Naghdi and Harooni, 2005). Previously Stau¨bli and Xu (1995) observed that 5-HT3 receptor antagonists enhanced hippocampal learning and modulated hippocampal plasticity (LTP). Moreover, the over-expression of 5-HT3 receptors in mice produced enhanced contextual conditioning, without having an effect on cued conditioning and latent inhibition enhancement, as well as inducing a heightened exploratory behaviour and a decrease in anxiety, as measured in an elevated-plus maze (Harrell and Allan, 2003). 5-HT3 receptors are primarily localized pre-synaptically as heteroreceptors (MacDermott et al., 1999). Their localization allows for the modulation of the release of neurotransmitters, such as DA (Campbell et al., 1996; Allan et al., 2001). It has been shown that in striatum, these receptors are present in potentially DArgic nerve terminals (Nayak et al., 2000), where they can increase evoked neurotransmitter release (Ronde´ and Nichols, 1998; Alex and Pehek, 2007). PFC application of 5-HT3 receptor agonists induces an increase in DA release and the antagonists produce a decrease. However, no evidence exists relating the effect of 5-HT3 receptor agonism on cognition and its effect on the DA system, although it has been implicated in motor control through its interaction with nigrostriatal DA neurons by its control of depolarization-dependent exocytosis only when central DA and 5-HT tone are concomitantly increased (Porras et al., 2003). Earlier studies have indicated that 5-HT acting through 5-HT6 and 5-HT7 receptors had no effect on improving memory formation or reverting amnesia. 5-HT6 and 5-HT7 receptors are distributed in areas involved in memory formation as striatum, AN, hippocampus and frontal cortex (Gerard et al., 1997). Using the 5-HT6 receptor antagonist RO4368554, Schreiber et al. (2007) tested scopolamine-impaired and unimpaired male

rats in several cognitive tests. They found that RO4368554 reversed the effects of scopolamine in novel object discrimination and PA, whereas it enhanced the performance in unimpaired animals in object discrimination after an interval of 4 h. No effects were observed on Morris water maze performance by the administration of RO4368554 to unimpaired animals. The effects of post-training systemic application of the 5-HT6 receptor agonist EMD in an associative autoshaping task (1–10 mg/kg) were tested both in STM and in LTM. The agonist at a dosage of 5.0 mg/kg impaired both short- and long-term memory. The 5-HT7 receptor agonist AS19 was applied using the same procedure and dosages, and (2S)-(+)-5-(1,3,5-trimethylpyrazol-4-yl)-2(dimethylamino) tetralin (AS19) significantly impaired STM (Meneses, 2007; Meneses et al., 2008). Gasbairri et al. (2008) evaluated the effect of the 5-HT7 receptor antagonist SB-269970 on radial arm maze performance using a procedure involving two phases to evaluate working memory during an acquisition phase and reference memory during a phase test. In this test, the antagonist improved memory in the test phase by affecting the reference memory, but had no effect on working memory. Whereas much data supports the 5-HT6 receptor modulation of cognitive ability through actions on cholinergic neurons (Mitchell and Neumaier, 2005), less evidence exists regarding 5-HT6/DA and 5-HT7/DA interaction. Thus, 5-HT, through its diversity of receptors, regulates different cognitive abilities, producing different effects that depend on the nature of the information processed (e.g., egocentric vs. allocentric information), and on the type of processing of the information (e.g., stimulus–response vs. stimulus–stimulus associations and STM vs. working memory). In the processing of information directed by cerebral regions under strong DArgic modulation, such as the striatum and the PFC, 5-HT antagonism or depletion appears to induce a facilitating effect, whereas 5-HT agonism appears to have a detrimental effect. Thus, a potential interactive effect of 5-HT/DA could be occurring in the organization of such abilities in these cerebral structures (Table 2).

579 Table 2. Effect of 5-HT receptors agonist and antagonist administration on learning and memory tasks in rat Receptor

Compound/ admon. via

Spatial function

5-HT1A/7 Ago

8-OHDPAT/ip

5-HT1A Ant 5-HT1B Ago 5-HT2 A Ago 5-HT2A Ant 5-HT2C Ant 5-HT3 Ago 5-HT3 Ant 5-HT4 Ago 5-HT4 Ant 5-HT6 5-HT6 5-HT7 5-HT7

Ago Ant Ago Ant

8-OHDPAT/IHB WAY-100635/ip CP 93129/ip DOM, MDA, MDMA/ip M100907/ip SB242084/ip MCPBG Ondansetron, Tropisetron SL65.0155/ip SDZ 205557, GR125487 EMD/ip RO4368554/ip AS19/ip SB 269970

STM/LTM

Working memory

Avoidance

WM

DNMPT

RAM RAM

RAM RAM DNMPT+ RAM=

AP+ Low dose AP High dose AP =, 

DNMPT+/ RAM

Conditioning

IC+, — RL-IC — RL-IC+ WM+

AST AST+ PA+ PA AST/

WMPL ¼

PA+ AST/=

RAM+

RAM=

Symbols: =, no changes; +; facilitation effect; ; detrimental effect. Abbreviations: BM, Biel’s maze; WM, water maze; RAM, radial arm maze; ST, Stone’s maze; TM, T maze; YM, Y maze; DeA, delayed alternation; DNMPT, delayed non-matching to position tests; S, simple conditioning; Go, go tests; no-go, no-go tests; PA, passive avoidance; AA, active avoidance; WMCL, water maze cue learning; WMEL, water maze egocentric learning, IHB, intra hippocampal bilateral; AST, autoshaping test; RL-IC, reversal learning in instrumental conditioning task. Chemical compounds, see abbreviations list.

Striatum and cognitive processes Striatal mediated cognitive processes and DA The striatum (caudate–putamen) part of the basal ganglia is a group of subcortical nuclei that also includes the subthalamic nucleus, globus pallidus and SN (Wilson, 1998). These nuclei participate in voluntary movement regulation, frequently called motor control, and are affected by diseases such as Parkinson’s and Huntington’s diseases: both diseases cause dementia because cognitive functions sustained by the basal ganglia are altered with the degeneration of these nuclei (Packard and Knowlton, 2002). The striatum constitutes the incoming pathway for cortical inputs (Packard and Knowlton, 2002), and has been associated with several experimental studies on procedural learning, sequential motor learning (implicit sequential motor information is a form of procedural learning), conditioning and

the establishment of stimulus–response associations, as well as egocentric learning (McDonald and White, 1994, 1996). These cognitive processes are directed through its interaction with the cerebral cortex via the arrival of aforementioned afferent information (Wilson, 1998; Packard and Knowlton, 2002). Temporal changes during a rewarded instrumental conditioning task, in which rats were trained to press a lever after a tone to obtain a food reward, were measured by Nakazato (2005). The reaction time for pressing the lever was measured as an index of learning, and the concentration of DA in the ventral anterior striatum was measured every week for a period of 5 months. The concentration of DA began to increase just after the cue presentation, and reached a peak near the time of pressing the lever, returning to the base level 1–2 s after pressing the lever. These changes were observed during the 5 months of training. The peak in DA after the cue presentation was higher when the task was not yet

580

perfected, and subsided towards the end of the training period. This indicates that increased DA release is required for instrumental conditioning acquisition and stops when the task is learned. Stimulus–response habit formation was evaluated after bilateral intrastriatal administration of 6-OH-DA to rats. Whereas the control animals required six training sessions to reach a criterion, 6-OH-DA-injected rats did not reach the criteria until the twelfth session, i.e., the lesioned animals were slower to acquire the instrumental actions, but after over-training, these animals performed similar to control animals. Moreover, the control animals did not show reward devaluation by specific satiety, which is indicative of habit formation, while the lesioned rats did show reward devaluation, which indicates that their stimulus– response was directed by goal expectancy, that is, no habit formation occurred (Faure et al., 2005). After unilateral nigrostriatal lesions, Hudzik et al. (2000) observed that rats were deficient in acquiring an operant task when pretrained animals were evaluated in a test requiring the achievement of response–duration differentiation, the unilateral lesions produced marked deficiencies too. There is also evidence that the dorsal striatum (or caudate– putamen) is involved in aversive conditioning. Lesions of this structure produce deficits in active avoidance (Kirkby and Polgar, 1974; Winocur, 1974) and PA (Winocur, 1974; Prado-Alcala et al., 1975). In aversive conditioning, a dissociation of functions for hippocampal and striatal processes has been observed. In Pavlovian aversive conditioning effected by the presentation of three-paired tones and foot shocks, application of D-amphetamine immediately post-training in either hippocampus or dorsal striatum causes a reduction in conditioned freezing measured 24 h later. However, this is only in response to contextual information by the hippocampal administration in rats and both for contextual and tone response for striatal infused rats. Thus, the dorsal striatum is involved in aversive conditioning to both contextual and discrete conditioned stimuli (White and Salinas, 2003). Dunnett and White (2006) observed an impairment in choice accuracy in an operant test of delayed alternation after bilateral

striatal lesions in rats, in both tests without a delayed response and in tests with a delayed response. This indicates an effect on the operant aspects of the task by the lesions more than alterations in working memory processes. Accordingly, the effect of unilateral or bilateral DA depletion, either in dorsal or ventral striatum, on the preparation and execution of a delayed response task in rats was evaluated by Florio et al. (1999). They observed that the dorsal striatum is related to stimulus–response learning because the animals lesioned in this area showed a lack of conditioned response, whereas the ventral striatum is related to temporal expectation and resulted in premature or omission responses. Specifically, the dorsolateral region of the striatum has been related to procedural tasks and habit learning (Featherstone and McDonald, 2004; Yin et al., 2004). Thus, with regard to striatum-dependent cognitive abilities, a role for DA in consolidation processes is well-documented (Castellano et al., 1991; Packard and White, 1991; Packard and McGaugh, 1994). Direct DA receptor agonist administration increases the retention of information in several tasks, including several versions of the radial arm and Morris water maze (Castellano et al., 1991; Packard and White, 1991; Packard and McGaugh, 1994). These effects are thought to be mediated by both D1 and D2 receptors in mice (Castellano et al., 1991), while in rats, D2 receptors have been more strongly implicated in early consolidation processes, whereas D1 receptors may play a more important role in later stages of learning (White et al., 1993). Moreover, it has been proposed that the concerted participation of D1 and D2 receptors is required in organizing the striatal-dependent cognitive ability (Wolterink et al., 1993; Watanabe and Kimura, 1998), and the co-activation of D1 and D2 receptors is required for LTD in the striatum (Calabresi et al., 1992), a mechanism proposed as underlying the memory processes (Fino et al., 2005). In rats, it is generally observed that D1-like receptor agonists impair, whereas D2-like receptor agonists enhance, responses in conditioning tests (Abrahams et al., 1998; Sutton et al., 2001). Shapovalova and Kamkina (2008) evaluated the effect of a bilateral blockade of DA receptors on

581

cognitive functions. They compared the systemic and intra-striatal application of the D1 receptor antagonist SCH23390 on the acquisition of a discriminative conditioned active avoidance reflex in a T maze, as well as the effect on motor activity in the open field. The antagonist caused a marked reduction in the number of conditioned responses (0.025 mg/kg) and reduction in motor activity in the open field. Striatal bilateral D1 receptor blockade did not have an effect on the conditioning, but affected the motor activity, causing a profound inhibition. Similar adverse effects on conditioning were observed after a bilateral infusion of the D2 receptor antagonist raclopride without any changes in motor activity. Thus, the effects observed in conditional learning after systemic application of D1 receptor agonist appear to be indirectly mediated, and occur through striatal D2 receptors (Shapovalova and Kamkina, 2008). Rats trained to release a lever in response to a visual cue within a reaction time limit were systemically administered with D1 (1-[(2-bromo4,5- dimethoxyphenyl) methyl]-l, 2,3,4-tetrahydro6-methoxy-2-methyl-7-isoquinolinol (A69024)), D2 (eticlopride) and D3 (nafadotride) receptor antagonists. The D1 receptor antagonist had no effect, whereas the D3 receptor antagonist produced a mild effect on performance in high doses (1 mg/kg s.c.) consisting of an increase of delayed responses. The D2 receptor antagonist produced profound deficits in performance in a dosedependent decrease in number of correct responses (0.005, 0.01 and 0.02 mg/kg s.c.), caused by an increase in the number of delayed responses and an increase in reaction time (Smith et al., 2000). Lesions to the prefrontal medial cortex with 6-OHDA, reducing DA levels in the PFC, did not alter the acquisition of fear conditioning. However, lesioned rats showed a delayed extinction of the conditioned response without an alteration of the initial acquisition (Morrow et al., 1999). This effect could be mediated by the D2 receptors, because a facilitation of extinction in a conditioned fear test was observed by applying the D2-receptor antagonist sulpiride, after a conditioning session pairing a tone with foot shock and pre-submission of the animals to extinction training (consisting of the

repeated CS presentations alone to generate extinction in mice). The extinction was measured during the extinction training and 24 h after the training in a free-drug condition; sulpiride treatment before the extinction training facilitated extinction memory 24 h later, and quinpirole (D2 receptor agonist) partially blocked the extinction (Ponnusamy et al., 2005). The D1 antagonist SCH 23390 (0.1–1 mg/kg) administrated before the conditioning training inhibited the acquisition of conditioning freezing in tests carried out 24 h later. When it was administrated after the foot-shock training, SCH 23390 did not affect the conditioned freezing (Inoue et al., 2000). Thus, both D1 and D2 receptors contribute to aversive conditioning. Although opposing effects in the electrophysiology of striatal spiny neurons mediated by D1 and D2 receptors have been reported, it has been proposed that a tonic D2 receptor-mediated inhibition of synaptic efficacy may be important in suppressing striatal output when cortical activity is relatively low, and when the D1 receptor activation is capable of depolarizing the membrane further, facilitating spike discharges. Thus, by controlling the excitability of striatal neurons via distinct effects on membrane activity and afferent drive, the DArgic system exerts a true modulatory influence over information processing in the striatum (West and Grace, 2002). Moreover, cooperative relationships between D1 and D2 receptors on striatum-dependent cognitive processes have also been shown. D1 and D2 receptors act simultaneously in mediating the cellular effects of DA regulating DA and glutamate release, and integrating DA with other neurochemical inputs to the striatum (Kiyatkin and Rebec, 1999). 5-HT could be one of the neurochemical inputs with a large repercussion on striatal DA-dependent cognitive processes. Striatal cognitive processes and 5-HT Clinical reports indicate that 5-HT function deteriorates in cerebral areas related to cognitive processing in patients with Alzheimer’s disease (Wenk et al., 1987), and PD patients show alterations of 5-HTergic neurotransmission besides a decline in DArgic (Graybiel, 1990).

