The psychogenetically selected Roman high- and low-avoidance rat lines: A model to study the individual vulnerability to drug addiction

ARTICLE IN PRESS

Neuroscience and Biobehavioral Reviews 31 (2007) 148–163 www.elsevier.com/locate/neubiorev

Review

The psychogenetically selected Roman high- and low-avoidance rat lines: A model to study the individual vulnerability to drug addiction Osvaldo Giorgi, Giovanna Piras, Maria G. Corda Department of Toxicology, University of Cagliari, Via Ospedale, 72, 09124 Cagliari, Italy Received 21 July 2006; accepted 22 July 2006

Abstract The Roman high- (RHA) and low-avoidance (RLA) rat lines were selected for, respectively, rapid vs poor acquisition of two-way active avoidance in the shuttle-box. Here, we review experimental evidence indicating that, compared with their RLA counterparts, RHA rats display a robust sensation/novelty seeking profile, a marked preference and intake of natural or drug rewards, and more pronounced behavioral and neurochemical responses to the acute administration of morphine and psychostimulants. Moreover, we show that (i) the repeated administration of morphine and cocaine elicits behavioral sensitization in RHA, but not RLA, rats, (ii) in sensitized RHA rats, acute morphine and cocaine cause a larger increment in dopamine output in the core, and an attenuated dopaminergic response in the shell of the nucleus accumbens, as compared with RHA rats repeatedly treated with saline, and (iii) such neurochemical changes are not observed in the mesoaccumbens dopaminergic system of the sensitization-resistant RLA line. Behavioral sensitization plays a key role in several cardinal features of addiction, including drug craving, compulsive drug seeking and propensity to relapse following detoxification. Comparative studies in the Roman lines may therefore represent a valid approach to evaluate the contribution of the genotype on the neural substrates of drug sensitization and addiction. r 2006 Elsevier Ltd. All rights reserved. Keywords: Morphine; Cocaine; Amphetamine; Genetic animal models of drug addiction; Dopamine; Nucleus accumbens core and shell; Opiate and psychostimulant sensitization; Brain dialysis; Roman high- and low-avoidance rats

Contents 1. 2. 3. 4. 5. 6. 7.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Phenotypic traits of the Roman lines. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acute effects of addictive drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Behavioral sensitization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Differential effects of repeated treatments with addictive drugs on dopaminergic transmission in the NAc of RHA and RLA rats . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Functional and pathologic implications of the adaptive changes in mesolimbic dopaminergic transmission associated with behavioral sensitization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Corresponding author. Tel.: +39 070 675 8631; fax: +39 070 675 8612.

E-mail address: [email protected] (O. Giorgi). 0149-7634/$ - see front matter r 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.neubiorev.2006.07.008

. . . .

. . . .

. . . .

. . . .

. . . .

. . . .

149 149 150 151

. . . . . . 153 . . . .

. . . .

. . . .

. . . .

. . . .

. . . .

157 159 160 160

ARTICLE IN PRESS O. Giorgi et al. / Neuroscience and Biobehavioral Reviews 31 (2007) 148–163

1. Introduction Drug addiction is a chronically relapsing disorder characterized by compulsive drug seeking and drug taking behavior despite severe adverse consequences (Leshner, 1997). There is a remarkable individual variation in the risk that casual users of addictive drugs may progress to a condition of continued and uncontrollable drug use; thus, only a small percentage of people exposed to drugs eventually become addicted according to the criteria for substance use disorders described in the Diagnostic and Statistical Manual of Mental Disorders (American Psychiatric Association, 1994; O’Brien and McLellan, 1996). Clinical studies have shown an association between some personality traits and the liability to substance abuse. For instance, there is considerable evidence that individuals with high scores for sensation/novelty seeking-related traits are at increased risk for using drugs of abuse relative to individuals with low scores in the same traits (Verheul and van den Brink, 2000). It is well established that the dopaminergic neurons originating in the ventral tegmental area (VTA) and projecting to the nucleus accumbens (NAc) play a key role in mediating the rewarding properties of drugs of abuse. Thus, either upon non-contingent treatment or when self-administered, most addictive drugs that differ in their primary molecular target share the ability to increase the extracellular concentration of dopamine (DA) in the NAc of experimental animals (for a review, see Pierce and Kumaresan, 2005). Dopaminergic transmission in the NAc is also critically involved in behavioral sensitization, a process characterized by the progressive augmentation of the motor activation induced by psychostimulants and opiates resulting from repeated drug administration. Accordingly, a large body of experimental evidence indicates that alterations in the mesolimbic DA system as well as in the glutamatergic neurons located in the medial prefrontal cortex (mPFCX), amygdala (AMYG), and hippocampus (HIPP) and projecting to the VTA and NAc contribute to the development and maintenance of behavioral sensitization (Vanderschuren and Kalivas, 2000; Kalivas et al., 2005). Notably, sensitization appears to be critically involved in some of the persistent features of addiction, such as drug craving, compulsive drug seeking behavior and propensity to relapse (Robinson and Berridge, 2001; Everitt and Wolf, 2002). The data from behavior genetic studies demonstrate that phenotypic variation in the liability to addiction is determined by differences in individual genotypes and in their interactions with different environmental conditions (Vanyukov and Tarter, 2000; Uhl et al., 2002). Accordingly, genetic factors account for 40–60% of risk in alcoholism, and similar rates of heritability have been demonstrated for addiction to opiates and psychostimulants (Reich et al., 1999; Nestler, 2000). Genetic factors also have a major influence in determining temperament and personality traits, including sensation/novelty seeking

149

in humans as well as in laboratory animals (Bardo et al., 1996; Ebstein et al., 2000; Vanyukov and Tarter, 2000). The complex heritability pattern of addiction is determined by multiple genes (i.e., is polygenic) and, to date, no specific associations between genes or gene markers and any of the different classes of addictive disorders have been identified with certainty. In turn, the limited information concerning the genetic underpinnings of addiction represents a major hurdle for the development of genetic animal models with heuristic value. Nevertheless, much effort has been dedicated in recent years to the characterization of valid animal models for studying the impact of the genetic background on the neural substrates of drug abuse and addiction (Crabbe, 2002; Laakso et al., 2002). One such model, the Roman high- (RHA) and low-avoidance (RLA) rat lines, were selected for, respectively, rapid vs poor acquisition of two-way active avoidance in the shuttle-box (Driscoll, 1986; Driscoll et al., 1998). This breeding process has generated two well-characterized phenotypes showing drastic differences in the responsiveness to aversive and rewarding stimuli (D’Angio et al., 1988; Ferre´ et al., 1995; Ferna´ndez-Teruel et al., 2002a, b; Giorgi et al., 2003), as well as in the susceptibility to the acute effects of addictive drugs on motor behavior and mesotelencephalic dopaminergic transmission (Giorgi et al., 1997, 2005b; Lecca et al. 2004; Piras et al., 2003). In the following sections, we examine experimental evidence supporting the view that comparative studies in the Roman lines represent a valid experimental approach to assess the influence of the genotype on the neural and behavioral traits involved in the major features of the individual vulnerability to addiction, including high sensitivity to drugs of abuse at the first exposure and the development of sensitization upon repeated administration. 2. Phenotypic traits of the Roman lines The selective breeding of the RHA and RLA rats for, respectively, rapid vs extremely poor acquisition of active avoidance in a shuttle box was started in Rome in 1965, using a stock of Wistar rats (Broadhurst and Bignami, 1965). In 1972, colonies of outbred RHA/Verh and RLA/ Verh rats were established in Switzerland (Driscoll and Ba¨ttig, 1982). It is noteworthy that, in both laboratories, the performance of randomly bred Wistar controls in the shuttle box was intermediate, suggesting that the Roman lines are the result of bidirectional selection for avoidance responding (Broadhurst and Bignami, 1965; Driscoll and Ba¨ttig, 1982). More recently, breeding nuclei from the Swiss sublines were used to establish other colonies, including in Cagliari (Giorgi et al., 2005b), from which the animals used in the present study were obtained. Three generations of outbred rats are produced per year in our colony and the stability of the selected phenotypes is tested every third generation in male and female rats from each litter. Currently, in the first 40-trial session, RHA rats