582

Intrastriatal (Yu and Liao, 2000) or systemic methamphetamine exposure causes monoamine depletion, and impairs sequential motor learning in a radial arm maze (Chapman et al., 2001). These motor learning deficiencies are associated with depletion of monoamines in striatum. A negative correlation between DA depletion in medial striatum and an increase in the number of direct movements (an index of sequential motor learning) was observed, as well as a correlation between the content of 5-HT in the lateral striatum and the number of direct movements (in both cases, the depletion of neurotransmitter was associated with a smaller increase in the number of direct movements) (Daberkow et al., 2005). Other experimental work indicates that 5-HT participates in modulation of memory and striataldependent learning processes in a complex manner. Early work has shown that an increase in 5-HT activity attenuates conditioned reward response, whereas reducing cerebral 5-HT activity selectively enhances conditioned responses (Fletcher et al., 1999). In addition, Prado-Alcala´ et al. (2003a, b) reported that intrastriatal administration of the 5-HT releasing drug PCA, or application of 5-HT, produces deficiencies in inhibitory avoidance tests. When 5-HT or PCA was striatally administrated pretraining (30, 15 or 5 min before training) and the retention measured 24 h later, an inversely related time-dependent deficit was found (Solana-Figueroa et al., 2002). Both tests were strongly dependent on DArgic function, as previously stated. Serotonergic DRN neurons project to basal ganglia predominantly in striatum, and send axonic collaterals to SN (Ferre´ et al., 1994; Gervais and Rouillard, 2000), and either stimulation of the DRN (Herve´ et al., 1979; De Simoni et al., 1987) or the administration of 5-HT induce changes in striatal DA release both in vivo and in vitro (De Belleroche and Bradford, 1980; Blandina et al., 1989). It has been suggested that serotonergic modulation is more evident during DA system activation (Palfreyman et al., 1993), which is known to occur during the establishment of conditioning (Rebec et al., 1997; Robinson et al., 2001) The effect of 5-HT or PCA directly infused into the striatum could involve a direct effect on DA function, since, 5-HT exerts a

presynaptic inhibitory action on cholinergic and DArgic terminals through 5-HT2 receptors, and an inhibitory action on striatal cells through 5-HT1 receptors. DA and ACh coactivation is required by the plastic changes that subserve striatal-mediated learning (Suzuki et al., 2001). According to this hypothesis, the post-trial intrastriatal infusion of the 5-HT2 receptor antagonist ketanserine produces an amnesic estate because of a lack of inhibition of DA release in striatum that in turn, could induce a reduction in cholinergic release by inhibition through D1 receptor activation (Ramı´ rez et al., 1997). Interaction between 5-HT/DA has been observed in tests on serial reaction. Profound 5-HT central depletion by ICV application of 5,7-DHT was established in rats trained to detect and locate brief visual stimuli randomly presented in one of five spatial positions. After the establishment of a performance criterion fixed at more than 80% of correct responses were attained, 5-HT was depleted, and later, the performance of 5-HTdepleted rats was as accurate as control animals, but a reduction in the proportion of omitted responses, and an increase in premature responses, indicated an increase in the impulsivity of these animals. On the other hand, an increase in the proportion of premature responses obtained after systemically administrated D-amphetamine was abolished by the 5-HT depletion, and reduced the decrease in correct responses induced by the application of the D2 receptor antagonist ()sulpiride. However, systemic administration of the D1 receptor antagonist SCH23390 blocked the impulsiveness increased by the 5-HT depletion. This is relevant, because it implies that impulsiveness generated by 5-HT depletion is mediated by the activation of D1 receptors under conditions of low 5-HT concentration, and because the accuracy of responses was not affected by the decrease in 5-HT, but was able to attenuate the deficiencies mediated by D2 receptor antagonist application (Harrison et al., 1997). Both findings indicate a relationship between the modulation of impulsiveness and attentional performance by 5-HT/DA interactive mechanisms. It is important to note that experimental prefrontal 5-HT depletion, which produces a reversal of learning deficiencies,

583

could be related to the increase in impulsiveness, and the possibility exists that a similar mediation of D1 receptors on impulsiveness after 5-HT depletion occurs in the PFC. However, this possible 5-HT/DA interaction has not been evaluated. Another striatal-dependent cognitive process is egocentric learning, which has been related to the neural memory system, including the striatum body (caudate–putamen) (McDonald and White, 1994, 1996) based on the evidence that lesions of the dorsal striatum disrupt the capability of rats to display egocentric responses (Brasted et al., 1997). Thus, rats with a caudate–putamen lesion are unable to use egocentric strategies (DeCoteau and Kesner, 2000). Striatal inactivation by lidocaine application induces an inability of the animals to use egocentric strategies without affecting the use of spatial allocentric information (Packard and McGaugh, 1996). Included among the behavioural tests in which animals showed a better performance after cerebral 5-HT depletion are those with strong egocentric components, that is, tests that include the learning of a sequential series of left– right turns. As previously mentioned, cerebral 5-HT depletion produces spatial egocentric learning facilitation (Olvera-Corte´s et al., 2001). The effect was apparently striatum-mediated, because Anguiano-Rodrı´ guez et al. (2007) evaluated the effect of striatal 5-HT depletion by intrastriatal application of 5,7-DHT on egocentric learning, and observed a facilitation of performance in rats. This task is difficult, because the animals were only permitted the use of propioceptive information. Intact rats were unable to learn this task in the ten trials constituting the test. Striatal-5-HT depleted rats successfully learnt the task in the ten trials. The facilitation was blocked by intrastriatal infusion of mixed D1 and D2 receptor antagonists (sulpiride and SCH23390), and was reinstated once the blockade of DA receptors was removed. This work implies that the DArgic system sustains the facilitating effect of 5-HT striatal-depletion on egocentric learning, but the precise mechanism remains unknown. In addition to the several mechanisms mentioned above that could underlie 5-HT/DA interaction in the modulation of cognitive process, it has been observed that free striatal

serotonergic terminals can modulate striatal activity (Soghomonian et al., 1989). An increase in DA and NA release in the frontal cortex, accumbens, and striatum has been reported to occur after administration of a 5HT2C receptor antagonist (Gobert et al., 2000). Moreover, 5-HT modulates acetylcholine, g-aminobutyric acid (GABA), DA, and 5-HT release through 5HT4 receptors (Barnes and Sharp, 1999). Thus, 5-HT modulates striatal DA release through 5HT4 receptor activation, whereas inhibition occurs when 5-HT2C receptors are stimulated (Alex et al., 2005). A growing body of evidence has highlighted the potential of central 5-HT2C receptors for an improved treatment of neuropsychiatric disorders related to DA (Wood et al., 2001). 5-HT2C receptors are expressed along striatal and mesocortico-limbic DArgic pathways, and exert phasic and tonic inhibitory controls of both basal DA neuronal fairing and basal DA release in the AN, striatum and frontal cortex (Di Giovanni et al., 1999; 2000; Gobert et al., 2000). 5-HT2C receptors potentiate the increase in DA release induced by drugs that stimulate DA neuronal firing, such as morphine (Hutson et al., 2000). Thus, it has been proposed that 5-HT2C receptors selectively modulate impulse-dependent release of DA in the accumbens and striatum, but only when DA release is associated with increased firing of DArgic neurons (Willins and Meltzer, 1998; Lucas et al., 2001). Through 5-HT6 receptors, 5-HT affects the nigrostriatal function through acetylcholine release regulation (Bourson et al., 1998), blockade of 5-HT6 receptors causes an increase in acetylcholine release, which in turn causes that the release of glutamate increases, along with increases in the performance in memory tasks (Sleight et al., 1999; Roth et al., 1994). The relationship between 5-HT6 receptor activity and DArgic function has been delineated, but there is confusion about the extent to which this interaction occurs (Mitchell and Neumaier, 2005). Apparently, 5-HT6 receptor blockade potentiates DA transmission by stimulatory drugs, such as amphetamine (Frantz et al., 2002). In the striatum, the role of 5-HT6 receptors on DA was evaluated in presence and absence of the DA transporter inhibitor/releaser amphetamine. Subcutaneous

584

administration of amphetamine induces an increase in extracellular DA, which is increased by SB-271046 (5-HT6 receptor antagonist), and generates an increase in 5-HT. Local infusion of amphetamine into the striatum induces an increase in DA, but no effect was observed after coadministration of a 5-HT6 receptor antagonist. Thus, 5HT6 receptors can modulate the striatal DA and 5HT systems when DA neurotransmission is enhanced (Dawson et al., 2003). Thus, many of the actions of 5-HT can be related with its modulation of the DA neurotransmitter system, especially those cognitive process that engage corticostriatal functioning. However, few studies that relate 5-HT and DA exist, despite the extensive biochemical evidence.

Prefrontal cortex and cognitive processes The PFC constitutes a higher level in the cortical hierarchy involved in the representation and execution of actions. In addition to cognitive control, the PFC plays a crucial role in behavioural control and influence (Fuster, 1997; 2001; Miller and Cohen, 2001). The key cellular elements in the direction of these functions are the pyramidal neurons, and the basic process in which the PFC participates is working memory: an essential process for human cognition (Goldman-Rakic, 1995). The PFC constitutes the more rostral region of the frontal lobe, with anatomical landmarks imprecise in diverse mammal species. However, in all species, the PFC posses a reciprocal connectivity with the mediodorsal thalamic nucleus (Groenewegen and Uylings, 2000; Fuster, 2001). In primates, the PFC comprises Brodmann’s areas 8–13, 24, 32, 46 and 47 (Brodmann, 1909). The PFC collectively consists of an interconnected network of subregions that send and receive projections from virtually all cortical sensory and motor systems, as well as a number of subcortical structures. Findings from human, non-human primate and rodent species suggest that specific aspects of cognitive processing are deferentially weighted across distinct subregions of the PFC. The lateral and mid-dorsal PFC are thought to be closely associated with sensory

processing, and these regions receive auditory, visual, and somatosensory information from temporal, occipital, and parietal cortices (GoldmanRakic and Schwartz, 1982; Barbas and Pandya, 1989). Thus, the dorsolateral region integrates information involved in the temporal organization of behaviour, working memory, language and reasoning (Vertes, 2004). The medial PFC, along with orbital regions, shares connections with limbic structures critical for memory and the processing of internal states, such as motivation and affects (Amaral and Price, 1984; Barbas and De Olmos, 1990). This region is also thought to be important for the process of behavioural inhibition (Fuster, 1980; Goldman-Rakic, 1987). Neuroanatomical studies divide the PFC of rats into three principal regions: lateral, orbital and medial. The latter region is also sub-divided into three zones (in dorso-ventral order): cingulated anterior (CG1), prelimbic (PL) and infralimbic (IL). Although the functional subdivision of these regions in rats is not well defined, recent studies infer from the projection pattern of the PL and PI zones, that the first region could be related to limbo-cognitive functions (homologues to the PFC of primates) and the second region participates in the control of visceral-autonomic activities (homologues to the orbital PFC of primates) (Vertes, 2004). Prefrontal cortex and DA It has long been recognized that DA in the PFC is critical in regulating cognitive processes, such as working memory, behavioural flexibility and decision making. These functions are disrupted in patients suffering with schizophrenia. Moreover, it is now understood that some optimal level of extracellular DA must be maintained within the cortex to sustain normal executive functioning, in that too much, or too little, cortical DA produces cognitive dysfunction (Goldman-Rakic et al., 2000; Winterer and Weinberger, 2004). Hypotheses concerning the role of DA in cognitive functions have focused on its ability to modulate executive functions (Sawaguchi and GoldmanRakic, 1991; Zahrt et al., 1997; Roitman et al., 2004). During the performance of a delayed alternation task, a measure of working memory,

585

monkeys displayed an increase in prefrontal DA release (Matsuda et al., 2001). In addition, both overstimulation and inhibition of the prefrontal DA system have been shown to decrease working memory performance (Sawaguchi and Goldman-Rakic, 1991; Aultman and Moghaddam, 2001; Abi-Dargham et al., 2002; Kellendon et al., 2006). The capability of both insufficient and excess DA to decrease performance in tasks of cognitive functioning further emphasizes the importance of a proper balance of DArgic activity. The ability of DArgic agents to influence performance of specific cognitive tasks, while leaving performance of others intact, provides further support for a tightly regulated and specialized role for DA in prefrontal cortical function (Briand et al., 2007). The mesocortical system originates in the VTA, terminating in the frontal cortex, forming synapses with cortical pyramidal glutamatergic neurons and non-pyramidal GABAergic interneurons (Fluxe et al., 1974). Furthermore, the VTA receives reciprocal input from the PFC (Sesack and Pickel, 1992). Afferents from the PFC innervate the mesoaccumbens GABAergic, but not the DArgic cells, as well as mesofrontal DArgic, but not the GABAergic neurons (Sesack and Carr, 2002). This specificity of the PFC innervations creates a oneto-one relationship with prefrontal efferents synapsing onto VTA DArgic cells that form reciprocal prefrontal connections. Possibly, this input is important for facilitating learning through the influence of prediction errors (Schultz, 1997; Schultz et al., 1997). DArgic transmission in the PFC is mediated by two DA receptor subtypes: D1 and D2 receptors. Although both receptor subtypes are present in the PFC, they display only a partially overlapping distribution. D2 receptor expression is considerably less dense than that of D1 receptors. D2 receptors are found almost exclusively in Layer V, while D1 receptors are most densely distributed in the superficial layers (Layers I–III), although they can be found in all layers (Goldman-Rakic et al., 1990). The differential distribution of D1 and D2 receptors is important due to their different second messenger cascades. D1 receptors are coupled to stimulatory G proteins, while D2 receptors are coupled to inhibitory G proteins (Kebabian et al., 1984). Along with

these differences in signalling mechanisms, D1 and D2 receptors exhibit differences in binding affinity, with D2 receptors responding to much lower levels of DA than D1 receptors do (Grace, 2000). The VTA DArgic neurons discharge in both tonic and phasic fashions, and these firing patterns result in tonic and phasic release of DA in the PFC (Stoof and Kebabian, 1981; Grace, 1991). Tonic DA release is activated by sustained increases in DA neuronal firing, or presynaptic stimulation of DA terminals by glutamate. In contrast, phasic DA release results from spikedependent mechanisms, and occurs in response to behaviourally relevant stimuli (Finlay et al., 1995; Rebec et al., 1997). Several studies have demonstrated the strikingly prolonged effect of DA release/application on PFC activity. For example, in vitro electrophysiological studies have shown that bath application of DA for 2–5 min produces modulations in current PFC interneurons (Gorelova et al., 2002) and pyramidal neurons (Gorelova and Yang, 2000) that lasts for tens of minutes, or until the recording is no longer viable (Seamans and Yang, 2004). Interestingly, these protracted increases in cortical current are generally D1 receptor, and not D2 receptor, dependent (Gorelova et al., 2002). This bidirectional characteristic of DA is particularly apparent regarding its modulation of key synaptic currents that regulate cortical activity, such as GABA and N-methyl-D-aspartate (NMDA) currents (Seamans et al., 2001b; Durstewitz and Seamans, 2002). For example, DA modulation of GABAergic inhibitory post-synaptic currents (IPSCs) in deep layer pyramidal neurons initially produce a D2-mediated reduction in IPSC amplitude, followed by a longer lasting D1-mediated increase in evoked IPSCs (Seamans et al., 2001a; Gonza´lez-Burgos et al., 2005). The initial D2-mediated effect is believed to occur via a novel signalling pathway involving inositol phosphate (IP3) receptors and increased intracellular Ca+2 (Trantham-Davidson et al., 2004), whereas the D1-mediated effect occurs via a cAMP/ PKA-dependent cascade in interneurons (Gorelova et al., 2002; Trantham-Davidson et al., 2008). D2-receptor activation also suppresses NMDA currents (Zheng et al., 1999), and Tseng and