ARTICLE IN PRESS 150

O. Giorgi et al. / Neuroscience and Biobehavioral Reviews 31 (2007) 148–163

average about 25 avoidance responses, whereas animals from the RLA line average less than 1 (Giorgi et al., 2005b). During the selective breeding of more than 100 generations of Roman rats, many other differences between these two lines have been identified. Thus, in a variety of tests used to assess emotionality and coping styles in rodents, RHA rats display ‘‘proactive’’ coping strategies associated with low intensity hypothalamuspituitary-adrenal (HPA) axis responses, whereas their RLA counterparts show a ‘‘reactive’’ coping pattern characterized by fear-related behaviors, like freezing and self-grooming, and elevated HPA axis reactivity (Driscoll et al., 1998; Escorihuela et al., 1995; Ferna´ndez-Teruel et al., 2002b; Giorgi et al., 2003; Koolhaas et al., 1999; Steimer and Driscoll, 2003; Steimer et al., 1997). There is also experimental evidence indicating that the RHA line is a valid model to investigate the neural basis of novelty (or sensation) seeking behavioral traits. In the hole board test in the presence of novel objects, a paradigm used to assess novelty seeking, RHA rats show a more robust exploratory behavior than RLA rats (Escorihuela et al., 1999; Ferna´ndez-Teruel et al., 2002a). Moreover, during the acquisition of a DRL-20 task, RHA rats display significantly higher impulsivity than their RLA counterparts, suggesting a reduced ability to inhibit irrelevant behaviors (Zeier et al., 1978). Lastly, RHA rats, like humans with high sensation seeking behavioral scores, show increasing amplitudes (i.e., augmenting) of the P1 component of the visual-evoked potential (VEP) to increasing intensities of light flash, whereas RLA rats, as well as low sensation seekers, display decreasing VEP amplitudes as a function of increasing flash intensity (Siegel et al., 1993; Zuckerman, 1996). Interestingly, the VEPreducing pattern of RLA rats in this paradigm is similar to that observed in non-selected Wistar rats (Siegel et al., 1993). Several lines of evidence support the view that the behavioral patterns that distinguish the Roman lines may be mediated, at least in part, by differences in the functional properties of their mesotelencephalic dopaminergic projections: (1) in vivo voltammetry and microdialysis studies have shown that a variety of stressors and anxiogenic drugs activate the mesocortical dopaminergic pathway of RHA, but not of RLA, rats (D’Angio et al., 1988; Giorgi et al., 2003), (2) RHA rats have a faster turnover rate of DA in the caudate nucleus (Driscoll et al., 1990) and display more intense stereotypies in response to an acute challenge with the DA receptor agonist apomorphine (Driscoll et al., 1985; Gimenez-Llort et al., 2005) than do RLA rats, and (3) binding studies indicate that the density of DA D1 receptors in the NAc is higher in RHA rats than in their RLA counterparts (Giorgi et al., 1994). Altogether, these findings suggest that the selective breeding of the Roman lines for extreme performances in the acquisition of avoidant behavior in the shuttle box has produced two phenotypes that consistently differ in the functional properties of the dopaminergic system. Of

interest in this context, recent studies in gerbils indicate that a transient increment in DA output in the medial prefrontal cortex (mPFCX) is required for the acquisition of the avoidant behavior in the shuttle-box, a process whereby the comparison of foregoing cognitive information to incoming information leads to the formation of an adequate behavioral response, that is, a coping strategy (Stark et al., 2004). Importantly, the increase in cortical DA output is positively correlated to the performance in this task: gerbils showing a marked improvement in avoidances during the acquisition phase also have a more robust increment in DA efflux in the mPFCX as compared with poor performers. Although similar studies have not been performed in Roman rats, it is plausible that the acquisition of active avoidance by RHA rats, which is the major criterion for selective breeding (Driscoll, 1986; Driscoll and Ba¨ttig, 1982; Giorgi et al., 2005b), may be causally related to a more robust dopaminergic tone of this line. 3. Acute effects of addictive drugs The Roman lines also differ in their behavioral and neurochemical responses to a variety of drugs of abuse. Brain microdialysis experiments have shown that the acute administration of morphine (0.5 mg/kg, s.c.), cocaine (5 mg/kg, i.p.) or amphetamine (0.15 mg/kg, i.p.) elicits a larger increment in DA output in the NAc shell than in the NAc core of RHA rats, whereas no significant differences in the neurochemical dopaminergic responses are observed between the accumbal compartments of RLA rats. Moreover, the magnitude of the dopaminergic responses in the NAc-core of RHA rats is statistically undistinguishable from that observed in the NAc-core and NAc-shell of their RLA counterparts (Lecca et al., 2004; Giorgi et al., 2005b). This line-related difference in the responsiveness of the mesolimbic dopaminergic projections is associated with a more robust, drug-induced increase in ambulatory and stationary (i.e., rearing, sniffing, and licking/gnawing) activities in RHA rats than in their RLA counterparts (Giorgi et al., 1997, 2005b; Lecca et al, 2004). Because of its well-established role as a neural interface, where information processing in the corticolimbic structures is integrated and related to the output motor systems, the NAc is considered to play a critical role in motivated behaviors (Bardo, 1998; Parkinson et al., 1999; Everitt et al., 2001). The NAc can be parcelled into the dorsolateral core and the ventromedial shell subdivisions (see Fig. 1), which can be dissociated immunocytochemically (JongenReˆlo et al., 1994) and on the basis of their differential patterns of connectivity (Heimer et al., 1991): the core projects to motor-output nuclei like the globus pallidus and the dorsolateral ventral pallidum, whereas the shell is predominantly connected with limbic structures such as the VTA, lateral hypothalamus, ventromedial ventral pallidum and brainstem autonomic centers (Zahm, 2000). Such hodological differences suggest that the accumbal

ARTICLE IN PRESS O. Giorgi et al. / Neuroscience and Biobehavioral Reviews 31 (2007) 148–163

Fig. 1. Atlas diagram showing the brain areas implanted with vertical microdialysis probes. The position of the active portion of the probes corresponding to the animals that were used for statistical analyses is schematically indicated by the gray bars which, for the clarity of presentation, are drawn in the right hemisphere for the NAc-shell and on the left hemisphere for the NAc-core. A single dialysis probe was implanted either in the NAc-shell or in the NAc-core of each rat, using the following stereotaxic coordinates (according to Paxinos and Watson, 1998): NAc-shell, A, +2.0 mm; L, 70.9 mm from bregma and V, 7.8 mm from dura; NAc-core, A, +1.6 mm; L, 71.6 mm from bregma; V, 7.2 from dura. The A–P coordinates are shown on the left side of each coronal section. Abbreviations: Co, NAc-core; Sh, NAc-shell; ca, anterior commissure; cc, corpus callosum; CPU, nucleus caudatus-putamen.

151

studies showing that opiates and psychostimulants, at doses that sustain intravenous self administration, produce a larger increase in the extracellular concentration of DA in the NAc-shell as compared with the core (Pontieri et al., 1995). The NAc-shell also plays a pivotal role in drugstimulated locomotion: in rats, local microinfusions of DA, D-1 DA receptor agonists and amphetamine into this accumbal subregion elicit robust locomotor activation (Swanson et al., 1997; Heidbreder and Feldon, 1998). Consistent with these findings, the motor activation induced by low doses of morphine and psychostimulants in RHA rats is associated with a preferential increase of DA output in the NAc-shell. In contrast, in RLA rats, the lack of a preferential enhancement in DA output in the NAc-shell relative to the NAc-core is associated with a blunted motor response to cocaine and with no significant change in spontaneous motor activity after the systemic administration of morphine and amphetamine (Lecca et al., 2004; Giorgi et al., 2005b). The line-related differences in the responsivity of mesolimbic dopaminergic transmission to drugs of abuse suggest that the Roman lines differ in the functional properties of neural circuits of reward. Several lines of evidence support this view. Firstly, in a two-bottle ethanol/water free choice paradigm, the RHA line shows a significantly higher ethanol preference relative to the RLA line (Ferna´ndez-Teruel et al., 2002a). Notably, the low-ethanol preference of RLA rats is similar to that exhibited by most randomly bred rats (reviewed by Overstreet et al., 1997). Secondly, exposure to a natural reward, like palatable food, elicits a more robust behavioral response associated with a larger activation of dopaminergic transmission in the NAc-shell of RHA rats as compared with RLA rats (Giorgi et al., 1999). Thirdly, RHA rats respond at higher rates than RLA rats during acquisition of intravenous cocaine self administration (unpublished results, 2006). 4. Behavioral sensitization

compartments may subserve distinct aspects of adaptive behaviors. Thus, the NAc-shell appears to play a central role in mediating the impact of primary reinforcers, including food and drugs (Cardinal et al., 2002), whereas the NAc-core appears to be especially important for the ability of conditioned reinforcers to maintain instrumental actions (Ito et al., 2004). A substantial body of evidence indicates that the dopaminergic projection to the NAc shell is an important link in the neural networks involved in the rewarding properties of psychostimulants and opiates, evaluated by either the self-administration of the drug or in the conditioned place preference paradigm (Bardo, 1998; Wise, 2004). The finding that in RHA rats the NAc-shell is more responsive than the NAc-core to acutely administered morphine, cocaine and amphetamine (Lecca et al., 2004; Giorgi et al., 2005b) is therefore consistent with previous

It has been proposed that, in subjects that are susceptible to become addicted, dysfunctions of the neural circuits encoding brain reward and goal-directed behaviors may account for the enhanced responsiveness to initial drug exposure and for the persistent adaptations (i.e., drug seeking and drug craving) leading to compulsive drug intake upon repeated exposure (O’Brien and McLellan, 1996). The intensification of drug craving that occurs with repeated drug exposure is considered to be modeled by behavioral sensitization in rodents (for reviews, see Robinson and Berridge, 2001; Everitt and Wolf, 2002). Behavioral sensitization to opiates and psychostimulants is characterized by the progressive increase in ambulatory activity and in the frequency of more focused, non-ambulatory, behaviors such as sniffing, rearing, licking, and gnawing, following repeated drug treatments (Segal and Kuczenski, 1987; Pierce and Kalivas, 1997;

ARTICLE IN PRESS 152

O. Giorgi et al. / Neuroscience and Biobehavioral Reviews 31 (2007) 148–163

Vanderschuren et al., 1997). This increased response is believed to reflect long lasting adaptations in neural circuits involved in motivation and reward (Li et al., 2004; Nestler, 2001; Robinson and Berridge, 2001; Everitt and Wolf, 2002). Accordingly, repeated exposure to psychostimulants also facilitates drug self-administration (Horger et al., 1990; Piazza et al., 1990; Mendrek et al., 1998; Lorrain et al., 2000) and potentiates the responses to conditioned rewards (Shippenberg and Heidbreder, 1995; Taylor and Horger, 1999), suggesting that the sensitization process may enhance the incentive motivational properties of addictive drugs. Based on the differences in the behavioral and neurochemical responses to the acute administration of addictive drugs that distinguish RHA and RLA rats (see Section 3), we hypothesized that the Roman lines may also differ in the propensity to develop behavioral sensitization. Therefore, we compared the behavioral effects of repeated exposure to morphine, cocaine, and amphetamine in these lines. To this aim we used experimental designs that included multiple test sessions of each animal in automated motility meter cages, thereby allowing for simultaneous comparisons across three factors: (a) animal line, (b) drug sensitization within groups, that is, before (i.e. pre-test) vs after (i.e. challenge) repeated saline or drug treatment, and (c) drug sensitization between groups, that is, drug effect after repeated drug treatment vs drug effect after repeated saline injections. It is well known that the expression of behavioral sensitization is markedly influenced by the characteristics of the pretreatment regimen. Thus, repeated intermittent treatment with low or moderate doses of psychostimulants or opiates is more effective in inducing behavioral sensitization than chronic exposure to high drug doses (Post, 1980; Vanderschuren et al., 1997; Li et al., 2004). On the basis of these findings, we used the following treatment schedules: (1) morphine, 5, 10, and 20 mg/kg, s.c., twice daily in the first, second, and third day, respectively (Piras et al., 2003), (2) cocaine, 10 mg/kg, i.p., for 14 days (Giorgi et al., 2005a), and (3) amphetamine, 1 mg/kg, s.c., for 10 days (Corda et al., 2005). These treatment schedules have been consistently shown to induce robust behavioral sensitization in other rat strains (Wolf et al., 1993; Henry and White, 1995; Cadoni and Di Chiara, 1999; Cadoni et al., 2000). Two major features of behavioral sensitization are its long-term character and the marked neurochemical differences observed between short- and long-term withdrawal periods (Henry and White, 1995; Pierce and Kalivas, 1997; Tjon et al., 1997). Accordingly, most authors distinguish two phases in the development and maintenance of the sensitization process: the initial induction phase, which takes place during repeated exposure to opiates and psychostimulants, or shortly thereafter, and the subsequent expression phase, which occurs at longer withdrawal periods (i.e., 47 days) (for reviews, see Pierce and Kalivas, 1997; Vanderschuren and Kalivas, 2000). We therefore

assessed the effects of challenge doses of morphine, cocaine, and amphetamine during the expression phase, when sensitized motor and neurochemical responses to these drugs are more intense (Paulson and Robinson, 1995; Pierce and Kalivas, 1997; Vanderschuren et al., 1999). The results of our experiments consistently indicated that the Roman lines differ drastically in the ability to develop behavioral sensitization to morphine and psychostimulants. Thus, in RHA rats, the morphine challenge (0.5 or 2 mg/kg, s.c., 21 days after withdrawal) produced a significantly larger motor activation in the group that had been repeatedly treated with morphine as compared with both, the control, repeated saline, group (which was also challenged with morphine) and the group tested with morphine 1 day before the beginning of the repeated treatment schedule (i.e., pre-test). At variance with these findings, in the RLA line, the motor activation elicited by the morphine challenge in animals repeatedly treated with morphine did not differ significantly from those observed either following the morphine challenge in the control (repeated saline) group or after the first exposure to morphine in the pre-test (see Piras et al., 2003 for details). Similar results were obtained with psychostimulants: when challenged with cocaine (5 or 10 mg/kg, i.p., after an 8-day withdrawal period), RHA rats that had received repeated cocaine injections exhibited significantly enhanced locomotor responses relative to their respective salinepretreated controls. Sensitization within the repeated cocaine treatment group was also evident, since RHA rats showed a more robust locomotor response to cocaine in the challenge session relative to their first exposure in the pretest. In contrast, this repeated treatment schedule was not able to induce sensitized ambulatory responses to either dose of cocaine in RLA rats (Giorgi et al, 2005a). Likewise, sensitized locomotor responses to challenge doses of amphetamine (0.125 and 0.25 mg/kg, s.c., 12 days after withdrawal) were observed only in RHA rats (Corda et al., 2005). It has been known for a long time that experimental animals exhibit considerable individual variation in the behavioral sensitization produced by the repeated administration of addictive drugs: some individuals appear to be very sensitive and others quite resistant to the sensitizing effects of psychostimulants (for review, see Robinson and Berridge, 2001). For instance, in a population of nonselected Sprague-Dawley rats, only 50–75% of animals receiving daily cocaine for a week developed behavioral sensitization as defined by an increase in locomotor activity (i.e., horizontal photocell counts) on day 7 compared with day 1 of daily injection (Pierce et al., 1996). These results are quite different from those observed in the Roman lines. Thus, using the same criterion to define sensitization to cocaine, we found that 490% of RHA rats could be classified as sensitized as compared with o10% of RLA rats fulfilling the criterion (not shown). These findings support the notion that the breeding program of RHA and RLA rats has produced a marked bidirectional selection of

ARTICLE IN PRESS O. Giorgi et al. / Neuroscience and Biobehavioral Reviews 31 (2007) 148–163

traits that influence the propensity to develop behavioral sensitization upon repeated exposure to psychostimulants. Therefore, in contrast with the considerable individual variability observed in most nonselected rat strains, the RHA and RLA lines represent, respectively, two homogeneous populations of sensitization-prone and sensitization-resistant rats that provide a valid experimental approach to evaluate the enduring neural adaptations underlying behavioral sensitization. 5. Differential effects of repeated treatments with addictive drugs on dopaminergic transmission in the NAc of RHA and RLA rats The findings reviewed in the previous section indicate that the RHA line, which displays more robust behavioral and neurochemical dopaminergic responses to morphine and psychostimulants at the first exposure as compared to the RLA line, is also more susceptible to develop behavioral sensitization upon repeated exposure to these drugs. A large body of experimental evidence supports the notion that multiple neuroadaptive changes play a critical role in the induction and long-term expression of behavioral sensitization to opiates and psychostimulants. Many of these plastic alterations have been observed in the dopaminergic neurons innervating the NAc and in their afferent and efferent neural connections, which are major components of the limbic circuitry involved in the control of motivated behavior (Robinson et al., 1988; Kalivas and Duffy, 1993; Spanagel et al., 1993; Paulson and Robinson, 1995; Pierce and Kalivas, 1997; Vanderschuren and Kalivas, 2000). However, studies designed to assess the specific roles of accumbal subregions in the sensitization to addictive drugs have yielded contrasting results: though some reports support a preferential augmentation in dopaminergic transmission (Cadoni and Di Chiara, 1999; Cadoni et al., 2000) and FOS expression in the NAc-core (He´dou et al., 2002), other results argue for predominant adaptive alterations in the NAc-shell (Pierce and Kalivas, 1995; Phillips et al., 2003). It was therefore considered of

153

interest to evaluate the presynaptic changes in accumbal dopaminergic transmission elicited by repeated treatments with morphine and cocaine in sensitization-prone RHA rats as compared with their sensitization-resistant RLA counterparts. To this aim, we used the repeated treatment schedules described in the previous section. Morphine: animals were treated twice daily (at 8:00 and 20:00) with escalating doses of morphine (5, 10, and 20 mg/kg, s.c., on the first, second, and third day, respectively) and controls were injected with an equivalent volume of saline (1 ml/kg, s.c.). Cocaine: animals received cocaine injections (10 mg/ kg, i.p.) or an equivalent volume of saline (2 ml/kg) once daily, for 14 consecutive days. Twenty days after the last morphine injection and 7 days after the last cocaine injection, a single dialysis probe was implanted in the NAccore or in the NAc-shell of each rat (Fig. 1). The effects of challenge injections with drugs or saline on the extracellular concentrations of DA were assessed ffi20–24 h later by HPLC with electrochemical detection, as previously described (Giorgi et al., 2005b). Moreover, animal behavior was monitored alongside dialysate sample collection using the previously described time sampling method (Lecca et al., 2004). Multifactor ANOVA of the baseline DA output values of all the experimental groups in this study showed no significant effect of animal line, accumbal compartment, treatment schedule or the interaction between these three factors (P40:05, see Table 1). This finding suggests that the repeated injections of morphine and cocaine did not alter the basal functional state of the dopaminergic projections to the NAc-shell and NAc-core of either line at the time points after withdrawal examined in our experiments. Similar results were obtained in a previous study using the ‘‘no net flux’’ method to determine the extracellular concentration of DA in the NAc, 14 days after discontinuing the repeated cocaine treatment (Kalivas and Duffy, 1993). The repeated treatment with morphine produced different modifications in the neurochemical responses to a subsequent drug challenge, depending on rat line and

Table 1 Baseline DA output in the NAc-shell and NAc-core of RHA and RLA rats repeatedly treated with morphine, cocaine or saline Experimental groups Morphine sensitization Repeated saline

NAc-core NAc-shell

Cocaine sensitization Repeated morphine

Repeated saline

Repeated cocaine

RHA

RLA

RHA

RLA

RHA

RLA

RHA

RLA

7878 (16) 8579 (14)

8777 (16) 9478 (12)

8577 (16) 8877 (14)

8075 (17) 9178 (12)

8179 (12) 7978 (15)

9078 (14) 7878 (14)

9176 (14) 8578 (15)

9079 (11) 8477 (14)

Results are expressed as the mean7SEM fmol/20 ml of dialysate. The number of animals in each experimental group is indicated in parenthesis. Only the baseline DA output values obtained from 116 RHA rats and 110 RLA rats, in which the correct placement of the dialysis probe was confirmed by direct observation of coronal brain slices prepared with a microtome, were used for data analyses. The data were compared by multifactor ANOVA [between groups factors: (i) line (i.e., RHA vs RLA), (ii) brain area (i.e., NAc-shell vs NAc-core), and (iii) treatment (i.e., saline or drug challenge after repeated saline treatment vs saline or drug challenge after repeated drug treatment]. The P values for the three main factors and their interactions were 40.05.