586

O’Donnell (2004) reported that this suppression was blocked by the GABA antagonists bicuculline and picrotoxin, suggesting that the inhibitory action of D2 receptors on NMDA-induced responses in the PFC is mediated by GABAergic interneurons. In contrast, activation of post-synaptic D1/D5 receptors increases the NMDA component of excitatory post-synaptic (EPSCs) in the PFC (Seamans et al., 2001b; Chen et al., 2004). Zheng et al. (1999) demonstrated that DA’s effect on cortical NMDA currents was concentration dependent. Specifically, at lower concentrations (10 mM), DA enhanced NMDA currents in the PFC (via D1-like receptors), whereas at high concentrations (100 mM) DA decreased the current (via D2-like receptors). According to this, it is believed that transitions between D1 and D2 receptor activation help stabilize cortical representations in the working memory (Seamans and Yang, 2004; Winterer and Weinberger, 2004; Durstewitz and Seamans, 2006). In all previous reports, it has been proposed that in the pathological PFC, abnormal cortical D1/D2 activation ratios, along with altered GABA and glutamate transmission, interfere with this process. In particular, D2-receptor stimulation of PFC pyramidal cells suppresses GABAergic and NMDA currents sufficiently to produce a permissive state in the cortex; putatively allowing multiple representations to be held in cortical networks simultaneously (Di Pietro and Seamans, 2007). This initial bias in the activation of D2 receptors is important in situations requiring response flexibility and open-ended problem solving, where many options for action must be held in the memory and compared (Seamans and Yang, 2004). Prefrontal cortex and 5-HT Serotonergic projections to the cortex arise primarily from the DRN and MRN (O’Hearn and Molliver, 1984). The DRN consists primarily of ipsilateral projections to the frontal cortex, while the MRN projects bilaterally to frontal, parietal and occipital cortices (O’Hearn and Molliver, 1984; Jacobs and Azmitia, 1992). While it is clear that the dorsal raphe send ascending projections to the PFC, it has only

recently been determined that it also receives reciprocal connections from the PFC (Peyron et al., 1998; Celada et al., 2001). Although many of the different receptor subtypes are located in the PFC, their specific neuronal locations (post-synaptically vs. somatodendritically and pyramidal cells vs. GABA interneurons) may allow for highly specific serotonergic effects on post-synaptic targets. The 5-HT2A receptor is the predominant 5-HT receptor found in the cortex, where it is located on all cortical pyramidal cells, as well as parvalbuminand calbindin-containing GABAergic interneurons. While the action at 5-HT2A receptors on GABAergic neurons is known to be involved in perisomatic inhibition of pyramidal cells, on pyramidal cells this receptor subtype is located post-synaptically, and its activation increases the excitability of the PFC neurons (Harvey, 1996; Buhot, 1997; Jakab and Goldman-Rakic, 2000). The 5-HT1A receptor is also found on the majority of pyramidal neurons and on more than 25% of the GABAergic interneurons (Buhot, 1997; Gu, 2002). These receptors are located somatodendritically and are generally thought to decrease neuronal excitability (Buhot, 1997). Research over the last decade supports the hypothesis that the DRN 5-HT system plays a specific role in prefrontal functions. For example, prefrontal 5-HT depletion in marmosets acts to impair reversal learning, while leaving attentional set-shifting intact (Clarke et al., 2005). Similarly, 5-HT depletion has also been shown to impair performance of a serial discrimination reversal task (Clarke et al., 2004). Although a decrease in prefrontal 5-HT leads to a decrease in cognitive flexibility, it seems as though this may work to increase focused attention (Schmitt et al., 2000). As the DRN is the primary source of prefrontal 5-HT, these projections and their reciprocal descending connections clearly play a role in specific cognitive functions (Briand et al., 2007). Prefrontal cortex and 5-HT/DA interaction Recent evidence suggests that 5-HT, in conjunction with DA, comodulates cortical activity and is a prime target of a newer atypical antipsychotic

587

agent. Early microdialysis work by Iyer and Bradberry (1996) demonstrated that 5-HT application (1–10 mM) increased extracellular DA in a dose-dependent manner to a greater extent in the PFC than in the striatum. Moreover, the increase in DA release was mediated by 5-HT1B/D receptors and not by 5-HT2A/C or 5-HT3 receptors. Since then, multiple studies have confirmed that 5-HT1 receptors increase cortical DA release (Matsumoto et al., 1999; Ichikawa et al., 2001; Dı´ az-Mataix et al., 2005). Moreover, there is evidence that 5-HT’s effects on extracellular DA are concentration dependent. A study by Dı´ az-Mataix et al. (2005) showed that reverse dialysis of the 5-HT1A receptor agonist R-()-2-{4-[(chroman-2-methyl)-amino]-butyl}-1, 1-dioxo-benzo-[d]isothiazol one HCl (BAYx3702) in the PFC produces bidirectional effects on DA release, whereby low concentrations increase and high concentrations decrease DA release. The decrease in DA with high 5-HT1A agonist concentration appears to be GABA-mediated, as decreases were not observed when GABAA receptors were blocked by perfusion with bicuculline. Interestingly, animals given BAYx3702 systemically displayed similar increases in cortical DA release, effects that were blocked following frontocortical transection. Together, these findings suggest that 5-HT1A receptors may be acting on pyramidal glutamatergic PFC cells projecting to the VTA to regulate DA release. Thus, given that 5-HT1A receptors mediate cortical DA release and that atypical drugs, such as clozapine, are weak partial agonists at the 5-HT1A receptors (Assie´ et al., 2005), it has been suggested that the therapeutic properties of atypical antipsychotic drugs (APDs) may be related to weak 5-HT1A receptor activation in conjunction with D2 receptor antagonism (Millan, 2000; Meltzer et al., 2003). Regarding the 5-HT2A receptor, it was shown that a discrete subpopulation of large neurons in the deep layers of the PFC are strongly excited by 5-HT2A receptor activation (Be´ı¨ que et al., 2007). These findings suggest that cortical 5-HT2A receptors mediate glutamatergic recurrent network activity in the PFC, which is a finding that could be significant, given that these pyramidal cells

may synapse onto mesocortical DA cell bodies in the VTA (Sesack and Pickel, 1992). On the other hand, the systemic administration of (7)-2, 5-dimethoxy-4-iodoamphetamine (DOI) increases glutamate efflux in the VTA (as well as DA efflux in the PFC), effects that are reversed following intra-PFC infusions with the 5-HT2A receptor antagonist M100907 (Gobert and Millan, 1999; Pehek et al., 2001). Thus, it appears that the activity of VTA DArgic neurons is under the excitatory control of 5-HT2A receptors in the PFC. Given these findings, Pehek et al. (2006) suggested that 5-HT2A receptor agonists may increase the activity of cortico-tegmental glutamatergic projection neurons, which in turn increase DA release and neuronal activity in the PFC. Hence, cortical 5-HT2A receptors may enhance the overall excitability of PFC networks indirectly via the mesocortical pathway, an effect that may contribute to the positive symptoms of schizophrenia (Di Pietro and Seamans, 2007). However, like DA, 5-HT’s effect on cortical NMDA synaptic currents is bidirectional and concentration dependent. Activation of 5-HT2A receptors can either facilitate or inhibit NMDAinduced responses in the PFC with a low concentrations of 5-HT agonist facilitating NMDA responses, and higher concentrations inhibiting them (Arvanov et al., 1999). In addition to these effects at NMDA receptors, 5-HT2A receptors have been shown to induce weak, but long-lasting enhancements of spontaneous EPSCs in conjunction with large desensitizing enhancements of spontaneous IPSCs (Zhou and Hablitz, 1999). In this way, APDs (especially those that act as 5-HT1A agonists) may help stabilize cortical activity by enhancing the effect of 5-HT1 while suppressing spontaneous 5-HT2-induced excitation. When coupled with the removal of D2-mediated reductions in NMDA and GABA currents and the potential activation of D1 receptors by elevated DA levels, atypical APDs should produce strong NMDA and GABA activation, with a reduction in spontaneous EPSCs to evoke the ideal blend of modulation necessary to enhance cortical signalto-noise ratios and improve cognition as predicted (Winterer and Weinberger, 2004).

588

In this manner, all the neurochemical and behavioural experimental results inferred from drugs used in the treatment of illnesses, such as depression and schizophrenia, support the existence of modulatory mechanisms involving 5-HT and DA systems as key players. However, experimental studies relating the interactive participation of these neurotransmitter systems in the regulation of prefrontally sustained cognitive processes are at an early stage. In conclusion, a complex picture is obtained from the data evaluating 5-HT and DA regulation of cognitive processes. From this, an interaction can be inferred on analyzing data from similar tests (similar in regard to cognitive process), but few studies have evaluated this interaction until now. Less is known about the possible modulation of 5-HTergic function by the DA system, despite the evidence that DArgic terminals on RN proceed into the SN (Afifi and Kaelber, 1965; Pasquier et al., 1977; Sakai et al., 1977; Lee and Geyer, 1984; Kale´n et al., 1988), and the high density of D2 receptors on raphe neurons (Bouthenet et al., 1987). Future work must address a more integrative approach to the organization of cognition by multiple neurotransmitter systems, because this is the better focus by which significant progress may be made in the development of therapeutic strategies.

Clinical implications of 5-HT/DA interaction Studies have been focused on DA–5HT interactions as a part of pathophysiological phenomena and therapeutic possibilities dealing with neurological and psychiatric diseases. This is the case of PD which primarily results from the death of dopaminergic neurons in the substantia nigra pars compacta (SNpc) at the origin of the nigrostriatal DArgic pathway. Loss of these DArgic neurons leads to striatal deficiency in DA neurotransmission, accounting for the major symptoms of PD, and supporting the proposal of replenishment of striatal DA through the DA precursor L-DOPA as an effective treatment to alleviate most of the motor symptoms of PD (Dauer and Przedborski, 2003).

Further, a profile of cognitive impairment of PD patients has been identified in relation to the spatio-temporal progression of DA depletion. In the early disease stages, cognitive deficits in PD patients are mainly associated to dorsal striatum dysfunction (impaired adaptation of well-established stimulus–response mappings and reduced updating within working memory). In fact, besides the improvement of motor symptoms, L-DOPA treatment may alleviate dorsal striatum-dependent cognitive alterations (Cools, 2006). However, L-DOPA may affect cognitive functions in PD patients through non-DArgic mechanisms such as reduction of 5-HTergic neurotransmission, as suggested by the similar effects of L-DOPA and 5-HT depletion on some learning processes (Clarke et al., 2004), as well as by the reduction of the content of brain 5-HT elicited by L-DOPA (Kostrzewa et al., 2005), and the opposite interaction between DA and 5-HT in the striatum and in the PFC (Millan et al., 1998; Di Giovanni et al., 2006) which may be relevant for the effects of L-DOPA on cognitive functions in PD patients. The involvement of disturbances of the cerebral 5-HTergic system in PD has been investigated in human beings both under post-mortem, as well as in vivo experimental designs by using histological, neurochemical and autoradiographic techniques, in view of the possibility that mood and cognitive problems appearing as clinically relevant components of PD, could be explained by disruption of 5-HT neurotransmission including damage to serotonin neurons (Kish, 2003), and because of the relevant role that has been recognized for the 5-HTergic system as a regulator of the functioning of basal ganglia (Di Giovanni et al., 2006). Degeneration of 5-HTergic neurons in the MRN (Halliday et al., 1990; Paulus and Jellinger, 1991) which could underlie the decreased content in 5-HT, its metabolites and the 5-HT transporter (SERT) in the striatum (Chinaglia et al., 1993; Kerenyi et al., 2003; Kim et al., 2003; Guttman et al., 2007; Kish et al., 2008), the cerebral cortex (Scatton et al., 1983) and the cerebrospinal fluid (Mayeux et al., 1984; Kuhn et al, 1996), as well as alterations on the activities of various 5-HT receptor subtypes (Cheng et al., 1991; Castro et al., 1998), have been demonstrated in PD patients.

589

The reductions of key markers of striatal 5-HTergic activity support the proposal of a 5-HTergic disturbance in PD. These reductions differentially affecting caudate and putamen (the greater reduction in caudate: 55%, the lesser reduction in putamen: 36%, as compared to healthy subjects), though quantitative individual differences suggest that some PD patients are affected more than others. Besides, a greater susceptibility to damage of raphe nucleus 5-HT neurons innervating the caudate, than those innervating the putamen and the primary involvement of caudate as a target of functional alterations caused by striatal serotonin disruption (possibly cognitive impairment, including cognitive aspects of motor control) could be inferred from these data (Kish et al., 2008), while dysfunction due to putamen 5-HT deficiency might be a secondary phathophysiological component of PD. It seems also possible that structural damage to raphe-striatal neurons in PD might be limited to the nerve terminal region, as suggested by the significantly reduced densities of SERT-binding sites in the basal ganglia of PD patients (Haapaniemi et al., 2001; Kerenyi et al., 2003; Kim et al., 2003), but the normal SERT binding in the dorsal raphe of patients showing decreased SERT biding in the striatum (Chinaglia et al., 1993). The reduction of these 5-HT markers in caudate supports a possible benefit of pharmacological measures aimed to correct the 5-HT deficiency in PD, as suggested by the antidyskinetic effect of MDMA in a monkey model of PD (Iravani et al., 2003) which has been explained by the ability of the amphetamine derivative to release 5-HT. In fact, improvement of bradykinesia and finger taps, was observed at 1 and 4 months during treatment with citalopram, a 5-HT reuptake inhibitor, in PD patients, and among them, a clear improvement of mood was observed in 15 of 16 PD patients with depression (Rampello et al., 2002). The possible functional significance of the reduction of 5-HTergic neurotransmission in these striatal regions is still unclear and deserves further study in PD. As has been hypothesized (Mayeux, 1990), the reduced serotonergic neurotransmission

may result in a compensatory adjustment for the reduced striatal DA activity. In this context, the role of 5-HT in the neuronal substrate forming the SNpc has not yet been well-established, but an inhibitory action of 5-HT over the SNpc neurons, has been recognized, as shown by studies involving the activation of 5-HTergic neurons located at the DRN and microiontophoretic application of 5-HT on SNpc DA neurons (Gervais and Rouillard, 2000); though 5-HT may on the other hand increase the firing rate of SNpc DA neurons in vitro. This inhibitory effect of 5-HT neurotransmission includes the DA release at the striatal nerve endings, as evidenced by the increase of DA release induced by 5HT2 and 5-HT2C antagonists; while the opposite effect is mediated by 5 HT1A and 5-HT2C receptors (Ugedo et al., 1989; Jacobs and Fornal, 1993; Murphy et al., 1998; Blackburn et al., 2002; Alex et al., 2005; Di Giovanni et al., 2006); as well as by suppression of spontaneous firing in the striatal cells following DRN stimulation. Both, a tonic and a phasic modulation of mesocorticolimbic DA functioning have been shown to be exerted through 5-HT2C receptor subtype (Di Matteo et al., 1998, 2000, 2004; Pierucci et al., 2004). Human post-mortem tissue from PD patients, have revealed that DA depletion may result in adjustments of 5-HT receptors. While a change in the density of striatal 5-HT2C receptors was not observed, striatal 5-HT2A receptors and 5-HT2C receptors in the susbstantia nigra pars reticulate appear to be upregulated (Fox and Brotchie, 2000a) in patients with PD. These changes might also be a compensatory consequence of a decreased level of 5-HT in these nuclei and thus, they potentially may be relevant for the neuronal mechanisms involved in PD and for possible pharmacological interventions. In this context, a 5-HT2C antagonist enhances the anti-parkinsonian effect of D1 and D2 agonists in a rat model (Fox and Brotchie, 2000b); ritanserin a 5-HT2A/2C receptor antagonist ameliorates exciting extrapyramidal side effects of classical APDs in schizophrenics (Bersani et al., 1990). The reduced motor side-effects during the antipsychotic treatment with clozapine have been ascribed to its 5-HT2C antagonist action which may result in