ARTICLE IN PRESS O. Giorgi et al. / Neuroscience and Biobehavioral Reviews 31 (2007) 148–163

154

control RHA group that had received daily saline (maximum effect: +44%) and with both RLA groups (Fig. 2, upper panels). On the other hand, there was no significant difference in DA output between the RLArepeated morphine group and the RLA-repeated saline group (respective maximum effects: +38% and +36%). Fig. 2 (lower panels) also shows that, in the NAc-shell, the increment in DA output was less pronounced in the RHArepeated morphine group (maximum effect: +39%) compared with the RHA-repeated saline group (maximum effect: +68%), with no significant difference in DA output between the RLA-repeated morphine group and the RLA-

accumbal subregion. Thus, multifactor ANOVA revealed significant effects (Po0:001) of (1) animal line and (2) time after the challenge; moreover, the following interactions also were significant (Po0:001): (1) brain area  repeated treatment, (2) line  time, (3) line  brain area  repeated treatment, (4) brain area  repeated treatment  time, and (5) line  brain area  repeated treatment  time. Importantly, pair wise post hoc comparisons indicated that the challenge with morphine induced a larger increment in DA output in the NAc-core of RHA rats that had received repeated morphine injections (maximum effect: +67% over the respective baseline value) as compared with the

SAL - SAL

SAL - MORPH

MORPH - SAL

MORPH - MORPH CORE 200

200

DOPAMINE OUTPUT (% of baseline)

RHA

RLA

150

150

100

100 -60

0

60

120

-60

180

0

60

120

180

120

180

SHELL 200

200 RHA

RLA

150

150

100

100 -60

0

60 MINUTES

120

180

-60

0

60 MINUTES

Fig. 2. Effects of a challenge with saline or morphine on DA output in the NAc-core and NAc-shell of rats repeatedly treated with drug or saline. The plots show the time course for DA output in the NAc-core (upper panels) and NAc-shell (lower panels). For each line and accumbal subregion, there were four treatment conditions (SAL–SAL, MORPH–SAL, SAL–MORPH, and MORPH–MORPH), with the repeated treatment indicated first and the challenge injection second. Results are expressed as a percent of the respective baseline values and are the mean7SEM of four animals in each saline challenge group and 8–13 animals in each morphine challenge group. Saline or morphine (0.5 mg/kg, i.p.; 1 ml/kg) were injected at the arrow. The eight saline-challenged groups were analyzed separately from the other eight morphine-challenged groups. Statistical comparisons were based on multifactor ANOVA for repeated measures over time after the challenge with saline or morphine. Main factors: (1) animal line (i.e., RHA vs RLA), (2) brain area (i.e., NAc-core vs NAc-shell), (3) repeated treatment (i.e., saline vs morphine). Solid symbols (K; ’): Po0:05 vs the respective baseline value; *: Po0:05 vs the time-matched value for the repeated saline-treated RHA group challenged with morphine (post hoc HSD Tukey test).

ARTICLE IN PRESS O. Giorgi et al. / Neuroscience and Biobehavioral Reviews 31 (2007) 148–163

repeated saline group (respective maximum effects: +39% and +37%). To the contrary, in both Roman lines, a saline challenge failed to modify the baseline DA output in either accumbal compartment (Fig. 2); consistent with this result, the frequency of ambulatory and stationary activities following the saline challenge was negligible in both lines (Fig. 3). In agreement with the data described in the previous section, the behavioral activation after the morphine challenge of RHA rats that had been repeatedly treated with the same drug was significantly more intense than that observed in line-matched animals that had received repeated saline, whereas no significant behavioral sensitization was observed in the RLA line (Fig. 3). Thus, statistical analysis of both, ambulatory and stationary activities, showed significant differences (Po0:05) for the main factors: (1) line, (2) repeated treatment, and (3) challenge with saline or morphine, as well as for the interactions: (1) line  challenge, (2) line  repeated treatment, (3) repeated treatment  challenge, and (4) line  repeated treatment  challenge. The results of the cocaine experiments are consistent with those obtained with morphine. Thus, as shown in Fig. 4 (upper panels), the challenge with cocaine elicited a larger increase in DA output in the NAc-core of RHA rats that had received repeated cocaine injections (peak effect: +105% at 40 min over the respective baseline value)

AMBULATORY ACTIVITY

15

155

as compared with the control RHA group that had received daily saline (peak effect: +63% at 40 min). To the contrary, the lower panels in Fig. 4 show that the increment in DA output in the NAc-shell was less pronounced in the RHA-repeated cocaine group (peak effect: +74% at 40 min) than in the RHArepeated saline group (peak effect: +122% at 40 min). On the other hand, in the NAc-core and NAc-shell of RLA rats, no significant difference in DA output was observed between the repeated cocaine group and the repeated saline group (respective peak effects at 40 min: NAc-core, +52% and +48%; NAc-shell, +77% and +67%; see Fig. 4). Furthermore, the cocaine challenge elicited a greater behavioral activation in RHA rats that had been repeatedly treated with the same drug as compared with RHA controls that had received repeated saline. In contrast, the repeated treatment with cocaine failed to induce behavioral sensitization in the RLA line (Fig. 5). Accordingly, statistical analysis of both, ambulatory and stationary activities, showed significant differences (Po0:05) for the main factors: (1) line, (2) repeated treatment, and (3) challenge with saline or cocaine; in addition, also the following interactions were significant (Po0:025): (1) line  challenge, (2) line  repeated treatment, (3) repeated treatment  challenge, and (4) line  repeated treatment  challenge.

STATIONARY ACTIVITY

20

RHA § * †

EPISODES / 3h

RLA

§ * † 15

10

10

5

. 5

0

0 (8) (8) CH :

SAL

(22) (20) MORPH

REPEATED SAL

(8) (8) SAL

(22) (21) MORPH

REPEATED MORPH

(8) (8)

(22) (20)

SAL MORPH REPEATED SAL

(8) (8) SAL

(22) (21) MORPH

REPEATED MORPH

Fig. 3. Effects of a challenge with saline or morphine on motor activity of rats repeatedly treated with drug or saline. The bar diagrams show the mean7SEM total number of ambulatory episodes/3 h (left panel) and stationary (i.e., sniffing+rearing+licking/gnawing) behavioral episodes/3 h (right panel) that were recorded in the same animals from which the brain microdialysis data shown in Fig. 2 were obtained, using the time sampling method described elsewhere (Giorgi et al., 2005b). The number of rats in each experimental group is indicated in parentheses at the base of the columns. The data were compared by multifactor ANOVA. Main factors: (1) animal line, (2) repeated treatment, and (3) challenge with saline or morphine. *: Po0.05 vs the treatment-matched RLA group; y: Po0:05 vs the line-matched group challenged with saline; y: Po0:05 vs the RHA group challenged with morphine after repeated treatment with saline (post hoc contrasts with the HSD Tukey test). Abbreviation: CH, challenge.

ARTICLE IN PRESS O. Giorgi et al. / Neuroscience and Biobehavioral Reviews 31 (2007) 148–163

156

SAL - SAL

SAL - COC

COC - SAL

COC - COC

CORE RHA

DOPAMINE OUTPUT (% of baseline)

250

200

200

150

150

100

100 -60

0

60

120

180

-60

200

200

150

150

100

100 -60

0

60

0

SHELL 250

RHA

250

RLA

250

120

180

MINUTES

60

120

180

120

180

RLA

-60

0

60

MINUTES

Fig. 4. Effects of a challenge with saline or cocaine on DA output in the NAc-core and NAc-shell of rats repeatedly treated with drug or saline. The plots show the time course for DA output in the NAc-core (upper panels) and NAc-shell (lower panels). For each line and accumbal subregion, there were four treatment conditions (SAL–SAL, COC–SAL, SAL–COC, and COC–COC), with the repeated treatment indicated first and the challenge injection second. Results are expressed as a percent of the respective baseline values and are the mean7SEM of four animals in each saline challenge group and 7–11 animals in each cocaine challenge group. Saline or cocaine (5 mg/kg, i.p.; 1 ml/kg) were injected at the arrow. Statistical comparisons were based on multifactor ANOVA for repeated measures over time after the challenge with saline or cocaine, as described in the legend to Fig. 2. Solid symbols (K; ’): Po0:05 vs the respective baseline value; *: Po0:05 vs the time-matched value for the repeated saline-treated RHA group challenged with cocaine (post hoc HSD Tukey test).

In keeping with the results of the morphine and cocaine experiments, we have recently reported that following a repeated treatment with amphetamine a challenge dose of the same drug elicits a more robust increment in DA output in the NAc-core associated with an attenuated dopaminergic response in the NAc-shell of sensitizationprone RHA rats, whereas no significant changes in accumbal DA output are observed in sensitization-resistant RLA rats (Giorgi et al., 2005b). In most previous studies designed to characterize the neurochemical alterations associated with behavioral sensitization, a drug is given repeatedly and then, after a drug free period, the presence of any persistent

neuroadaptive changes is assessed in the brain of the sensitized animals. However, in such studies it is not possible to tell if any given drug-induced neuroadaptation is related specifically to the development of behavioral sensitization, or whether it is due to mere drug history. Therefore, the finding that the alterations in accumbal dopaminergic transmission elicited by chronic exposure to morphine and psychostimulants occur in sensitization-prone RHA rats, but not in sensitizationresistant RLA rats, provide experimental support to the hypothesis that such adaptive changes are causally related to the concomitant development of behavioral sensitization.

ARTICLE IN PRESS O. Giorgi et al. / Neuroscience and Biobehavioral Reviews 31 (2007) 148–163

AMBULATORY ACTIVITY

STATIONARY ACTIVITY § * †

20 RHA

157

RLA

50

§ * †

40

EPISODES / 3h

15

30 10 † 20 . 5 10

0

.. (8) (8)

CH :

SAL

(19) (20) COC

REPEATED SAL

(8) (8)

(21) (17)

SAL

COC

REPEATED COC

0

(8) (8)

(19) (20)

SAL

COC

REPEATED SAL

(8) (8) SAL

(21) (17) COC

REPEATED COC

Fig. 5. Effects of a challenge with saline or cocaine on motor activity of rats repeatedly treated with drug or saline. The bar diagrams show the mean7SEM total number of ambulatory episodes/3 h (left panel) and stationary behavioral episodes/3 h (right panel) that were recorded along dialysate sample collection after acute saline or cocaine in the same animals from which the brain microdialysis data shown in Fig. 4 were obtained. The number of rats in each experimental group is indicated in parentheses at the base of the columns. The data were compared by multifactor ANOVA as described in the legeng to Fig. 3. *: Po0:05 vs the treatment-matched RLA group; y: Po0:05 vs the line-matched group challenged with saline; y: Po0:05 vs the RHA group challenged with cocaine after repeated treatment with saline (post hoc contrasts with the HSD Tukey test). Abbreviation: CH, challenge.

6. Functional and pathologic implications of the adaptive changes in mesolimbic dopaminergic transmission associated with behavioral sensitization The opposite alterations in dopaminergic transmission in the NAc-core and NAc-shell of RHA rats elicited by the repeated exposure to addictive drugs may result from functional interactions between these accumbal subregions. Although the mechanisms and neural circuitry involved in such interactions are unclear at present, recent anatomical studies in primates suggest that striato-nigro-striatal (SNS) pathways form an ascending spiral from the NAc-shell to the dorsolateral striatum via the mesencephalic DA cells (Haber et al., 2000). These circuits represent a neural substrate of the limbic-cognitive-motor interface (Mogenson et al., 1993) whereby the NAc-shell and its limbic connections influence the motor output signals of the NAccore, and provide a theoretical framework to explain the present results. As discussed in Section 3, the dopaminergic projections from the VTA to the NAc-shell of RHA rats are more responsive to a novel stimulus, such as the initial injections of opiates or psychostimulants, as compared with the projections to the NAc-core (Fig. 6, left panel). When the same stimulus is presented repeatedly, however, the dopaminergic response of the NAc-shell is blunted as a result of a more robust inhibition mediated by the direct reciprocal loop, whereas the response of the NAc-core is

enhanced by the potentiated activity of the indirect disinhibitory spiral (Johnson and North, 1992, see Fig. 6, right panel). On the contrary, in RLA rats, the weaker responsivity of the mesolimbic dopaminergic projections to the initial injections of addictive drugs precludes the triggering of this sequence of events and the consequent development of behavioral sensitization. This interpretation is consistent with the view that the NAc-shell and NAc-core may be sequentially involved in the sensitization process. Thus, during the induction phase, the dopaminergic input to the NAc-shell may play a central role in associative learning mechanisms that provoke, via activation of SNS circuitry, long-term plastic changes in the dopaminergic projections to the NAc-core that account for the enduring nature of behavioral sensitization. Several lines of evidence are consistent with this interpretation and support the important role of the NAc-core in the longterm maintenance of opiate and psychostimulant sensitization. First, the results of studies using electrolytic and excitotoxin-induced lesions indicate that, although the NAc-shell plays an important role in the induction phase of psychostimulant sensitization (Todtenkopf et al., 2002a), the bilateral disruption of this accumbal subregion does not affect the long-term expression of sensitized responses to cocaine (Todtenkopf et al., 2002b). Second, chronic in vivo administration of cocaine elicits a significant depression of excitatory synaptic transmission

ARTICLE IN PRESS O. Giorgi et al. / Neuroscience and Biobehavioral Reviews 31 (2007) 148–163

158

BASELINE STATE

AMYG

mPFCX-v

SENSITIZED STATE

AMYG

mPFCX-d

HIPP

mPFCXv

mPFCXd

HIPP

Sh

SNS

SNS

circuit

circuit Sh

Co

Co

NAc

NAc

motor output

1

VTA

2

motor output

4

dt

vt

1

VTA

3

DA

2

4

dt

vt

3

GABA

GLU

Fig. 6. Putative adaptive changes in the neural circuitry of the NAc-core and NAc-shell induced by the repeated administration of morphine and psychostimulants. In this schematic diagram, line thickness reflects the functional tone of the dopaminergic (green) and GABAergic (black) neurons. The NAc-shell receives glutamatergic input (red arrows) primarily from the ventral compartment of the medial prefrontal cortex (mPFCX-v), amygdala (AMYG), and hippocampus (HIPP), whereas the NAc-core receives glutamatergic projections from the dorsal aspect of the medial prefrontal cortex (mPFCX-d). The dopaminergic projections from the VTA to the NAc-shell (1) are connected with GABAergic neurons (2) that project to the dorsal tier (dt) of the VTA, thereby forming a ‘‘direct’’ reciprocal inhibitory loop. The GABAergic neurons (2) of the NAc-shell also project to GABAergic interneurons (3) located in the ventral tier (vt) of the VTA, thereby forming an ‘‘indirect’’ disinhibitory spiral that modulates the firing rate of the dopaminergic neurons of the ventral tier (vt) of the VTA (4), which in turn feed forward to the NAc-core. The spiral continues through the SNS circuit (blue) with pathways originating in the NAc-core and projecting, via the substantia nigra, to the dorsolateral striatum and other motor output areas. Left: Baseline state. The dopaminergic projections from the VTA to the NAc-shell are more responsive to novel stimuli (i.e., the first injection of cocaine or morphine) than the projections to the NAc-core. Right: Sensitized state. The response of the dopaminergic innervation of the NAc-shell is blunted following repeated stimulation as a result of a more robust inhibition mediated by the direct reciprocal loop. In contrast, the activity of the indirect disinhibitory spiral is enhanced, which in turn facilitates burst firing of the dopaminergic neurons projecting to the NAc-core, thereby amplifying the motor output via the dorsolateral striatum.

in the NAc-shell during the expression phase of behavioral sensitization (Thomas et al., 2001). Third, bilateral excitotoxic lesions of the NAc-core profoundly impair the acquisition of drug-seeking behavior maintained by conditioned cues associated to the drug, whereas selective bilateral lesions of the NAc-shell fail to disrupt drug selfadministration or the acquisition of cocaine-seeking (Ito et al., 2004). Fourth, reversible inactivation of the NAc-core blocks cocaine-primed drug seeking behavior in an animal model of relapse (McFarland and Kalivas, 2001). Fifth, cocaine sensitization is associated with an increase in the density of dendritic spines in the NAc-core, but not in the NAc-shell (Li et al, 2004). Besides the mesolimbic dopaminergic projections, other neurotransmitter systems and brain areas that are part of the circuitry involved in the control of motivated behavior (reviewed by Pierce and Kalivas, 1997; Vanderschuren and Kalivas, 2000; Everitt and Wolf, 2002) may contribute to the adaptive changes elicited by the repeated exposure to

addictive drugs in RHA rats. Thus, the NAc not only conforms to the pattern of the SNS circuitry outlined in the previous section (Alexander et al., 1990; Haber et al., 2000), but is also connected with a large array of limbic structures, including the mPFCX, the HIPP, and the AMYG (see Fig. 6). The functional and pathological roles of several major components of these neural circuits have been identified in recent years (Cardinal et al., 2002; Chambers et al., 2003; Kalivas et al., 2005). Glutamatergic neurons of the dorsal compartment of the mPFCX project mainly to the NAccore whereas the NAc-shell receives fibers from the ventral mPFCX (Gorelova and Yang, 1997). Furthermore, glutamatergic output from the mPFCX to the VTA modulates the firing rate of DA neurons which project to the NAc. There is a growing consensus that these neural pathways are critically involved in sensitization and addiction. Thus, inactivation of the dorsal aspect of the mPFCX disrupts cocaine-induced (McFarland and Kalivas, 2001)