590

anti-parkinsonian activity, possibly counteracting the pro-parkinsonian effects of the DA blockade elicited by the APD (Durif et al., 2004). Cerebral 5-HT activity has also been shown to be involved in cognitive functions, (Buhot et al., 2000) thus, memory consolidation is impaired in healthy human beings as a consequence of ATD (Riedel et al., 1999), a procedure that allows to study in human beings the relationship between cerebral 5-HT activity and mood, cognitive and motor functions in vivo (Booij et al., 2003; Gallagher et al., 2003; Hughes et al., 2003). When the effects of ATD are assessed in earlystage PD patients, the acute reduction of cerebral 5-HT levels does not affect several parameters of cognitive function (impairment of delayed recall and delayed recognition in the Visual Verbal Learning Task) and motor performance (shortening of reaction times) in a different manner as it does in healthy subjects (Riedel et al., 1999; Scholtissen et al., 2006). Besides, the ATD does not improve PD motor symptoms (Unified Parkinson Disease Rating Scale), as could be expected in view of the proposed inhibitory effects of 5-HT on striatal DA release. In general, the sole effects of ATD in PD patients, neither support a direct role of 5-HT on cognitive and motor functioning other than in healthy subjects, nor a compensatory role of 5-HT adjustments for the nigrostriatal DA activity; though, it could also be expected that distinct short-term and long-term neural mechanisms were involved in the development of motor and cognitive impairments in PD, even if cerebral 5-HT activity is reduced in the early stages of the disease. Serotonin neurons innervating the striatum (caudate and putamen) in PD patients could be a neural substrate that favours the anti-parkinsonian action of L-DOPA, by assuming that serotonin neurons in human beings can convert exogenous DOPA to DA, as well as store and release the neurotransmitter from their striatal nerve endings as occurs in other species (Tanaka et al., 1999; Maeda et al., 2005). Besides, it has also been discussed (Kish et al., 2008) that if L-DOPAinduced dyskinesias might be caused in part by a drug-induced exaggerated increase in striatal synaptic DA, and 5-HT nerve terminals which

can take up DA from the extracellular space, could be of some benefit by helping to normalize extracellular DA concentration. However, the above described mechanism for striatal DA synthesis and release from exogenous L-DOPA, has rather been proposed as a possible cause of L-DOPA-induced dyskinesias, given the association between dyskinesias and excessively increased synaptic DA as suggested by PET imaging findings in human PD (De la FuenteFernandez et al., 2004; Pavese et al., 2006). In this context, dyskinesias could be explained by deregulated swings of L-DOPA-induced extracellular DA, released from the remaining striatal 5-HT neurons that are unable to normally regulate the DA release. Thus the relative preservation of 5-HTergic function in the putamen would be detrimental to the patient with PD with respect to this L-DOPA adverse effect, a situation in which decreasing striatal 5-HTergic activity by either lesion or pharmacological treatment can actually block L-DOPA-induced dyskinesias in experimental animals (Carta et al., 2007). However SERT binding has shown to be similar in putamen of those clinically advanced PD living patients having more versus less severe drug-induced dyskinesias (Guttman et al., 2007). The therapeutic success of novel atypical APDs, as shown by their better efficiency against mood alterations and the reduced side effects in schizophrenic patients has been ascribed to drug effects on both 5-HT and DA systems involved or able to positively influence this pathophysiological condition (Alex and Pehek, 2007; Stone and Pilowsky, 2007). Even though an improvement of mood negative symptoms and behavioural alterations has been the main objective of APDs clinical studies (Kapur and Remington, 1996; Truffinet et al., 1999; Bandelow and Meier, 2003; Iwakawa et al., 2004; Werkman et al., 2006; Mamo et al., 2007), attention has also been paid to the effects of these drugs on the cognitive dysfunctions of schizophrenic patients (Araki et al., 2006; Di pietro and Seamans, 2007; Gray and Roth, 2007; Scholes et al., 2007). Different aspects of cognitive functions are shown to be affected under APDs treatment, depending on the chosen drug, the duration of treatment, and on specific individual

591

characteristics of the disease. Thus, attention, psychomotor, speed-executive skills, working memory and spatial memory, verbal memory are among other cognitive functions differentially affected by APDs. Both DArgic and serotonergic mechanisms have been identified in the effects of the abuse drug 3-4-methylenedioxymethamphetamine (MDMA, ‘Ecstasy’) on the CNS (Green et al., 2003). However, cognitive impairment elicited by MDMA, has rather been ascribed to reduced serotonergic activity, due to permanent neurotoxic brain damage (Reneman et al., 2000; GouzoulisMayfrank et al., 2000, 2003; Colado et al., 2004; Able et al., 2006; Quednow et al., 2006; Hoshi et al., 2007; Zakzanis et al., 2007) which may remain for years (Ward et al., 2006). Although the complete clinical significance of DA–serotonin interactions could be addressed by future in vivo studies in human beings, it is wellrecognized today that cognitive dysfunction in neurological and psychiatric diseases, as well as under some drug abuse conditions, in which neurotransmitter impairments are involved, account for long-term disability, especially difficult to be treated, and being, in some patients the main factors responsible for a bad quality of life.

DA DOI DOM DRN DSP4 EPSCs GABA GR125487

ICV IL IPSCs IP3 LTD LTM LTP L745,870

mCPBG MDA MDMA MPTP

Abbreviations AAPA AN AS19

A69024

A77636

BAYx3702

BMN CG1

active allothetic place avoidance accumbens nucleus (2S)-(+)-5-(1,3,5-trimethylpyrazol-4-yl)-2-(dimethylamino) tetralin 1-[(2-bromo-4,5- dimethoxyphenyl) methyl]-l, 2,3,4-tetrahydro-6methoxy-2-methyl-7-isoquinolinol ((1R-cis-)-1-(aminomethyl)-3,4dihydro-3-tricyclo[3.3.1.13.7]dec1-yl-[1H]-2-benzopyran-5,6-diol hydrochloride) R-()-2-{4-[(chroman-2-methyl)amino]-butyl}-1,1-dioxo-benzo[d]isothiazol one HCl basal magnocellular nucleus cingulated cortex 1

MRN M100907

NA NAN-190

NAD-229 NMDA PCA PCPA PFC PL RN RO4368554

dopamine (7)-2,5-dimethoxy-4-iodoamphetamine 2,5-dimethoxy-4-methylamphetamine dorsal raphe nucleus N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine excitatory post-synaptic currents gamma-aminobutyric acid [1-[2(methylsufonyl)amino]ethyl]4-piperidinyl] methyl-5-fluoro-2methoxy-1H-indole-3-carboxylate intracerebroventricular infralimbic cortex inhibitory post-synaptic currents inositol phosphate long term depression long term memory long term potentiation 3-(4-[4-Chlorophenyl] piperazin-1-yl)-methyl-1Hpyrrolo[2,3-b]pyridine trihydrochloride m-chlorophenylbiguanide (+/)-3,4-(methylenedioxy)amphetamine methylenedioxymethamphetamine 1-methyl-1-4-phenyl1-1,2,3,6-tetrahydropyridine medial raphe nucleus [R-(+)-d-(2,3-dimethoxyphenil)1-[4-fluorophenylethyl]-4-piperidinemethanol] noradrenaline 1-(2-methoxyphenyl)-4-[4-(2phthalimido)butyl]piperazine hydrobromide 2H-1-benzopyran-5-carboxamide N-methyl-D-aspartate p-chloroamphetamine p-chlorophenylalanine prefrontal cortex prelimbic cortex raphe nuclei (3-benzenesulfonyl-7-(4-methylpiperazine-1-yl)-H-indole

592

SB242084

6-chloro-5-methyl-1-[2(2-methyl pyridyl-3-oxy)-pyrid-5-yl carba moxyl]indoline SB269970 (R)-3-(2-(2-(4-methylpiperidin-1yl)ethyl)pyrrolidine-1-sulfonyl)phenol SCH23390 ((R)-(+)-7-chloro-8-hydroxy-3methyl-1-phenyl-2,3,4,5,-tetrahydro-1H-3-benzazepine hydrochloride. SDZ 205557 (2-methoxy-4-amino-5-chloroben zoic acid 2-(diethylamino) ethyl ester hydrochloride SKF82958 [(7)-1-phenyl-2,3,4,5-tetrahydro(1H)-3-benzazepine-7,8-diol hydrobromide] SL65.0155 (5-(8-amino-7-chloro-2,3-dihydro-1,4-benzodioxin-5-yl)-3[1-(2-phenylethyl)-4-piperidinyl]1,3,4-oxadiazol-2(3H)-one-monohydrochloride) SN substantia nigra STM short-term memory Trp tryptophan VTA ventral tegmental area WAY-100635 N-[2-[4-(2-methoxyphenyl)-1piperazinyl]ethyl]-N-(2-pyridinyl) cyclohexane carboxamide trihydrochloride 5-HT serotonin 5,7-DHT 5,7-dihydroxytriptamine 6-OHDA 6-hydroxydopamine 8-OH-DPAT 8-hydroxy-2(di-N-propylamino)tetralin

References Abi-Dargham, A., Mawlawi, O., Lombardo, I., Gil, R., Martinez, D., Huang, Y., Hwang, D.R., Keilp, J., Kochan, L., Van Heertum, R., Gorman, J.M. and Laruelle, M. (2002) Prefrontal dopamine D1 receptors and working memory in schizophrenia. J. Neurosci., 22(9): 3708–3719. Able, J.A., Gudelsky, G.A., Vorhees, C.V. and Williams, M.T. (2006) 3,4-methylenedioxymethamphetamine in adult rats produces deficits in path integration and spatial reference memory. Biol. Psychiatry, 59(12): 1219–1226.

Abrahams, B.S., Rutheford, J.D., Mallet, P.E. and Beninger, R.J. (1998) Place conditioning with the dopamine D1-like receptor agonist SKF 8295 but not SKF 81297 or SKF 77434. Eur. J. Pharmacol., 343(2–3): 111–118. Afifi, A and Kaelber, W.W. (1965) Efferent connections of the substantia nigra in the cat. Exp. Neurol., 11: 474–482. Alex, K.D. and Pehek, E.A. (2007) Pharmacologic mechanisms of serotonergic regulation of dopamine neurotransmission. Pharmacol. Ther., 113(2): 296–320. Alex, K.D., Yavanian, G.J., McFarlane, H.G., Pluto, C.P. and Pehek, E.A. (2005) Modulation of dopamine release by striatal 5-HT2C receptors. Synapse, 55(4): 242–251. Allan, A.M., Galindo, R., Chynowet, J., Engel, S.R. and Savage, D.D. (2001) Conditioned place preference for cocaine is attenuated in mice over-expressing the 5-HT(3) receptor. Psychopharmacol. (Berl.), 158(1): 18–27. Altman, H.J., Normile, H.J., Galloway, M.P., Ramirez, A. and Azmitia, E.C. (1990) Enhanced spatial discrimination learning in rats following 5,7-DHT-induced serotonergic deafferentation of the hippocampus. Brain Res., 518(1–2): 61–66. Amaral, D.G. and Price, J.L. (1984) Amygdalo-cortical projections in the monkey (Macaca fascicularis). J. Comp. Neurol., 230(4): 465–496. Anguiano-Rodrı´ guez, P., Gayta´n.Tocave´n, L. and OlveraCorte´s, M.E. (2007) Striatal serotonin depletion facilitates rat egocentric learning via dopamine modulation. Eur. J. Pharmacol., 556(1–3): 91–98. Araki, T., Yamasue, H., Sumiyoshi, T., Kuwabara, H., Suga, M., Iwanami, A., Kato, N. and Kasai, K. (2006) Perospirone in the treatment of schizophrenia: effect on verbal memory organization. Progr. Neuropsychopharmacol. Biol. Psychiatry, 30(2): 204–208. Arvanov, V.L., Liang, X., Magro, P., Roberts, S. and Wang, R.Y. (1999) A pre- and post-synaptic modulatory action of 5-HT and 5-HT2A, 2C receptor agonist DOB on NMDAevoked responses in the rat medial prefrontal cortex. Eur. J. Neurosci., 11(8): 2917–2934. Asin, K.E. and Fibiger, H.C. (1984) Spontaneous and delayed spatial alternation following damage to specific neuronal elements within the nucleus medianus raphe. Behav. Brain. Res., 13(3): 241–250. Assie´, M.B., Ravhaile, V., Faucillon, V., Newman-Tancredi, A. (2005) Contrasting contribution of 5-hydroxytryptamine 1A receptor activation to neurochemical profile of novel antipsychotics: frontocortical dopamine and hippocampal serotonin release in rat brain. 315(1): 265–272. Aultman, J.M. and Moghaddam, B. (2001) Distinct contributions of glutamate and dopamine receptors to temporal aspects of rodent working memory using a clinically relevant task. Psychopharmacol. (Berl.), 153(3): 353–364. Azmitia, E.C. and Segal, M. (1978) An autoradiographic analysis of the differential ascending projections of the dorsal and median raphe nuclei in the rat. J. Comp. Neurol., 179(3): 641–667. Badgaiyan, R.D., Fischman, A.J. and Alpert, N.M. (2007) Striatal dopamine release in sequential learning. Neuroimage, 38(3): 549–556.

593 Bandelow, B. and Meier, A. (2003) Aripiprazole, a ‘‘dopamineserotonin system stabilizer’’ in the treatment of psychosis. Ger. J. Psychiatry, 6(1): 9–16. Barbas, H. and De Olmos, J. (1990) Projections from the amygdala to basoventral and mediodorsal prefrontal regions in the rhesus monkey. J. Comp. Neurol., 300(4): 549–571. Barbas, H. and Pandya, D.N. (1989) Architecture and intrinsic connections of the prefrontal cortex in the rhesus monkey. J. Comp. Neurol., 286(3): 353–375. Barnes, J.M., Costall, B., Coughlan, J., Domeney, A.M., Gerrard, P.A., Kelly, M.E., Naylor, R.J., Onaivi, E.S., Tomkins, D.M. and Tyers, M.B. (1990) The effects of ondansetron, a 5-HT3 receptor antagonist, on cognition in rodents and primates. Pharmacol. Biochem. Behav., 35(4): 955–962. Barnes, N.M. and Sharp, T. (1999) A review of central 5-HTreceptors and their function. Neuropharmacology, 38(8): 1083–1152. Beart, P.M. and McDonald, D. (1982) 5-Hydroxytryptamine 5-hydroxytryptaminergic–dopaminergic interactions in the ventral area of rat brain. J. Pharm. Pharmacol., 34(9): 591–593. Be´ı¨ que, J.C., Imad, M., Mladenovic, L., Gingrich, J.A. and Andrade, R. (2007) Mechanism of the 5-hydroxytryptamine 2A receptor-mediated facilitation of synaptic activity in prefrontal cortex. Proc. Natl. Acad. Sci. U.S.A., 104(23): 9870–9875. Bersani, G., Grispini, A., Marini, S., Pasini, A., Valducci, M. and Ciani, N. (1990) 5-HT2 antagonist ritanserin in neuroleptic-induced parkinsonism: a double-blind comparison with orphenadrine and placebo. Clin. Neuropharmacol., 13(6): 500–506. Biggio, G., Fadda, F., Fanni, P., Tagliamonte, A. and Gessa, G.L. (1974) Rapid depletion of serum tryptophan, brain tryptophan, serotonin and 5-hydroxyindoleacetic acid by a tryptophan-free diet. Life Sci., 14(7): 1321–1329. Blackburn, T.P., Minabe, Y., Middlemiss, D.N., Shirayama, Y., Hashimoto, K. and Ashby, C.R., Jr. (2002) Effect of acute and chronic administration of the selective 5-HT2C receptor antagonist SB-243213 on midbrain dopamine neurons in the rat: an in vivo extracellular single cell study. Synapse, 46(3): 129–139. Blandina, P., Goldfarb, J., Craddock-Royal, B. and Green, J.P. (1989) Release of endogenous dopamine by stimulation of 5-hydroxytryptamine3 receptors in rat striatum. J. Pharmacol. Exp. Ther., 251(3): 803–809. Booij, L., Van der Does, A.J. and Riedel, W.J. (2003) Monoamine depletion in psychiatric and healthy populations. Mol. Psychiatry, 8(12): 951–973. Boulougouris, V., Glennon, J.C. and Robbins, T.W. (2008) Dissociable effects of selective 5-HT2(A) and 5-HT2(C) receptor antagonists on serial spatial reversal learning in rats. Neuropsychopharmacology, 33(2): 2007–2019. Bourson, A., Boess, F.G., Bo¨s, M. and Sleight, A.J. (1998) Involvement of 5-HT6 receptors in nigro-striatal function in rodents. Br. J. Pharmacol., 125(7): 1562–1566.