ARTICLE IN PRESS O. Giorgi et al. / Neuroscience and Biobehavioral Reviews 31 (2007) 148–163

and cue-induced (McLaughlin and See, 2003) reinstatement of extinguished drug seeking through interaction with glutamate-dependent mechanisms in the NAc-core (McFarland et al., 2003, 2004). These findings suggest that long-term exposure to drugs of abuse may alter the functional activity of frontal cortical areas involved in inhibitory response control. This results in an impaired ability to inhibit inappropriate unconditioned or conditioned responses elicited by drugs and by drug-related cues (Chambers et al., 2003; Jentsch and Taylor, 1999). Hence, it has been posited (Jentsch and Taylor, 1999) that two mutually interacting mechanisms are critically involved in the development and maintenance of behavioral sensitization and compulsive drug-seeking: on the one hand, an increase in the incentive motivational properties of the drug as a result of accumbal DA dysfunction (Robinson and Berridge, 2001) and, on the other hand, an impairment in the inhibitory control of behavior due to functional alterations of the frontal cortex (Chambers et al., 2003; Jentsch and Taylor, 1999; Robbins and Everitt, 1999). In keeping with this hypothesis, the growing body of convergent evidence outlined in the previous sections indicates that the functional properties of the mesolimbic and mesocortical dopaminergic projections that distinguish the Roman lines may play a key role in the more intense impulsivity, novelty- and drug-seeking behaviors displayed by RHA rats relative to their RLA counterparts. There is also considerable evidence that the firing patterns of neurons located in both the NAc and the mPFCX are influenced by glutamatergic inputs from the HIPP and the AMYG, suggesting that abnormalities in these structures may be involved in motivational disorders and addiction (Chambers et al., 2003). Thus, a dense glutamatergic projection originating in the ventral HIPP innervates the medial NAc (Groenewegen et al., 1987; Brog et al., 1993), and indirect connections from the HIPP to the mPFCX or ventral pallidal neurons, which in turn project to the VTA, are also involved in the control of dopaminergic transmission in the NAc (Floresco et al., 2001, 2003; Legault et al., 2000). Of particular interest in this context is the finding that electrical stimulation of the HIPP reinstates extinguished drug-seeking through interaction with glutamatergic neurotransmission in the VTA (Vorel et al., 2001). In addition, the AMYG has extensive reciprocal connections with sensory neocortical areas and the frontal lobes, and projects heavily to the NAc (reviewed by Cardinal et al., 2002). In keeping with this anatomical evidence, recent studies have shown that glutamatergic projections from the AMYG to the NAc strongly influence cocaine seeking behavior under the control of drugassociated conditioned reinforcers (Di Ciano and Everitt, 2004; McLaughlin and See, 2003). Collectively, these findings are consistent with the view that region-specific alterations in the reciprocal interactions between the mesotelencephalic dopaminergic projections and the glutamatergic limbic inputs may be critically involved in the adaptive changes in DA ouput in the

159

NAc-core and NAc-shell elicited by the repeated administration of addictive drugs to sensitization-prone RHA rats. Studies aimed at testing this hypothesis are under way in our laboratory. 7. Conclusions A major challenge for the neuroscience of drug addiction is to understand why some individuals undergo a transition from casual and recreational drug use to the compulsive patterns of drug seeking and drug-taking behavior, as well as the propensity to relapse, that are the hallmarks of addiction (O’Brien and McLellan, 1996; Koob et al., 2004). In this context, it is widely accepted that, besides drug pharmacodynamics, the environment and genetically determined predisposing factors also play a relevant role in the pathogenesis of addiction (Nestler, 2000; Vanyukov and Tarter, 2000). Hence, different animal models, including inbred strains or selected outbred lines of rodents, as well as gene knockouts, have been developed to evaluate how genes affect multiple responses to addictive drugs, and which of these behavioral and neurochemical responses share common genetic influences (Crabbe, 2002; Laakso et al., 2002; McClung and Nestler, 2003). The Roman lines represent one of these genetic animal models: during the selective breeding of more than 100 generations of RHA and RLA rats for, respectively, rapid vs poor acquisition of two-way active avoidance in the shuttle-box (Broadhurst and Bignami, 1965; Driscoll and Ba¨ttig, 1982), other phenotypic differences between these two lines have been identified. RHA and RLA rats differ drastically in their responsiveness to aversive and rewarding natural stimuli, as well as in the susceptibility to the acute and chronic effects of addictive drugs. The studies reviewed in the present article support the view that the behavioral traits that distinguish the Roman lines are at least partly mediated by differences in the functional properties of their mesocortical and mesolimbic dopaminergic projections. Our findings also suggest that experimental subjects that are more responsive to the acute effects of addictive drugs, such as RHA rats, are also more susceptible to develop behavioral sensitization upon repeated drug exposure, a situation that resembles clinical observations. Accordingly, it has been proposed that: ‘‘individuals for whom the initial psychological responses to the drug are extremely pleasurable may be more likely to repeat the drug taking and some of them will develop an addiction’’ (O’Brien and McLellan, 1996). Given the postulated role of sensitization in compulsive drug intake (Robinson and Berridge, 2001), our results add to the view that the individual susceptibility to develop drug addiction is influenced by genetically determined functional patterns of the mesocortical and mesolimbic dopaminergic system and associated neural circuits encoding brain reward and goal-directed behaviors. These dysfunctional brain circuits may account for the enhanced responsiveness of the individual to initial drug exposure and for the adaptations

ARTICLE IN PRESS 160

O. Giorgi et al. / Neuroscience and Biobehavioral Reviews 31 (2007) 148–163

leading to compulsive drug intake that occur upon repeated exposure. In closing, we propose that the Roman lines represent a valid model to investigate the contribution of the genotype, and its interactions with environmental factors, on the neural substrates of drug sensitization and addiction. Comparative studies on the effects of stressors and repeated treatments with addictive drugs in self-administration, conditioned place preference, or reinstatement paradigms (Shaham et al., 2003) in the Roman lines may therefore further our understanding of the mechanisms by which the mesocortical and mesolimbic dopaminergic projections and related circuitry lower the threshold of drug exposure required to trigger the transition from casual to addictive drug use. Acknowledgements This work was supported by grants to O.G. from Ministero dell’Universita` e della Ricerca Scientifica (MIUR) and to M.G.C. from the Government of the Autonomous Region of Sardinia (R.A.S.). References Alexander, G.E., Crutcher, M.D., DeLong, M.R., 1990. Basal gangliathalamocortical circuits: parallel substrates for motor, oculomotor, ‘‘prefrontal’’ and ‘‘limbic’’ functions. Progress in Brain Research 85, 119–146. American Psychiatric Association, 1994. Diagnostic and Statistical Manual of Mental Disorders, fourth ed. American Psychiatric Association, Washington, DC, pp. 175–272. Bardo, M.T., 1998. Neuropharmacological mechanisms of drug reward: beyond dopamine in the nucleus accumbens. Critical Reviews in Neurobiology 12, 37–67. Bardo, M.T., Donohew, R.L., Harrington, N.G., 1996. Psychobiology of novelty seeking and drug seeking behavior. Behavioural Brain Research 77, 23–43. Broadhurst, P.l., Bignami, G., 1965. Correlative effects of psychogenetic selection: a study of the Roman high and low avoidance strains of rats. Behaviour Research and Therapy 18, 273–280. Brog, J.S., Salyapongse, A., Deutch, A.Y., Zahm, D.S., 1993. The patterns of afferent innervation of the core and shell in the ‘‘accumbens’’ part of the rat ventral striatum: immunohistochemical detection of retrogradely transported fluoro-gold. Journal of Comparative Neurology 338, 255–278. Cadoni, C., Di Chiara, G., 1999. Reciprocal changes in dopamine responsiveness in the nucleus accumbens shell and core and in the dorsal caudate-putamen in rats sensitized to morphine. Neuroscience 90, 447–455. Cadoni, C., Solinas, M., Di Chiara, G., 2000. Psychostimulant sensitization: differential changes in accumbal shell and core dopamine. European Journal of Pharmacology 388, 69–76. Cardinal, R.N., Parkinson, J.A., Hall, J., Everitt, B.J., 2002. Emotion and motivation: the role of the amygdala, ventral striatum, and prefrontal cortex. Neuroscience and Biobehavioral Reviews 26, 321–352. Chambers, R.A., Taylor, J.R., Potenza, M.N., 2003. Developmental neurocircuitry of motivation in adolescence: a critical period of addiction vulnerability. American Journal of Psychiatry 160, 1041–1052. Corda, M.G., Piras, G., Lecca, D., Ferna´ndez-Teruel, A., Driscoll, P., Giorgi, O., 2005. The psychogenetically selected Roman rat lines differ in the susceptibility to develop amphetamine sensitisation. Behavioural Brain Research 157, 147–156.

Crabbe, J.C., 2002. Genetic contributions to addiction. Annual Review of Psychology 53, 435–462. D’Angio, M., Serrano, A., Driscoll, P., Scatton, B., 1988. Stressful environmental stimuli increase extracellular DOPAC levels in the prefrontal cortex of hypoemotional (Roman high-avoidance) but not hyperemotional (Roman low-avoidance) rats. An in vivo voltammetric study. Brain Research 451, 237–247. Di Ciano, P., Everitt, B.J., 2004. Direct interactions between the basolateral amygdala and nucleus accumbens core underlie cocaineseeking behavior by rats. Journal of Neuroscience. 24, 7167–7173. Driscoll, P., 1986. Roman high- and low-avoidance rats: present status of the Swiss sublines, RHA/Verh and RLA/Verh, and effects of amphetamine on shuttle box performance. Behavior Genetics 16, 355–364. Driscoll, P., Ba¨ttig, K., 1982. Behavioral, emotional and neurochemical profiles of rats selected for extreme differences in active, two-way avoidance performance. In: Lieblich, I. (Ed.), Genetics of the Brain. Elsevier, Amsterdam, pp. 95–123. Driscoll, P., Dedek, J., Fuchs, A., Gentsch, C., 1985. Stereotypic, hypothermic, and central dopaminergic effects of apomorphine in Roman high-avoidance (RHA/Verh) and Roman low-avoidance (RLA/Verh) rats. Behavior Genetics 15, 591–592. Driscoll, P., Dedek, J., D’Angio, M., Claustre, Y., Scatton, B., 1990. A genetically-based model for divergent stress responses: behavioral, neurochemical and hormonal aspects. In: Pliska, I., Stranzinger, G. (Eds.), Advances in Animal Breeding and Genetics, vol. 5, pp. 97–107. Driscoll, P., Escorihuela, R.M., Ferna´ndez-Teruel, A., Giorgi, O., Schwegler, H., Steimer, T., Wiersma, A., Corda, M.G., Flint, J., Koolhaas, J.M., Langhans, W., Schulz, P.E., Siegel, J., Toben˜a, A., 1998. Genetic selection and differential stress responses: the Roman lines/strains of rats. Annals of the New York Academy of Sciences 851, 501–510. Ebstein, R.P., Benjamin, J., Belmaker, R.H., 2000. Personality and polymorphisms of genes involved in aminergic neurotransmission. European Journal of Pharmacology 410, 205–214. Escorihuela, R.M., Toben˜a, A., Driscoll, P., Ferna´ndez-Teruel, A., 1995. Effects of training, early handling, and perinatal flumazenil on shuttle box acquisition in Roman low-avoidance rats: toward overcoming a genetic deficit. Neuroscience and Biobehavioral Reviews 19, 353–367. Escorihuela, R.M., Ferna´ndez-Teruel, A., Gil, L., Aguilar, R., Toben˜a, A., Driscoll, P., 1999. Inbred Roman high- and low-avoidance rats: differences in anxiety, novelty-seeking, and shuttlebox behaviors. Physiology & Behavior 67, 19–26. Everitt, B.J., Wolf, M.E., 2002. Psychomotor stimulant addiction: a neural systems perspective. Journal of Neuroscience 22, 3312–3320. Everitt, B.J., Dickinson, A., Robbins, T.W., 2001. The neuropsychological basis of addictive behaviour. Brain Research Reviews 36, 129–138. Ferna´ndez-Teruel, A., Driscoll, P., Gil, L., Aguilar, R., Toben˜a, A., Escorihuela, R.M., 2002a. Enduring effects of environmental enrichment on novelty seeking, saccharin and ethanol intake in two rat lines (RHA/Verh and RLA/Verh) differing in incentive-seeking behavior. Pharmacology Biochemistry and Behavior 73, 225–231. Ferna´ndez-Teruel, A., Escorihuela, R.M., Gray, J.A., Aguilar, R., Gil, L., Gimenez-Llort, L., Toben˜a, A., Bhomra, A., Nicod, A., Mott, R., Driscoll, P., Dawson, G.R., Flint, J., 2002b. A quantitative trait locus influencing anxiety in the laboratory rat. Genome Research 12, 618–626. Ferre´, P., Ferna´ndez-Teruel, A., Escorihuela, R.M., Driscoll, P., Corda, M.G., Giorgi, O., Toben˜a, A., 1995. Behavior of the Roman/Verh high- and low-avoidance rat lines in anxiety tests: relationship with defecation and self-grooming. Physiology & Behavior 58, 1209–1213. Floresco, S.B., Todd, C.L., Grace, A.A., 2001. Glutamatergic afferents from the hippocampus to the nucleus accumbens regulate activity of ventral tegmental area dopamine neurons. Journal of Neuroscience 21, 4915–4922. Floresco, S.B., West, A.R., Ash, B., Moore, H., Grace, A.A., 2003. Afferent modulation of dopamine neuron firing differentially regulates

ARTICLE IN PRESS O. Giorgi et al. / Neuroscience and Biobehavioral Reviews 31 (2007) 148–163 tonic and phasic dopamine transmission. Nature Neuroscience 6, 968–973. Gimenez-Llort, L., Can˜ete, T., Guitart-Masip, M., Ferna´ndez-Teruel, A., Toben˜a, A., 2005. Two distinctive apomorphine-induced phenotypes in the Roman high- and low-avoidance rats. Physiology & Behavior 86, 458–466. Giorgi, O., Orlandi, M., Escorihuela, R.M., Driscoll, P., Lecca, D., Corda, M.G., 1994. GABAergic and dopaminergic transmission in the brain of Roman high-avoidance and Roman low-avoidance rats. Brain Research 638, 133–138. Giorgi, O., Corda, M.G., Carboni, G., Frau, V., Valentini, V., Di Chiara, G., 1997. Effects of cocaine and morphine in rats from two psychogenetically selected lines: a behavioral and brain dialysis study. Behavior Genetics 27, 537–546. Giorgi, O., Valentini, V., Piras, G., Di Chiara, G., Corda, M.G., 1999. Palatale fod differentially activates dopaminergic function in the CNS of Roman/Verh lines and strains of rats. Society of Neuroscience Meeting Abstract Book 25, 2152. Giorgi, O., Lecca, D., Piras, G., Driscoll, P., Corda, M.G., 2003. Dissociation between mesocortical dopamine release and fear-related behaviors in two psychogenetically selected lines of rats that differ in coping strategies to aversive conditions. European Journal of Neuroscience 17, 2716–2726. Giorgi, O., Piras, G., Lecca, D., Corda, M.G., 2005a. Behavioural effects of acute and repeated cocaine treatments: a comparative study in sensitisation-prone RHA rats and their sensitisation-resistant RLA counterparts. Psychopharmacology 180, 530–538. Giorgi, O., Piras, G., Lecca, D., Corda, M.G., 2005b. Differential activation of dopamine release in the nucleus accumbens core and shell after acute or repeated amphetamine injections: a comparative study in the Roman high- and low-avoidance rat lines. Neuroscience 135, 987–998. Gorelova, N., Yang, C.R., 1997. The course of neural projection from the prefrontal cortex to the nucleus accumbens in the rat. Neuroscience 76, 689–706. Groenewegen, H.J., Vermeulen-Van der Zee, E., te Kortschot, A., Witter, M.P., 1987. Organization of the projections from the subiculum to the ventral striatum in the rat. A study using anterograde transport of Phaseolus vulgaris leucoagglutinin. Neuroscience 23, 103–120. Haber, S.N., Fudge, J.L., McFarland, N.R., 2000. Striatonigral pathways in primates form an ascending spiral from the shell to the dorsolateral striatum. Journal of Neuroscience 20, 2369–2382. He´dou, G., Jongen-Reˆlo, A.L., Murphy, C.A., Heidbreder, C.A., Feldon, J., 2002. Sensitized Fos expression in subterritories of the rat medial prefrontal cortex and nucleus accumbens following amphetamine sensitization as revealed by stereology. Brain Research 950, 165–179. Heidbreder, C., Feldon, J., 1998. Amphetamine-induced neurochemical and locomotor responses are expressed differentially across the anteroposterior axis of the core and shell subterritories of the nucleus accumbens. Synapse 29, 310–322. Heimer, L., Zahm, D.S., Churchill, L., Kalivas, P.W., Wohltmann, C., 1991. Specificity in the projection patterns of accumbal core and shell in the rat. Neuroscience 41, 89–125. Henry, D.J., White, F.J., 1995. The persistence of behavioral sensitization to cocaine parallels enhanced inhibition of nucleus accumbens neurons. Journal of Neuroscience 15, 6287–6299. Horger, B.A., Shelton, K., Schenk, S., 1990. Preexposure sensitizes rats to the rewarding effects of cocaine. Pharmacology Biochemistry and Behavior 37, 707–711. Ito, R., Robbins, T.W., Everitt, B.J., 2004. Differential control over cocaine seeking behavior by nucleus accumbens core and shell. Nature Neuroscience 7, 389–397. Jentsch, J.D., Taylor, J.R., 1999. Impulsivity resulting from frontostriatal dysfunction in drug abuse: implications for the control of behavior by reward-related stimuli. Psychopharmacology 146, 373–390. Johnson, S.W., North, R.A., 1992. Opioids excite dopamine neurons by hyperpolarization of local interneurons. Journal of Neuroscience 12, 483–488.