Bouthenet, M.L., Martres, M.P., Sales, N. and Schwartz, J.C. (1987) A detailed mapping of dopamine D-2 receptors in rat central nervous system by autoradiography with [125I]iodosulpride. Neuroscience, 20(1): 117–155. Brasted, P.J., Humby, T., Dunnett, S.B. and Robbins, T.W. (1997) Unilateral lesions of the dorsal striatum in rats disrupt responding in egocentric space. J. Neurosci., 17(22): 8919–8926. Briand, L.A., Gritton, H., Howe, W.M., Young, D.A. and Sarter, M. (2007) Modulators in concert for cognition: modulator interactions in the prefrontal cortex. Prog. Neurobiol., 83(2): 69–91. Brodmann, K. (1909) Vergleichende lokalisationslehre der grosshinhinde. Barth, Leipzig. Buhot, M.C. (1997) Serotonin receptors in cognitive behaviors. Curr. Opin. Neurobiol., 7(2): 243–254. Buhot, M.C., Martin, S. and Segu, L. (2000) Role of serotoinin in memory impairment. Ann. Med., 31(3): 210–221. Buhot, M.C., Patra, S.K. and Naı¨ li, S. (1995) Spatial memory deficits following stimulation of hippocampal 5-HT1B receptors in the rat. Eur. J. Pharmacol., 285(3): 218–221. Bubser, M. and Schmidt, W.J. (1990) 6-Hydroxydopamine lesion of the rat prefrontal cortex increases locomotor activity, impairs acquisition of delayed alternation tasks, but does not affect uninterrupted tasks in the radial maze. Behav. Brain Res., 37(2): 157–168. Calabresi, P., Pisani, A., Mercuri, N.B. and Bernardi, G. (1992) Long-term potentiation in the striatum is unmasked by removing the voltage-dependent blockade of NMDA receptor channel. Eur. J. Neurosci., 4(10): 929–935. Campbell, A.D., Kohl, R.R. and McBride, W.J. (1996) Serotonin-3 receptor and ethanol-stimulated somatodendritic dopamine release. Alcohol, 13(6): 569–574. Carbon, M.A., Ma, Y., Barnes, A., Dhawan, V., Chaly, T., Ghilardi, M.F. and Eidelberg, D. (2004) Caudate nucleus: influence of dopaminergic input on sequence learning and brain activation in Parkinsonism. Neuroimage, 21(4): 1497–1507. Carli, M., Luschi, R., Garofalo, P. and Samanin, R. (1995) 8OH-DPAT impairs spatial but not visual learning in a water maze by stimulating 5-HT1A receptors in the hippocampus. Behav. Brain Res., 67(1): 67–74. Carli, M., Silva, S., Balducci, C. and Samanin, R. (1999) WAY 100635, a 5-HT1A receptor antagonist, prevents the impairment of spatial learning caused by blockade of hippocampal NMDA receptors. Neuropharmacology, 38(8): 1165–1173. Carta, M., Carlsson, T., Kirik, D. and Bjo¨kund, A. (2007) Dopamine released from 5-HT terminals is the cause of L-DOPA-induced dyskinesia in parkinsonian rats. Brain, 130(7): 1819–1833. Castellano, C., Cestari, V., Cabib, S. and Puglisi-Allegra, S. (1991) Post-training dopamine receptor agonists and antagonists affect memory storage in mice irrespective of their selectivity for D1 and D2 receptors. Behav. Neural. Biol., 56(3): 283–291. Castro, M.E., Pascual, J., Romon, T., Bercianno, J., Figols, J. and Pazos, A. (1998) 5-HT1B receptor binding in degenerative movement disorders. Brain Res., 790(1–2): 323–328.

594 Celada, P., Puig, M.V., Casanovas, J.M., Guillazo, G. and Artigas, F. (2001) Control of dorsal raphe serotonergic neurons by the medial prefrontal cortex: involvement of serotonin-1A, GABA(A), and glutamate receptors. J. Neurosci., 21(24): 9917–9929. Chapman, D.E., Hanson, G.R., Kesner, R.P. and Keefe, K.A. (2001) Long-term changes in basal ganglia function after a neurotoxic regimen of methamphetamine. J. Pharmacol. Exp. Ther., 296(2): 520–527. Chen, G., Greengard, P. and Yan, Z. (2004) Potentiation of NMDA receptor currents by dopamine D1 receptors in prefrontal cortex. Proc. Natl. Acad. Sci. U.S.A., 101(8): 2596–2600. Cheng, A.V., Ferrier, I.N., Morris, C.M., Jabeen, S., Shagal, A., McKeith, I.G., Edwardson, J.A., Pery, R.H. and Perry, E.K. (1991) Cortical serotonin-S2 receptor binding in Lewy body dementia, Alzheimer’s and Parkinson’s diseases. J. Neurol. Sci., 106(1): 50–55. Chinaglia, G., Landwehrmeyer, B., Probst, A. and Palacios, J.M. (1993) Serotoninergic terminal transporters are differentially affected in Parkinson’s disease and progressive nuclear palsy: an autoradiographic study with [3H]citalopram. Neuroscience, 54(3): 691–699. Cimadevilla, J.M., Wesierska, M., Fenton, A.A. and Bures, J. (2001) Inactivating one hippocampus impairs avoidance of a stable room-defined place during dissociation of arena cues from room cues by rotation of the arena. Proc. Natl. Acad. Sci. U.S.A., 98(6): 3531–3536. Clarke, H.F., Dalley, J.W., Crofts, H.S., Robbins, T.W. and Roberts, A.C. (2004) Cognitive inflexibility after prefrontal serotonin depletion. Science, 304(5672): 878–880. Clarke, H.F., Walker, S.C., Crofts, H.S., Dalley, J.W., Robbins, T.W. and Robertsm, A.C. (2005) Prefrontal serotonin depletion affects reversal learning but not attentional set shifting. J. Neurosci., 25(2): 532–538. Colado, M.I., O’Shea, E. and Green, A.R. (2004) Acute and long-term effects of NDMA on cerebral dopamine biochemistry and function. Psychopharmacology, 173(3–4): 249–263. Cools, R. (2006) Dopaminergic modulation of cognitive function-implications for L-DOPA treatment in Parkinsonus disease. Neurosci. Biobehav. Rev., 30(1): 1–23. Daberkow, D.P., Kesner, R.P. and Keefe, K.A. (2005) Relation between methamphetamine-induced monoamine depletions in the striatum and sequential motor learning. Pharmacol. Biochem. Behav., 81(1): 198–204. Dauer, W. and Przedborski, S. (2003) Parkinson disease: mechanisms and models. Neuron, 39(6): 889–909. Daw, N.D., Kakade, S. and Dayan, P. (2002) Opponent interactions between serotonin and dopamine. Neural Netw., 15(4–6): 603–616. Dawson, L.A., Nguyen, H.Q. and Li, P. (2003) Potentiation of amphetamine-induced changes in dopamine and 5-HT by a 5-HT(6) receptor antagonist. Brain Res. Bull., 59(6): 513–521. De Belleroche, J.S. and Bradford, H.F. (1980) Presynaptic control of the synthesis and release of dopamine from striatal synaptosomes: a comparison between the effects of

5-hydroxytryptamine, acetylcholine, and glutamate. J. Neurochem., 35(5): 1227–1234. DeCoteau, W.E. and Kesner, R.P. (2000) A double dissociation between the rat hippocampus and medial caudoputamen in processing two forms of knowledge. Behav. Neurosci., 114(6): 1096–1108. De la Fuente-Fernandez, R., Sois, V., Huang, Z., Furatado, S., Lu, J.Q., Calne, D.B., Ruth, T.J. and Stoessl, A.J. (2004) Levodopa-induced changes in synaptic dopamine levels increase with progression of Parkinson’s disease: implications for dyskinesias. Brain, 127(pt. 12): 2747–2754. De Simoni, M.G., Dal Toso, G., Fodritto, F., Sokola, A. and Algeri, S. (1987) Modulation of striatal dopamine metabolism by the activity of dorsal raphe serotonergic afferences. Brain Res., 411(1): 81–88. Dı´ az-Mataix, L., Scorza, M.C., Bortolozzi, A., Toth, M., Celada, P. and Artigas, F. (2005) Involvement of 5-HT1A receptors in prefrontal cortex in the modulation of dopaminergic activity: role in atypical antipsychotic action. J. Neurosci., 25(47): 10831–10843. Di Giovanni, G., De Dewaerde´re, P., Di Mascio, M., Di Matteo, V., Esposito, E. and Spampinato, U. (1999) Selective blockade of serotonin-2B/2C receptors enhances mesolimbic and mesostriatal dopaminergic function: A combined in vivoelectrophysiological and microdialisys study. Neuroscience, 91(2): 587–597. Di Giovanni, G., Di Matteo, V., Di Mascio, M. and Esposito, E. (2000) Preferential modulation of mesolimbic vs. nigrostriatal dopaminergic function by serotonin(2C/2B) receptor agonists: a combined in vivo electrophysiological and microdialysis study. Synapse, 35(1): 53–61. Di Giovanni, G., Di Matteo, V., Pierucci, M., Benigno, A. and Espo´sito, E. (2006) Serotonin involvement in the basal ganglia pathophysiology: could the 5-HT2C receptor be a new target for therapeutic strategies? Curr. Med. Chem., 13(25): 3069–3081. Di Matteo, V., Di Giovanni, G., Di Mascio, M. and Espo´sito, E. (1998) Selective blockade of serotonin 2C/2B receptors enhances dopamine release in the rat nucleus accumbens. Neuropharmacology, 37(2): 265–272. Di Matteo, V., Di Giovanni, G., Di Mascio, M. and Espo´sito, E. (2000) Biochemical and electrophysiological evidence that RO 60-0175 inhibits mesolimbic dopaminergic function through serotonin (2C) receptors. Brain Res., 865(1): 85–90. Di Matteo, V., Pierucci, M. and Espo´sito, E. (2004) Selective stimulation of seotonin 2c receptors blocks the enhancement of strital and accumbal dopamine release induced by nicotina. J. Neurochem., 89(2): 418–429. Di Pietro, N.C. and Seamans, J.K. (2007) Dopamine and serotonin interactions in the prefrontal cortex: insights on antipsychotic drugs and their mechanism of action. Pharmacopsychiatry, 40(Suppl. 1): S27–S33. Dunnett, S.B. and White, A. (2006) Striatal grafts alleviate bilateral striatal lesion deficits in operant delayed alternation in the rat. Exp. Neurol., 199(2): 479–489. Durif, F., Debilly, B., Galitzky, M., Morand, D., Viallet, F., Borg, M., Thobois, S., Broussolle, E. and Rascol, O. (2004)

595 Clozapine improves dyskinesias in Parkinson disease: a double-blind, placebo-controlled study. Neurology, 62(3): 381–388. Durstewitz, D. and Seamans, J.K. (2002) The computational role of dopamine D1 receptors in working memory. Neural Netw., 15(4–6): 561–572. Durstewitz, D. and Seamans, J.K. (2006) The computational role of dopamine D1 receptors in working memory. Neural Netw., 15(4–6): 561–572. Egashira, N., Yano, A., Ishigami, N., Mishima, K., Iwasaki, K., Fujioka, M., Matsushita, M., Nishimura, R. and Fujiwara, M. (2006) Investigation of mechanisms mediating 8-OH-DPAT-induced impairment of spatial memory: involvement of 5-HT1A receptors in the dorsal hippocampus of rats. Brain Res., 1069(1): 54–62. Eglen, R.M., Jasper, J.R., Chang, D.J. and Martin, G.R. (1997) The 5-HT7 receptor: orphan found. Trends. Pharmacol. Sci., 18(4): 104–107. Eglen, R.M., Wong, E.H., Dumius, A. and Bockaert, J. (1995) Central 5-HT4 receptors. Trends Pharmacol. Sci., 16(11): 391–398. Faure, A., Haberland, U., Conde´, F. and Massioui, N.E. (2005) Lesion to the nigrostriatal dopamine system disrupts stimulus–response habit formation. J. Neurosci., 25(11): 2771–2780. Featherstone, R.E. and McDonald, R.J. (2004) Dorsal striatum and stimulus–response learning: lesions of the dorsolateral, but not dorsomedial, striatum impair acquisition of a simple discrimination task. Behav. Brain. Res., 150(1–2): 15–23. Ferna´ndez-Pe´rez, S., Pache, D.M. and Sewell, R.D. (2005) Coadministration of fluoxetine and WAY100635 improves short-term memory function. Eur. J. Pharmacol., 522(1–3): 78–83. Ferre´, S., Corte´s, R. and Artigas, F. (1994) Dopaminergic regulation of the serotonergic raphe-striatal pathway: microdialysis studies in freely moving rats. J. Neurosci., 14(8): 4839–4846. Finlay, J.M., Zigmond, M.J. and Abercrombie, E.D. (1995) Increased dopamine and norepinephrine release in medial prefrontal cortex induced by acute and chronic stress: effects of diazepam. Neuroscience, 64(3): 619–628. Fino, E., Glowinski, J. and Venance, L. (2005) Bidirectional activity-dependent plasticity at corticostriatal synapses. J. Neurosci., 25(49): 11279–11287. Fletcher, P.J., Korth, K.M. and Chambers, J.W. (1999) Selective destruction of brain serotonin neurons by 5,7dihydroxytryptamine increases responding for a conditioned reward. Psychopharmacol. (Berl.), 147(3): 291–299. Florio, T., Capozzo, A., Nisini, A., Lupi, A. and Scarnati, E. (1999) Dopamine denervation of specific striatal sub-regions differentially affects preparation and execution of delayed response task in the rat. Behav. Brain. Res., 104(1–2): 51–62. Fluxe, K., Ho¨kfelt, T., Johansson, O., Jonsson, G., Lidbrink, P. and Ljungdahl, A. (1974) The origin of the dopamine nerve terminals in limbic and frontal cortex: evidence for mesocortico dopamine neurons. Brain Res., 82(2): 349–355.

Fox, S.H. and Brotchie, J.M. (2000a) 5-HT2C receptor binding is increased in the substantia nigra pars reticulate in Parkinson’s disease. Mov. Disord., 15(6): 1064–1069. Fox, S.H. and Brotchie, J.M. (2000b) 5-HT(2C) receptor antagonists enhance the behavioural response to dopamine D(1) receptor agonists in the 6-hydroxydopamine-lesioned rat. Eur. J. Pharmacol., 398(1): 59–64. Frantz, K.J., Hansson, K.J., Stouffer, D.G. and Parsons, L.H. (2002) 5-HT6 receptor antagonism potentiates the behavioral and neurochemical effects of amphetamine but not cocaine. Neuropharmacology, 42(2): 170–180. Fuster, J. (1980) The Prefrontal Cortex. Raven, New York. Fuster, J.M. (1997) The prefrontal cortex: anatomy, physiology and neuropsychology of the frontal lobe (3rd edn.). Lippincott-Raven, Philadelphia. Fuster, J.M (2001) The prefrontal cortex- an update: time is of the essence. Neuron, 30(2): 319–333. Galeotti, N., Gheraldini, C. and Bartolini, A. (1998) Role of 5-HT4 receptors in the mouse passive avoidance test. J. Pharmacol. Exp. Ther., 286(3): 1115–1121. Gallagher, P., Massey, A.E., Young, A.E., et al. (2003) Effects of acute tryptophan depletion on executive function in healthy male volunteers. Psychiatry, (3): 1–9. Gasbairri, A., Cifariello, A., Pompili, A. and Meneses, A. (2008) Effect of 5-HT(7) antagonist SB-269970 in the modulation of working and reference memory in the rat. Behav. Brain Res., doi:10.1016/j.bbr.2007.12.020. Gerard, C., Martres, M.P., Lefevre, K., Miquel, M.C., Verge, D., Lanfumey, L., Doucet, E., Hamon, M. and el Mestikawy, S. (1997) Immuno-localizationof serotonin 5-HT6 receptorlike material in the rat central nervous system. Brain Res., 764(1–2): 207–219. Gervais, J. and Rouillard, C. (2000) Dorsal raphe stimulation differentially modulates dopaminergic neurons in the ventral tegmental area and substantia nigra. Synapse, 35(4): 281–291. Geyer, M.A., Puerto, A., Dawsey, W.J., Knapp, S., Bullard, W.P. and Mandell, A.J. (1976) Histologic and enzymatic studies of the mesolimbic and mesostriatal serotonergic pathways. Brain Res., 106(2): 241–256. Gobert, A. and Millan, M.J. (1999) Serotonin (5-HT)2A receptor activation enhances dialysate levels of dopamine and noradrenaline, but not 5-HT, in the frontal cortex of freely-moving rats. Neuropharmacology, 38(2): 315–317. Gobert, A., Rivet, J.M., Lejeune, F., Newman-Tancredi, A., Adhumeau-Auclair, A., Nicolas, J.P., Cistarelli, L., Melon, C. and Millan, M.J. (2000) Serotonin(2C) receptors tonically suppress the activity of mesocortical dopaminergic and adrenergic, but not serotonergic, pathways: a combined dialysis and electrophysiological analysis in the rat. Synapse, 36(3): 205–221. Goldman-Rakic, P.S. (1987) Circuitry of Primate Prefrontal Cortex and Regulation of Behavior by Representational Memory. American Physiological Behavior, Bethesda. Goldman-Rakic, P.S. (1995) Cellular basis of working memory. Neuron, 14(3): 477–485. Goldman-Rakic, P.S., Lidow, M.S. and Gallager, D.W. (1990) Overlap of dopaminergic, adrenergic, and serotoninergic

596 receptors and complementarity of their subtypes in primate prefrontal cortex. J. Neurosci., 10(7): 2125–2138. Goldman-Rakic, P.S., Muly, E.C., III and Williams, G.V. (2000) D(1) receptors in prefrontal cells and circuits. Brain Res. Rev., 31(2–3): 295–301. Goldman-Rakic, P.S. and Schwartz, M.L. (1982) Interdigitation of contralateral and ipsilateral columnar projections to frontal association cortex in primates. Science, 216(4547): 755–757. Gonza´lez-Burgos, G., Kroener, S., Seamans, J.K., Lewis, D.A. and Barrionuevo, G. (2005) Dopaminergic modulation of short-term synaptic plasticity in fast-spiking interneurons of primate dorsolateral prefrontal cortex. J. Neurophysiol., 94(6): 4168–4177. Gonza´lez-Burgos, I., Pe´rez-Vega, M.I., Del Angel-Meza, A.R. and Feria-Velasco, A. (1998) Effect of tryptophan restriction on short-term memory. Physiol. Behav., 63(2): 165–169. Gorelova, N., Seamans, J.K. and Yang, C.R. (2002) Mechanisms of dopamine activation of fast-spiking interneurons that exert inhibition in rat prefrontal cortex. J. Neurophysiol., 88(6): 3150–3166. Gorelova, N. and Yang, C.R. (2000) Dopamine D1/D5 receptor activation modulates a persistent sodium current in rat prefrontal cortical neurons in vitro. J. Neurophysiol., 84(1): 75–87. Gouzoulis-Mayfrank, E., Daumann, J., Tutchenhagen, F., Pelz, S., Becker, S., Kunert, H-J., Fimm, B. and Sass, H. (2000) Impaired cognitive performance in drug free users of recreational ecstasy (NDMA). J. Neurol. Neurosurg. Psychiatry, 68(6): 719–725. Gouzoulis-Mayfrank, E., Thimm, B., Rezk, M., Hensen, G. and Daumann, J. (2003) Memory impairment suggests hippocampal dysfunction in abstinent ecstasy users. Prog. Neuropsychopharmacol. Biol. Psychiatry, 27(5): 819–827. Grace, A.A. (1991) Phasic versus tonic dopamine release and the modulation of dopamine system responsivity: a hypothesis for the etiology of schizophrenia. Neuroscience, 41(1): 1–24. Grace, A.A. (2000) The tonic/phasic model of dopamine system regulation and its implications for understanding alcohol and psychostimulant craving. Addiction, 95(Suppl. 2): S119–S128. Gray, J.A. and Roth, B.L. (2007) Molecular targets for treating cognitive dysfunction in schizophrenia. Schizophr. Bull., (5): 1100–1119. Graybiel, A.M., Hirsch, E.C., Agid, Y. (1990) The nigrostriatal system in Parkinson’s disease, Adv. Neurol., 153, 17–29. Green, A.R., Mechan, A.O., Elliot, M., OuShea, E. and Colado, M.I. (2003) The pharmacology and clinical pharmacology of 3-4-methylenedioxymethamphetamine (NDMA, ‘Ecstasy’). Pharmacol. Rev., 55(3): 463–508. Groenewegen, H.J. and Uylings, H.B. (2000) The prefrontal cortex and the integration of sensory, limbic and autonomic information. Prog. Brain Res., 126: 3–28. Gu, Q. (2002) Neuromodulatory transmitter systems in the cortex and their role in cortical plasticity. Neuroscience, 111(4): 815–835.

Guttman, M., Boileau, I., Warsh, J., Saint-Cyr, J.A., Ginovart, N., McCluskey, T., Houle, S., Wilson, A., Mundo, E., Rusjan, P., Meyer, J. and Kish, S.J. (2007) Brain serotonin transporter binding in non-depressed patients with Parkinson’s disease. Eur. J. Neurol., 14(5): 523–528. Haapaniemi, T.H., Ahonen, A., Torniainen, P., Sotaniemi, K.A. and Myllyla¨, V.V. (2001) [1231] Beta-CIT SPECT demonstrates decreased brain dopamine and serotonin transporter levels in untreated parkinsonian patients. Mov. Disord., 16(1): 124–130. Halliday, G.M., Blumbergs, P.C., Cotton, R.G.H., Blesing, W.W. and Geffen, L.B. (1990) Loss of brainstem serotonin and substance P-containing neurons in Parkinson’s disease. Brain Res., 510(1): 104–107. Harrell, A.V. and Allan, A.M. (2003) Improvements in hippocampal-dependent learning and decremental attention in 5-HT(3) receptor overexpressing mice. Learn. Mem., 10(5): 410–419. Harrison, A.A., Everitt, B.J. and Robbins, T.W. (1997) Central 5-HT depletion enhances impulsive responding without affecting the accuracy of attentional performance: interactions with dopaminergic mechanisms. Psychopharmacol. (Berl.), 133(4): 329–342. Harrison, A.A., Everitt, E.J. and Robbins, T.W. (1999) Central serotonin depletion impairs both the acquisition and performance of a symmetrically reinforced go/no-go conditional visual discrimination. Behav. Brain. Res., 100(1–2): 99–112. Harvey, J.A. (1996) Serotonergic regulation of associative learning. Behav. Brain Res., 73(1–2): 47–50. Herve´, D., Simon, H., Blanc, G., Lisoprawski, A., Le Moal, M., Glowinski, J. and Tassin, J.P. (1979) Increased utilization of dopamine in the nucleus accumbens but not in the cerebral cortex after dorsal raphe lesion in the rat. Neurosci. Lett., 15(2–3): 127–133. Hong, E. and Meneses, A. (1996) Systemic injection of pchloroamphetamine eliminates the effect of the 5-HT3 compounds on learning. Pharmacol. Biochem. Behav., 53(4): 765–769. Hoshi, R., Mullins, K., Boundy, C., Brignell, C., Piccini, P. and Curran, H.V. (2007) Neurocognitive function in current and ex-users of ecstasy in comparison to both matched polydrugusing controls and drug-naı¨ ve controls. Psychopharmacol. (Berl.), 194(3): 371–379. Hritcu, L., Clicinschi, M. and Nabeshima, T. (2007) Brain serotonin depletion impairs short-term memory, but not long-term memory in rats. Physiol. Behav., 91(5): 652–657. Hudzik, T.J., Howell, A., Georger, M.M. and Cross, A.J. (2000) Disruption of acquisition and performance of operant response-duration differentiation by unilateral nigrostriatal lesions. Behav. Brain Res., 114(1–2): 65–77. Hughes, J.H., Galllagher, P., Stewart, M.E., Mattheus, D., Kelly, T.P. and Young, A.H. (2003) The effects of acute tryptophan depletion on neuropsychological function. J. Psychopharmacol., 17(3): 300–309. Hutson, P.H., Barton, C.L., Jay, M., Blurton, P., Burkamp, F., Clarkson, R. and Bristow, L.J. (2000) Activation of

597 mesolimbic dopamine function by phencyclidine is enhanced by 5-HT(2C/2B) receptor antagonists: neurochemical and behavioural studies. Neuropharmacology, 39(12): 2318–2328. Ichikawa, J., Ishii, H., Bonaccorso, S., Fowler, W.L., O’Laughlin, I.A. and Meltzer, H.Y. (2001) 5-HT(2A) and D(2) receptor blockade increases cortical DA release via 5-HT(1A) receptor activation: a possible mechanism of atypical antipsychotic-induced cortical dopamine release. J. Neurochem., 76(5): 1521–1531. Ikemoto, S. and Panksepp, J. (1999) The role of nucleus accumbens dopamine in motivated behavior: a unifying interpretation with special reference to reward-seeking. Brain Res. Brain Res. Rev., 31(1): 6–41. Inoue, T., Izumi, T., Maki, Y., Muraki, I. and Koyama, T. (2000) Effect of dopamine D(1/5) antagonist SCH 23390 on the acquisition of conditioned fear. Pharmacol. Biochem. Behav., 66(3): 573–578. Iravani, M.M., Jackson, M.J., Kuoppama¨ki, M., Smith, L.A. and Jenner, P. (2003) 3,4-methylenedioxyamphetamine (ecstasy) inhibits dyskinesia expression and normalizes motor activity in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated primates. J. Neurosci., 23: 9107–9115. Isayama, S., Sugimoto, Y., Nishiga, M. and Kamei, C. (2001) Effects of histidine on working memory de´ficits induced by 5-HT1A receptor agonist 8-OH-DPAT. Jpn. J. Pharmacol., 86(4): 451–453. Iyer, R.N. and Bradberry, C.W. (1996) Serotonin-mediated increase in prefrontal cortex dopamine release: pharmacological characterization. J. Pharmacol. Exp. Ther., 277(1): 40–47. Iversen, S.D. (1984) 5-HT and anxiety. Neuropharmacology, 23(12B): 1553–1560. Iwakawa, M., Terao, T., Soya, A., Kojima, H., Inoue, Y., Ueda, N., Yoshimura, R. and Nakamura, J. (2004) A novel antipsychotic, prospirone, has antiserotonergic and antidopaminergic effects in human brain: findings from neuroendocrine challenge tests. Psychopharmacology, 176(3–4): 407–411. Jacobs, B.L. and Azmitia, E.C. (1992) Structure and function of the brain serotonin system. Physiol. Rev., 72(1): 165–229. Jacobs, B.L. and Fornal, C.A. (1993) 5-HT and motor control: a hypothesis. Trends Neurosci., 16(1): 346–352. Jakab, R.L. and Goldman-Rakic, P.S. (2000) Segregation of serotonin 5-HT2A and 5-HT3 receptors in inhibitory circuits of the primate cerebral cortex. J. Comp. Neurol., 417(3): 337–348. Jay, T.M. (2003) Dopamine: a potential substrate for synaptic plasticity and memory mechanisms. Prog. Neurobiol., 69(6): 375–390. Kaczmarek, L.K. and Levitan, I.B. (1987) Neuromodulation: the biochemical control of neuronal excitability. Oxford University Press, New York. Kale´n, P., Skagerberg, G. and Lindvall, O. (1988) Projections from the ventral tegmental area and mesencephalic raphe to the dorsal raphe nucleus in the rat: evidence for a minor dopaminergic component. Exp. Brain. Res., 73(1): 69–77.

Kapur, S. and Remington, G. (1996) Serotonin–dopamine interaction and its relevance to schizophrenia. Am. J. Psychiatry, 153(4): 466–476. Katz, P.S. (1999) What are we talking about? modes of neuronal communication. In: Katz P.S. (Ed.), Beyond Neurotransmission. Oxford University Press, New York, pp. 1–28. Kebabian, J.W., Beaulieu, M. and Itoh, Y. (1984) Pharmacological and biochemical evidence for the existence of two categories of dopamine receptor. Can. J. Neurol. Sci., 11(Suppl. 1): 114–117. Kelland, M.D., Freeman, A.S. and Chiodo, L.A. (1990) Serotonergic afferent regulation of the basic physiology and pharmacological responsiveness of nigrostriatal dopamine neurons. J. Pharmacol. Exp. Ther., 253(2): 803–811. Kellendon, C., Simposn, E.H., Polan, H.J., Malleret, G., Vronskaya, S., Winiger, V., Moore, H. and Kandel, E.R. (2006) Transient and selective overexpression of dopamine D2 receptors in the striatum causes persistent abnormalities in prefrontal cortex functioning. Neuron, 49(4): 603–615. Kerenyi, L., Ticaurte, G.A., Schretlen, D.J., McCann, U., Varga, J., Matheus, W.B., Ravert, H.T., Dannals, R.F., Hilton, J., Wong, D.F. and Szabo, Z. (2003) Positron emission tomography of striatal serotonin transporters in Parkinson’s disease. Arch. Neurol., 60(9): 1223–1229. Kim, S.E., Choi, J.Y., Choe, Y.S., Choi, Y. and Lee, W.Y. (2003) Serotonin transporters in the midbrain of Parkinson’s disease patients: a study with 1231-beta-CIT SPECT. J. Nucl. Med., 44(6): 870–876. Kinney, J.W., Starosta, G. and Crawley, J.N. (2003) Central galanin administration blocks consolidation of spatial learning. Neurobiol. Learn. Mem., 80(1): 42–54. Kirkby, R.J. and Polgar, S. (1974) Active avoidance in the laboratory rat following lesions of the dorsal or ventral caudate nucleus. Physiol. Psychol., 2: 301–306. Kish, S.J. (2003) Biochemistry of Parkinson’s disease: is a brain serotonergic deficiency a characteristic of idiopathic Parkinson’s disease? Adv. Neurol., 91(1): 39–49. Kish, S.J., Tong, J., Hornykiewicz, O., Rajput, A., Chang, L.J., Guttman, M. and Furukawa, Y. (2008) Preferential loss of serotonin markers in caudate versus putamen in Parkinson’s disease. Brain, 131(1): 120–131. Kiyatkin, E.A. and Rebec, G.V. (1999) Striatal neuronal activity and responsiveness to dopamine and glutamate after selective blockade of D1 and D2 dopamine receptors in freely moving rats. J. Neurosci., 19(9): 3594–3609. Kostrzewa, R., Nowak, P., Kostrzewa, J., Kostrzewa, R. and Brus, R. (2005) Peculiarities of L-DOPA: treatment of Parkinson’s disease. Amino Acids, 28(2): 157–164. Kuhn, W., Muller, T., Gerlach, M., Sofic, E., Fuchs, G., Heye, N., Prautsch, R. and Przuntek, H. (1996) Depression in Parkinson’s disease: biogenic amines in CSF of ‘‘de novo’’ patients. J. Neural Transm., 103(12): 1441–1445. Kupfermann, I. (1979) Modulatory actions of neurotransmitters. Ann. Rev. Neurosci., 2: 447–465. Latgen, M., Elvander, E., Madjid, N. and Ogren, S.O. (2005) Analyses of the role of 5-HT1A receptors in spatial and

598 aversive learning in the rat. Neuropsychopharmacology, 48(6): 830–852. Lee, E.H. and Geyer, M.A. (1984) Dopamine autoreceptor mediation of the effects of apomorphine on serotonin neurons. Pharmacol. Biochem. Behav., 21(2): 301–311. Lehmann, O., Bertrand, F., Jeltsch, H., Morer, M., Lazarus, C., Will, B. and Cassel, J.C. (2002) 5,7-DHT-induced hippocampal 5-HT depletion attenuates behavioural deficits produced by 192 IgG-saporin lesions of septal cholinergic neurons in the rat. Eur. J. Neurosci., 15(12): 1991–2006. Lemon, N. and Manahan-Vaughan, D. (2006) Dopamine D1/D5 receptors gate the acquisition of novel information through hippocampal long-term potentiation and long-term depression. J. Neurosci., 26(29): 7723–7729. Lewis, S.J., Slabosz, A., Robbins, T.W., Barker, R.A. and Owen, A.M. (2005) Dopaminergic basis for deficits in working memory but not attentional set-shifting in Parkinson’s disease. Neuropsychologia, 43(6): 823–832. Liao, R.M., Lai, W.S. and Lin, J.Y. (2002) The role of catecholamines in retention performance of a partially baited radial eight-arm maze for rats. Chin. J. Physiol., 45(4): 177–185. Lucas, G., Di Matteo, V., De Deurwaerde`re, P., Porras, G., Martı´ n-Ruiz, R., Artigas, F., Esposito, E. and Spampinato, U. (2001) Neurochemical and electrophysiological evidence that 5-HT4 receptors exert a state-dependent facilitatory control in vivo on nigrostriatal, but not mesoaccumbal, dopaminergic function. Eur. J. Neurosci., 13(5): 889–898. MacDermott, A.B., Role, L.W. and Siegelbaum, S.A. (1999) Presynaptic ionotropic receptors and the control of transmitter release. Annu. Rev. Neurosci., 22: 443–485. McDonald, R.J. and White, N.M. (1993) A triple dissociation of memory systems: hippocampus, amygdale, and dorsal striatum. Behav. Neurosci., 107(1): 3–22. Maeda, T., Nagata, K., Yoshida, Y. and Kannary, K. (2005) Serotonergic hyperinnervation into the dopaminergic denervated striatum compensates for dopamine conversion from exogenously administered L-DOPA. Brain Res., 1046(1–2): 230–233. Mamo, D., Graff, A., Mizrahi, R., Shammi, C.M., Romeyer, F. and Kapur, S. (2007) Differential effects of aripiprazole on D(2), 5-HT(2), and 5-HT(1A) receptor occupancy in patients with schizophrenia: a triple tracer PET study. Am. J. Psychiatry, 164(9): 141–147. Matsuda, T., Sakaue, M., Ago, Y., Sakamoto, Y., Koyama, Y. and Baba, A. (2001) Functional alteration of brain dopaminergic system in isolated aggressive mice. Nihon Shinkei Seishin Yakurigaku Zasshi., 21(3): 71–76. Matsumoto, M., Togashi, H., Mori, K., Ueno, K., Miyamoto, A. and Yoshioka, M. (1999) Characterization of endogenous serotonin-mediated regulation of dopamine release in the rat prefrontal cortex. Eur. J. Pharmacol., 383(1): 39–48. Mayeux, R. (1990) The serotonin hypothesis for depression and Parkinson’s disease. Adv. Neurol., 53(1): 163–166. Mayeux, R., Stern, Y., Cote, L. and Williams, J.B. (1984) Altered serotonin metabolism in depressed patients with Parkinson’s disease. Neurology, 34(5): 642–646.

McDonald, R.J. and White, M.N. (1994) Parallel information processing in the water maze: evidence for independent memory systems involving dorsal striatum and hippocampus. Behav. Neural. Biol., 61(3): 260–270. McDonald, R.J. and White, M.N. (1996) Hippocampal and non hippocampal contributions to place learning in rats. Behav. Neurosci., 109(4): 579–593. Meltzer, H.Y., Li, Z., Kaneda, Y. and Ichikawa, J. (2003) Serotonin receptors: their key role in drugs to treat schizophrenia. Prog. Neuropsychopharmacol. Biol. Psychiatry, 27(7): 1159–1172. Meneses, A. (2007) Stimulation of 5-HT1A, 5-HT1B, 5-HT2A/ 2C, 5-HT3, and 5-HT4 receptors or 5-HT uptake inhibition: short- and long-term memory. Behav. Brain Res., 184(1): 81–90. Meneses, A., Pe´rez-Garcı´ a, G., Liy-Salmeron, G., FloresGalvez, D., Castillo, C. and Castillo, E. (2008) The effects of 5-HT(6) receptor agonist EMD and 5-HT(7) receptor agonist AS19 on memory formation. Behav. Brain Res., doi:10.1016/j.bbr.2007.11.023. Micale, V., Leggio, G.M., Mazzola, C. and Drago, F.C. (2006) Cognitive effects of SL65.0155, a serotonin 5-HT4 receptor partial agonist, in animal models of amnesia. Brain Res., 1121(1): 207–215. Millan, M.J. (2000) Improving the treatment of schizophrenia: focus on serotonin (5-HT)(1A) receptors. J. Pharmacol. Exp. Ther., 295(3): 853–861. Millan, M.J., Dekeyene, A. and Gobert, A. (1998) Serotonin (5-HT)2C receptors tonically inhibit dopamine (DA) and noradrenaline (NA), but not 5-HT release in the frontal cortex in vivo. Neuropharmacology, 37(7): 953–955. Miller, E.K. and Cohen, J.D. (2001) An integrative theory of prefrontal cortex function. Annu. Rev. Neurosci., 24: 167–202. Mirenowicz, J. and Schultz, W. (1994) Importance of unpredictability for reward responses in primate dopamine neurons. J. Neurophysiol., 72(2): 1024–1027. Misane, I., Johansson, C. and O¨gren, S.O. (1988) Analysis of the 5-HT1A receptor involvement in passive avoidance in the rat. Br. J. Pharmacol., 125(3): 499–509. Misane, I. and O¨gren, S.O. (2000) Multiple 5-HT receptors in passive avoidance: comparative studies of p-chloroamphetamine and 8-OH-DPAT. Neuropsychopharmacology, 22(2): 168–190. Misane, I. and O¨gren, S.O. (2002) Multiple 5-HT receptors in passive avoidance: comparative studies of p-chloroamphetamine and 8-OH-DPAT. Neuropsychopharmacology, 22(2): 168–190. Mishkin, M., Malamut, B. and Bachevalier, J. (1984) Memories and habits: two neuronal systems. In: McGrawHill J.L. and Weinberger N.M. (Eds.), Neurobiology of Human Learning and Memory. The Guilford press, New York, pp. 65–87. Mitchell, E.S. and Neumaier, J.F. (2005) 5-HT6 receptors: a novel target for cognitive enhancement. Pharmacol. Ther., 108(3): 320–333. Morrow, B.A., Elsworth, J.D., Rasmusson, A.M. and Roth, R.H. (1999) The role of mesoprefrontal dopamine neurons in

599 the acquisition and expression of conditioned fear in the rat. Neuroscience, 92(2): 553–564. Mu¨ller, U., von Cramon, D.Y. and Pollmann, S. (1998) D1versus D2-receptor modulation of visuospatial working memory in humans. J. Neurosci., 18(7): 2720–2728. Murphy, D.L., Andrews, A.M., Wichems, C.H., Li, Q., Tohoda, M. and Greenberg, B. (1998) Brain serotonin neurotransmission: an overview and update with emphasis on serotonin system heterogeneity, multiple receptors, interactions with other neurotransmitter systems, and consequent implications for understanding the actions of serotonergic drugs. J. Clin. Psychiatry, 59(Suppl. 15): 4–12. Murtha, J.E.S. and Pappas, A.B. (1994) Neurochemical, histopatological and mnemonic effect of combined lesions of the medial septal and serotonin afferents to the hippocampus. Brain Res., 651(1–2): 16–26. Naghdi, N. and Harooni, H.E. (2005) The effect of intrahippocampal injections of ritanserin (5HT2A/2C antagonist) and granisetron (5HT3 antagonist) on learning as assessed in the spatial version of the water maze. Behav. Brain Res., 157(2): 205–210. Nakazato, T. (2005) Striatal dopamine release in the rat during a cued lever-press task for food reward and the development of changes over time measured using high-speed voltammetry. Exp. Brain. Res., 166(1): 137–146. Nayak, S.V., Ronde´, P., Spier, A.D., Lummis, S.C. and Nichols, R.A. (2000) Nicotinic receptors co-localize with 5-HT(3) serotonin receptors on striatal nerve terminals. Neuropharmacology, 39(13): 2681–2690. Nedergaard, S., Bolam, J.P. and Greenfield, S.A. (1988) Facilitation of a dendritic calcium conductance by 5-hydroxytriptamine in the substantia nigra. Nature, 333(6169): 174–177. Normile, H.J., Jenden, D.J., Khun, D.M., Wolf, W.A. and Altman, H.J. (1990) Effects of combined serotonin depletion and lesions of the nucleus basalis magnocellularis on acquisition of a complex spatial discrimination task in the rat. Brain Res., 563(1–2): 245–250. O¨gren, S.O. (1985) Central serotonin neurons in avoidance learning: interactions with noradrenaline and dopamine neurons. Pharmacol. Biochem. Behav., 23(1): 107–123. O¨gren, S.O. (1986) Analysis of the avoidance learning deficit induced by the serotonin releasing compound p-chloroamphetamine. Brain Res. Bull., 16(5): 645–660. O¨gren, S.O. (2000) Multiple 5-HT receptors in passive avoidance: comparative studies of p-chloroamphetamine and 8-OH-DPAT. Neuropsychopharmacology, 22(2): 168–190. O’Hearn, E. and Molliver, M.E. (1984) Organization of raphecortical projections in rat: a quantitative retrograde study. Brain Res. Bull., 13(6): 709–726. Olvera-Corte´s, E., Brarajas-pe´rez, M., Morales Villagra´n, A. and Gonza´lez-Burgos, I. (2001) Cerebral serotonin depletion induces egocentric learning improvement in developing rats. Neurosci. Lett., 313(1–2): 29–32. Packard, M.G. and Knowlton, B.J. (2002) Learning and memory functions of the basal ganglia. Annu. Rev. Neurosci., 25: 563–593.

Packard, M.G. and McGaugh, J.L. (1994) Quinpirole and D-amphetamine administration post-training enhances memory on spatial and cued discriminations in a water maze. Psychobiology, 22: 54–60. Packard, M.G. and McGaugh, J.L. (1996) Inactivation of hippocampus or caudate nucleus with lidocaine differentially affects expression of place and response learning. Neurobiol. Learn. Mem., 65(1): 65–72. Packard, M.G. and White, N.M. (1991) Dissociation of hippocampus and caudate nucleus memory systems by post-training intracerebral injection of dopamine agonist. Behav. Neurosci., 105(2): 295–306. Palfreyman, M.G., Schmidt, C.J., Sorensen, S.M., Dudley, M.W., Kehne, J.H., Moser, P., Gittos, M.W. and Carr, A.A. (1993) Electrophysiological, biochemical and behavioral evidence for 5-HT2 and 5-HT3 mediated control of dopaminergic function. Psychopharmacol. (Berl.), 112(Suppl. 1): S60–S67. Parent, A., Descarries, L. and Beaudet, A. (1981) Organization of ascending serotonin systems in the adult rat brain. A radioautographic study after intraventricular administration of [3H]5-hydroxytryptamine. Neuroscience, 6: 115–138. Pasquier, D.A., Kemper, T.L., Forbes, W.B. and Morgane, P.J. (1977) Dorsal raphe, substantia nigra and locus coeruleus: interconnections with each other and the neostriatum. Brain Res. Bull., 2(5): 323–339. Paulus, W. and Jellinger, K. (1991) The neuropathological basis of different clinical subgroups of Parkinson’s disease. J. Neuropathol. Exp. Neurol., 50(6): 743–755. Pavese, N., Evans, A.H., Tay, Y.F., Hotton, G., Brooks, D.J., Lees, A.J. and Piccini, P. (2006) Clinical correlates of levodopa-induced dopamine release in Parkinson’s disease: a PET study. Neurology, 67(9): 1612–1617. Pehek, E.A., McFarlane, H.G., Maguschak, K., Price, B. and Pluto, C.P. (2001) M100,907, a selective 5-HT(2A) antagonist, attenuates dopamine release in the rat medial prefrontal cortex. Brain Res., 888(1): 51–59. Pehek, E.A., Nocjar, C., Roth, B.L., Byrd, T.A. and Mabrouk, O.S. (2006) Evidence for the preferential involvement of 5-HT2A serotonin receptors in stress- and drug-induced dopamine release in the rat medial prefrontal cortex. Neuropsychopharmacology, 31(2): 265–277. Pe´rez-vega, M.I., Feria-Vela´sco, A. and Gonza´lez-Burgos, I. (2000) Prefrontocortical serotonin depletion results in plastics changes of prefrontocortical pyramidal neurons, underlying greater efficiency of short-term memory. Brain Res. Bull., 53(3): 291–300. Peyron, C., Petit, J.M., Rampon, C., Jouvet, M. and Luppi, P.H. (1998) Forebrain afferents to the rat dorsal raphe nucleus demonstrated by retrograde and anterograde tracing methods. Neuroscience, 82(2): 443–468. Pierucci, M., Di Matteo, V. and Espo´sito, E. (2004) Stimulation of serotonin2C receptors blocks the hyperactivation of midbrain dopamine neurons induced by nicotine administration. J. Pharmacol. Exp. Ther., 3009(1): 109–118. Pizzagalli, D.A., Evins, A.E., Schetter, E.C., Frank, M.J., Pajtas, P.E., Santesso, D.L. and Culhane, M. (2008) Single

600 dose of dopamine agonist impairs reinforcement learning in humans: behavioral evidence from a laboratory-based measure of reward responsiveness. Psychopharmacol. (Berl.), 196(2): 221–232. Plasse, G., Meerker, D.T.J., Lieben, C.K.J., Blokland, A. and Feenstra, M.G.P. (2007) Lack of evidence for reduced prefrontal cortical serotonin and dopamine efflux after acute tryptophan depletion. Psychopharmacol. (Berl.), 195(3): 377–385. Pompeiano, M., Palacios, J.M. and Mengod, G. (1992) Distribution and cellular localization of mRNA coding for 5-HT1A receptor in the rat brain: correlation with receptor binding. J. Neurosci., 12(2): 440–453. Ponnusamy, R., Nissin, H.A. and Barad, M. (2005) Systemic blockade of D2-like dopamine receptors facilitate extinction of conditioned fear in mice. Learn. Mem., 12(4): 399–406. Porras, G., De Deurwaerdere, P., Moison, D. and Spampinato, U. (2003) Conditional involvement of striatal serotonin3 receptors in the control of in vivo dopamine outflow in the rat striatum. Eur. J. Neurosci., 17(4): 771–781. Prado-Alcala, R.A., Grinberg, Z.J., Arditti, Z.L., Garcia, M.M., Prieto, H.G. and Brust-Carmona, H. (1975) Learning deficits produced by chronic and reversible lesions of the corpus striatum in rats. Physiol. Behav., 15(3): 283–287. Prado-Alcala´, R.A., Ruiloba, M.I., Rubio, L., SolanaFigueroa, R., Medina, C., Salado-Castillo, R. and Quirarte, G.L. (2003a) Regional infusions of serotonin into the striatum and memory consolidation. Synapse, 47(3): 169–175. Prado-Alcala´, R.A., Solana-Figueroa, R., Galindo, L.E., Medina, A.C. and Quitarte, G.L. (2003b) Blockade of striatal 5-HT2 receptors produces retrograde amnesia in rats. Life Sci., 74(4): 481–488. Quednow, B.B., Jessen, F., Kuhn, K.U., Maier, W., Daum, I. and Wagner, M. (2006) Memory deficits in abstinent NDMA (ecstasy) users: neuropsychological evidence of frontal dysfunction. J. Neuropsychopharmacol., 20(3): 373–384. Ramı´ rez, M.J., Cenarruzabeitia, E., Lasheras, B. and Del Rio, J. (1997) 5-HT2 receptor regulation of acetylcholine release induced by dopaminergic stimulation in rat striatal slices. Brain Res., 757(1): 17–23. Rampello, L., Chiechio, S., Rafaele, R.R., Vecchio, I. and Nicoletti, F. (2002) The SSRI citalopram improves bradykinesia in patients with Parkinson’s disease treated with L-Dopa. Clin. Neuropharmacol., 25(1): 21–24. Rebec, G.V., Christensen, J.R., Guerra, C. and Bardo, M.T. (1997) Regional and temporal differences in real-time dopamine efflux in the nucleus accumbens during free-choice novelty. Brain Res., 776(1–2): 61–67. Reneman, L., Booij, J., Schmand, B., Van der Brink, W. and Gunning, B. (2000) Memory disturbances in ‘‘Ecstasy’’ users are correlated with an altered brain serotonin neurotransmission. Psychopharmacology, 148(3): 322–324. Richter-Levin, G. and Segal, M. (1989) Spatial performance is severely impaired in rats with combined reduction of serotonergic and cholinergic transmission. Brain Res., 477(1–2): 404–407.

Riedel, W.L., Klaannen, T., Deutz, N.E.P., Van Someten, A. and Van Praag, H.R. (1999) Tryptophan depletion in normal volunteers produces selective impairment in memory consolidation. Psychopharmacol. (Berl.), 141(4): 362–369. Robbins, T.W. and Roberts, A.C. (2007) Differential regulation of fronto-executive function by the monoamines and acetylcholine. Cereb. Cortex. Suppl., 1: i151–i160. Robinson, D.L., Phillips, P.E., Budygin, E.A., Trafton, B.J., Garris, P.A. and Wightman, R.M. (2001) Sub-second changes in accumbal dopamine during sexual behavior in male rats. Neuroreport, 12(11): 2549–2552. Roitman, M.F., Stuber, G.D., Phillips, P.E., Wightmanm, R.M. and Carelli, R.M. (2004) Dopamine operates as a subsecond modulator of food seeking. J. Neurosci., 24(6): 1265–1271. Ronde´, P. and Nichols, R.A. (1998) High calcium permeability of serotonin 5-HT3 receptors on presynaptic nerve terminals from rat striatum. J. Neurochem., 70(3): 1094–1103. Roth, B.L., Craigo, S.C., Choudhary, M.S., Uluer, A., Monsma, F.J., Jr., Shen, Y., Meltzer, H.Y. and Sibley, D.R. (1994) Binding of typical and atypical antipsychotic agents to 5-hydroxytryptamine-6 and 5-hydroxytryptamine-7 receptors. J. Pharmacol. Exp. Ther., 268(3): 1403–1410. Ruotsalainen, S., McDonald, E., Koivisto, E., Stefanski, R., Haapalinna, A., Riekkinen, P., Jr. and Sirvio¨, J. (1998) 5-HT1A receptor agonist (8-OH-DPAT) and 5-HT2 receptor agonist (DOI) disrupt the non-cognitive performance of rats in a working memory task. J. Psychopharmacol., 12(2): 177–185. Sakai, K., Salvert, D., Touret, M. and Jouvet, M. (1977) Afferent connections of the nucleus raphe dorsalis in the cat as visualized by the horseradish peroxidase technique. Brain Res., 137(1): 11–35. Salomone, J.D., Cousins, M.S. and Snyder, B.J. (1997) Behavioral functions of nucleus accumbens dopamine: empirical and conceptual problems with the anhedonia hypothesis. Neurosci. Biobehav. Rev., 21(3): 341–359. Sawaguchi, T. and Goldman-Rakic, P.S. (1991) D1 dopamine receptors in prefrontal cortex: involvement in working memory. Science, 251(4996): 947–950. Scatton, B., Javoy-Agid, F., Rouquier, L., Dubois, B. and Agid, Y. (1983) Reduction of cortical dopamine, noradrenaline, serotonin and their metabolites in Parkinson’s disease. Brain Res., 275(2): 321–328. Schmitt, J.A., Jorissen, B.L., Sobczak, S., van Boxtel, M.P., Hogervorst, E., Deutz, N.E. and Riedel, W.J. (2000) Tryptophan depletion impairs memory consolidation but improves focussed attention in healthy young volunteers. J. Psychopharmacol., 14(1): 21–29. Scholes, K.E., Harrison, B.J., OuNeurill, B.V., Leung, S., Croft, R.J., Pipingas, A., Phan, K.L. and Nathan, P.J. (2007) Acute serotonin and dopamine depletion improves attentional control: findings from the stroop task. Neuropsychopharmacology, 32(7): 1600–1610. Scholtissen, B., Verhey, F.R.J., Adam, J.J., Prickaerts, J. and Leentjens, A.F. (2006) Effects of acute tryptophan depletion

601 on cognition, memory and motor performance in Parkinson’s disease. J. Neurol. Sci., 248(1–2): 259–265. Schultz, W. (1997) Dopamine neurons and their role in reward mechanisms. Curr. Opin. Neurobiol., 7(2): 191–197. Schultz, W. (1998) Predictable reward signal of dopamine neurons. J. Neurophysiol., 80(1): 1–27. Schultz, W., Dayan, P. and Montague, P.R. (1997) A neural substrate of prediction and reward. Science, 275(5306): 1593–1599. Seamans, J.K., Durstewitz, D., Christie, B.R., Stevens, C.F. and Sejnowski, T.J. (2001a) Dopamine D1/D5 receptor modulation of excitatory synaptic inputs to layer V prefrontal cortex neurons. Proc. Natl. Acad. Sci. U.S.A., 98(1): 301–306. Seamans, J.K., Gorelova, N., Durstewitz, D. and Yang, C.R. (2001b) Bidirectional dopamine modulation of GABAergic inhibition in prefrontal cortical pyramidal neurons. J. Neurosci., 21(10): 3628–3638. Seamans, J.K. and Yang, C.R. (2004) The principal features and mechanisms of dopamine modulation in the prefrontal cortex. Prog. Neurobiol., 74(1): 1–58. Sesack, S.R. and Carr, D.B. (2002) Selective prefrontal cortex inputs to dopamine cells: implications for schizophrenia. Physiol. Behav., 77(4–5): 513–517. Sesack, S.R. and Pickel, V.M. (1992) Prefrontal cortical efferents in the rat synapse on unlabeled neuronal targets of catecholamine terminals in the nucleus accumbens septi and on dopamine neurons in the ventral tegmental area. J. Comp. Neurol., 320(2): 145–160. Shapovalova, K.B. and Kamkina, Y.V. (2008) Motor and cognitive functions of the neostriatum during bilateral blockade of its dopamine receptors. Neurosci. Behav. Physiol., 38(1): 71–79. Simon, H., Scatton, B. and Moal, M.L. (1980) Dopaminergic A10 neurons are involved in cognitive functions. Neurosci. Lett., 15(2–3): 319–324. Sleight, A.J., Consolo, S., Martin, J.R., Boes, M., Boess, F.G., Bentley, J.C. and Bourson, A. (1999) 5-HT6 receptors: functional correlates and potential therapeutic indications. Behav. Pharmacol., 10: p. S86. Smith, A.D., Smith, D.L., Zigmond, M.J., Amalric, M. and Koob, G.F. (2000) Differential effects of dopamine receptors subtype blockade on performance of rats in a reaction-time paradigm. Psychopharmacology, 148(4): 355–360. Soghomonian, J.J., Descarries, L. and Watkins, K.C. (1989) Serotonin innervation in adult rat neostriatum II ultrastructural features: a radioautographic and immunocytochemical study. Brain Res., 481(1): 67–86. Solana-Figueroa, R., Salado-Castillo, R., Galindo, L.E., Quitarte, G.L. and Prado-Alcala´, R.A. (2002) Effects of pretraining with intrastriatal administration of p-chloroamphetamine on inhibitory avoidance. Neurobiol. Learn. Mem., 78(1): 178–185. Schreiber, R., Vivian, J., Hedley, L., Szczepanski, K., Secchi, R.L., Zuzow, M., van Laarhoven, S., Moreau, J-L., Martin, J.R. and Blokland, A. (2007) Effects of the novel 5-HT6

receptor antagonist RO4368554 in rat model for cognition and sensorimotor gating. Eur. Neuropsychopharmacol, 17: 277–288. Stau¨bli, U. and Xu, B. (1995) Effects of 5-HT3 receptor antagonism on hippocampal theta rhythm, memory, and LTP induction in the freely moving rat. J. Neurosci., 15(3, pt 2): 2445–2452. Stone, J.M. and Pilowsky, L.S. (2007) Novel targets for drugs in schizophrenia. CNS Neurol. Disord. Drug Targets, 6(4): 265–272. Stoof, J.C. and Kebabian, J.W. (1981) Opposing roles for D-1 and D-2 dopamine receptors in efflux of cyclic AMP from rat neostriatum. Nature, 294(5839): 366–368. Stuchlik, A. (2007) Further study of the effects of dopaminergic D1 drugs on place avoidance behavior using pretraining: some negative evidence. Behav. Brain Res., 178(1): 47–52. Stuchlik, A., Rehakova, L., Telensky, P. and Vales, K. (2007) Morris water maze learning in Long–Evans rats is differentially affected by blockade of D1-like and D2-like dopamine receptors. Neurosci. Lett., 422(3): 169–174. Stuchlik, A., Rezacova, L., Vales, K., Bubenikova, V. and Kubuk, S. (2004) Application of a novel allothetic place avoidance task (AAAPA) in testing a pharmacological model of psychosis in rats: comparison with the Morris water maze. Neurosci. Lett., 366(2): 162–166. Stuchlik, A. and Vales, K. (2006) Effect of dopamine D1 receptor antagonist SCH23390 and D1 agonist A77636 on active allothetic place avoidance, a spatial cognition task. Behav. Brain Res., 172(2): 250–255. Sutton, M.A., Rolfe, N.G. and Beninger, R.J. (2001) Biphasic effects of 7-OH-DPAT on the acquisition of responding for conditioned reward in rats. Pharmacol. Biochem. Behav., 69(1–2): 195–200. Suzuki, T., Miura, M., Nishimura, K. and Aosaki, T. (2001) Dopamine-dependent synaptic plasticity in the striatal cholinergic interneurons. J. Neurosci., 21(17): 6492–6501. Tanila, H., Bjo¨rklund, M. and Riekkinen, P., Jr. (1998) Cognitive changes in mice following moderate MPTP exposure. Brain Res. Bull., 45(6): 577–582. Tanaka, H., Kannari, K., Maeda, T., Tomiyama, M., Suda, T. and Matsunaga, M. (1999) Role of serotonergic neurons in L-DOPA-derived extracellular dopamine in the striatum of 6-OHDA-lesioned rats. Neuroreport, 10(3): 631–634. Tinaz, S., Schendan, H.E., Schon, K. and Stern, C.E. (2006) Evidence for the importance of basal ganglia output nuclei in semantic event sequencing: an fMRI study. Brain Res., 1067(1): 239–249. Trantham-Davidson, H., Kro¨ner, S. and Seamans, J.K. (2008) Dopamine modulation of prefrontal cortex interneurons occurs independently of DARPP-32. Cereb. Cortex., 0: bhm133v1. Trantham-Davidson, H., Neely, L.C., Lavin, A. and Seamans, J.K. (2004) Mechanisms underlying differential D1 versus D2 dopamine receptor regulation of inhibition in prefrontal cortex. J. Neurosci., 24(47): 10652–10659.

602 Trimmer, B.A. (1999) The messenger is not the message; or is it? In: Katz P.S. (Ed.), Beyond Neurotransmission. Oxford University Press, New York, pp. 29–82. Truffinet, P., Tamminga, C., Fabre, L.F., Meltzr, H.Y., Riviere, M.-E. and Papillon-Downey, C. (1999) Placebo-controlled study of the D4/5-HT24 antagonist fananserin in the treatment of schizophrenia. Am. J. Psychiatry, 156(3): 418–425. Tseng, K.Y. and O’Donnell, P. (2004) Dopamine-glutamate interactions controlling prefrontal cortical pyramidal cell excitability involve multiple signaling mechanisms. J. Neurosci., 44(5): 1526–1539. Ugedo, L., Grenhoff, J. and Svenson, T.H. (1989) Ritanserin, 5-HT2 receptor antagonist, activate midbrain dopamine neurons by blocking serotonin inhibition. Psychopharmacol. (Berl.), 98(1): 45–50. Vales, K. and Struchlik, A. (2005) A central muscarinic blockade interferes with learning and retrieval of the active allothetic place avoidance task despite spatial pretraining. Behav. Brain Res., 161: 238–244. Vertes, R.P. (2004) Differential projections of the infralimbic and prelimbic cortex in the rat. Synapse, 51(1): 32–58. Ward, J., Hall, K. and Haslam, C. (2006) Patterns of memory dysfunction in current and 2-year abstinent NDMA users. J. Clin. Exp. Neuropsychol., 28(3): 306–324. Ward, B.O., Wilkinson, L.S., Robbins, T.W. and Everitt, B.J. (1999) Forebrain serotonin depletion facilitates the acquisition and performance of a conditional visual discrimination task in rats. Behav. Brain. Res., 100(1–2): 51–65. Watanabe, K. and Kimura, M. (1998) Dopamine receptormediated mechanisms involved in the expression of learned activity of primate striatal neurons. J. Neurophysiol., 79(5): 2568–2580. Wenk, G., Hughey, D., Boundy, V., Kim, A., Walker, L. and Olton, D. (1987) Neurotransmitters and memory: role of cholinergic, serotonergic, and noradrenergic systems. Behav. Neurosci., 101(3): 325–332. Werkman, T.R., Glennon, J.C., Wadman, W.J. and McCreary, A.C. (2006) Dopamine receptor pharmacology: interactions with serotonin receptors and significance for the aetiology and treatment of schizophrenia. CNS Neurol. Disord. Drug Targ., 5(1): 3–23. West, A.R. and Grace, A.A. (2002) Opposite influences of endogenous dopamine D1 and D2 receptor activation on activity states and electrophysiological properties of striatal neurons: studies combining in vivo intracellular recordings and reverse microdialysis. J. Neurosci., 22(1): 294–304. White, N.M., Packard, M.G. and Seamans, J. (1993) Memory enhancement by post-training peripheral administration of low doses of dopamine agonists: possible autoreceptor effect. Behav. Neural Biol., 59(3): 230–241. White, N.M. and Salinas, J.A. (2003) Mnemonic functions of dorsal striatum and hippocampus in aversive conditioning. Behav. Brain Res., 142(1–2): 99–107. Willins, D.L. and Meltzer, H.Y. (1998) Serotonin 5-HT2C agonists selectively inhibit morphine-induced dopamine

efflux in the nucleus accumbens. Brain Res., 781(1–2): 291–299. Wightman, R.M. and Robinson, D.L. (2002) Transient changes in mesolimbic dopamine and their association with ‘reward’. J. Neurochem., 82(4): 721–735. Wilkerson, A. and Levin, E.D. (1999) Ventral hippocampal dopamine D1 and D2 systems and spatial working memory in rats. Neuroscience, 89(3): 743–749. Wilson, Ch.J. (1998) Basal ganglia. In Shepherd, G. M (Ed.), The Synaptic Organization of the Brain, Fourth edn. Chap. 9, pp. 329–375. Winocur, G. (1974) Functional dissociation within the caudate nucleus of rats. J. Comp. Physiol. Psychol., 86(3): 432–439. Winterer, G. and Weinberger, D.R. (2004) Genes, dopamine and cortical signal-to-noise ratio in schizophrenia. Trends Neurosci., 27(11): 683–690. Wolf, M.E., Deutch, A. Y., and Roth, R.H. (1987) Pharmacology of central dopaminergic neurons. In F.A. Henn & L.E. DeLisi (Eds.), Handbook of Neurochemistry and Neuropharmacology of Schizophrenia, New York: Elsevier Science Publishers BV. Vol. 2., Chap. 4, pp. 101–147. Wolterink, G., Phillips, G., Cador, M., Donselaar-Wolterink, I., Robbins, T.W. and Everitt, B.J. (1993) Relative roles of ventral striatal D1 and D2 dopamine receptors in responding with conditioned reinforcement. Psychopharmacol. (Berl.), 110(3): 355–364. Wood, M.D., Reavill, C., Trail, B., Wilson, A., Stean, T., Kennett, G.A., Lightowler, S., Blackburn, T.P., Thomas, D., Gager, T.L., Riley, G., Holland, V., Bromidge, S.M., Forbes, I.T. and Middlemiss, D.N. (2001) SB-243213, a selective 5-HT2C receptor inverse agonist with improved anxiolytic profile: lack of tolerance and withdrawal anxiety. Neuropharmacology, 41(2): 186–199. Yin, H.H., Knowlton, B.J. and Balleine, B.W. (2004) Lesions of the dorsolateral striatum preserve outcome expectancy but disrupt habit formation in instrumental learning. Eur. J. Neurosci., 19(1): 181–189. Yu, L. and Liao, P.C. (2000) Estrogen and progesterone distinctively modulate methamphetamine-induced dopamine and serotonin depletions in C57BL/6J mice. J. Neural. Transm., 107(10): 1139–1147. Zahrt, J., Taylor, J.R., Mathew, R.G. and Arnsten, A.F. (1997) Supranormal stimulation of D1 dopamine receptors in the rodent prefrontal cortex impairs spatial working memory performance. J. Neurosci., 17(21): 8528–8535. Zakzanis, K.K., Campbell, Z. and Jovanovski, D. (2007) The neuropsychology of ecstasy (NDMA) use: a review. Hum. Psychopharmacol., 22(7): 427–435. Zheng, P., Zhang, X.X., Bunney, B.S. and Shi, W.X. (1999) Opposite modulation of cortical N-methyl-D-aspartate receptor-mediated responses by low and high concentrations of dopamine. Neuroscience, 91(2): 527–535. Zhou, F.M. and Hablitz, J.J. (1999) Activation of serotonin receptors modulates synaptic transmission in rat cerebral cortex. J. Neurophysiol., 82(6): 2989–2999.