161

Jongen-Reˆlo, A.L., Voorn, P., Groenewegen, H.J., 1994. Immunohistochemical characterization of the shell and core territories of the nucleus accumbens in the rat. European Journal of Neuroscience 6, 1255–1264. Kalivas, P.W., Duffy, P., 1993. Time course of extracellular dopamine and behavioral sensitization to cocaine. I. Dopamine axon terminals. Journal of Neuroscience 13, 266–275. Kalivas, P.W., Volkow, N., Seamans, J., 2005. Unmanageable motivation in addiction: a pathology in prefrontal-accumbens glutamate transmission. Neuron 45, 647–650. Koob, G.F., Ahmed, S.H., Boutrel, B., Chen, S.A., Kenny, P.J., Markou, A., O’Dell, L.E., Parsons, L.H., Sanna, P.P., 2004. Neurobiological mechanisms in the transition from drug use to drug dependence. Neuroscience and Biobehavioral Reviews 27, 739–749. Koolhaas, J.M., Korte, S.M., De Boer, S.F., Van Der Vegt, B.J., Van Reenen, C.G., Hopster, H., De Jong, I.C., Ruis, M.A., Blokhuis, H.J., 1999. Coping styles in animals: current status in behavior and stressphysiology. Neuroscience and Biobehavioral Reviews 23, 925–935. Laakso, A., Mohn, A.R., Gainetdinov, R.R., Caron, M.G., 2002. Experimental genetic approaches to addiction. Neuron 36, 213–228. Lecca, D., Piras, G., Driscoll, P., Giorgi, O., Corda, M.G., 2004. A differential activation of dopamine output in the shell and core of the nucleus accumbens is associated with the motor responses to addictive drugs: a brain dialysis study in Roman high- and low-avoidance rats. Neuropharmacology 46, 688–699. Legault, M., Rompre, P.P., Wise, R.A., 2000. Chemical stimulation of the ventral hippocampus elevates nucleus accumbens dopamine by activating dopaminergic neurons of the ventral tegmental area. Journal of Neuroscience 20, 1635–1642. Leshner, A.I., 1997. Addiction is a brain disease, and it matters. Science 278, 45–47. Li, Y., Acerbo, M.J., Robinson, T.E., 2004. The induction of behavioural sensitization is associated with cocaine-induced structural plasticity in the core (but not shell) of the nucleus accumbens. European Journal of Neuroscience 20, 1647–1654. Lorrain, D.S., Arnold, G.M., Vezina, P., 2000. Previous exposure to amphetamine increases incentive to obtain the drug: long-lasting effects revealed by the progressive ratio schedule. Behavioural Brain Research 107, 9–19. McClung, C.A., Nestler, E.J., 2003. Regulation of gene expression and cocaine reward by CREB and DeltaFosB. Nature Neuroscience 11, 1208–1215. McFarland, K., Kalivas, P.W., 2001. The circuitry mediating cocaineinduced reinstatement of drug-seeking behavior. Journal of Neuroscience 21, 8655–8663. McFarland, K., Lapish, C.C., Kalivas, P.W., 2003. Prefrontal glutamate release into the core of the nucleus accumbens mediates cocaineinduced reinstatement of drug-seeking behavior. Journal of Neuroscience 23, 3531–3537. McFarland, K., Davidge, S.B., Lapish, C.C., Kalivas, P.W., 2004. Limbic and motor circuitry underlying footshock-induced reinstatement of cocaine-seeking behavior. Journal of Neuroscience 24, 1551–1560. McLaughlin, J., See, R.E., 2003. Selective inactivation of the dorsomedial prefrontal cortex and the basolateral amygdala attenuates conditioned-cued reinstatement of extinguished cocaine-seeking behavior in rats. Psychopharmacology 168, 57–65. Mendrek, A., Blaha, C.D., Phillips, A.G., 1998. Pre-exposure of rats to amphetamine sensitizes self-administration of this drug under a progressive ratio schedule. Psychopharmacology 135, 416–422. Mogenson, G.J., Brudzynski, S.M., Wu, M., 1993. From motivation to action: a review of dopaminergic regulation of limbic-nucleus accumbens-ventral pallidum-pedunculopontine nucleus circuitries involved in limbic-motor integration. In: Kalivas, P.W., Barnes, C.D. (Eds.), Limbic Motor Systems and Neuropsychiatry. CRC Press, Boca Raton, pp. 193–236. Nestler, E.J., 2000. Genes and addiction. Nature Genetics 26, 277–281. Nestler, E.J., 2001. Molecular basis of long-term plasticity underlying addiction. Nature Reviews Neuroscience 2, 119–128.

ARTICLE IN PRESS 162

O. Giorgi et al. / Neuroscience and Biobehavioral Reviews 31 (2007) 148–163

O’Brien, C.P., McLellan, A.T., 1996. Myths about the treatment of addiction. Lancet 347, 237–240. Overstreet, D.H., Halikas, J.A., Seredenin, S.B., Kampov-Polevoy, A.B., Viglinskaya, I.V., Kashevskaya, O., Badishtov, B.A., Knapp, D.J., Mormede, P., Kiianmaa, K., Li, T.K., Rezvani, A.H., 1997. Behavioral similarities and differences among alcohol-preferring and -nonpreferring rats: confirmation by factor analysis and extension to additional groups. Alcoholism-Clinical and Experimental Research 21, 840–848. Parkinson, J.A., Olmstead, M.C., Burns, L.H., Robbins, T.W., Everitt, B.J., 1999. Dissociation in effects of lesions of the nucleus accumbens core and shell on appetitive pavlovian approach behavior and the potentiation of conditioned reinforcement and locomotor activity by D-amphetamine. Journal of Neuroscience 19, 2401–2411. Paulson, P.E., Robinson, T.E., 1995. Amphetamine-induced timedependent sensitization of dopamine neurotransmission in the dorsal and ventral striatum: a microdialysis study in behaving rats. Synapse 19, 56–65. Paxinos, G., Watson, C., 1998. The Rat Brain in Stereotaxic Coordinates. Academic Press, London. Phillips, G.D., Setzu, E., Vugler, A., Hitchcott, P.K., 2003. An immunohistochemical examination of the effects of sensitisation on the mesotelencephalic dopaminergic response to d-amphetamine. Neuroscience 117, 741–753. Piazza, P.V., Deminiere, J.M., le Moal, M., Simon, H., 1990. Stress- and pharmacologically-induced behavioral sensitization increases vulnerability to acquisition of amphetamine self-administration. Brain Research 514, 22–26. Pierce, R.C., Kalivas, P.W., 1995. Amphetamine produces sensitized increases in locomotion and extracellular dopamine preferentially in the nucleus accumbens shell of rats administered repeated cocaine. Journal of Pharmacology and Experimental Therapeutics 275, 1019–1029. Pierce, R.C., Kalivas, P.W., 1997. A circuitry model of the expression of behavioral sensitization to amphetamine-like psychostimulants. Brain Research Reviews 25, 192–216. Pierce, R.C., Kumaresan, V., 2005. The mesolimbic dopamine system: the final common pathway for the reinforcing effect of drugs of abuse? Neuroscience and Biobehavioral Reviews 30, 215–238. Pierce, R.C., Bell, K., Duffy, P., Kalivas, P.W., 1996. Repeated cocaine augments excitatory amino acid transmission in the nucleus accumbens only in rats having developed behavioral sensitization. Journal of Neuroscience 16, 1550–1560. Piras, G., Lecca, D., Corda, M.G., Giorgi, O., 2003. Repeated morphine injections induce behavioural sensitization in Roman high- but not in Roman low-avoidance rats. Neuroreport 14, 2433–2438. Pontieri, F.E., Tanda, G., Di Chiara, G., 1995. Intravenous cocaine, morphine, and amphetamine preferentially increase extracellular dopamine in the ‘‘shell’’ as compared with the ‘‘core’’ of the rat nucleus accumbens. Proceedings of the National Academy of Sciences of the United States of America 92, 12304–12308. Post, R.M., 1980. Intermittent versus continuous stimulation: effect of time interval on the development of sensitization or tolerance. Life Science 26, 1275–1282. Reich, T., Hinrichs, A., Culverhouse, R., Bierut, L., 1999. Genetic studies of alcoholism and substance dependence. American Journal of Human Genetics 65, 599–605. Robbins, T.W., Everitt, B.J., 1999. Drug addiction: bad habits add up. Nature 398, 567–570. Robinson, T.E., Berridge, K.C., 2001. Incentive-sensitization and addiction. Addiction 96, 103–114. Robinson, T.E., Jurson, P.A., Bennett, J.A., Bentgen, K.M., 1988. Persistent sensitization of dopamine neurotransmission in ventral striatum (nucleus accumbens) produced by prior experience with (+)amphetamine: a microdialysis study in freely moving rats. Brain Research 462, 211–222. Segal, D.S., Kuczenski, R., 1987. Individual differences in responsiveness to single and repeated amphetamine administration: behavioral

characteristics and neurochemical correlates. Journal of Pharmacology and Experimental Therapeutics 242, 917–926. Shaham, Y., Shalev, U., Lu, L., De Wit, H., Stewart, J., 2003. The reinstatement model of drug relapse: history, methodology and major findings. Psychopharmacology 168, 3–20. Shippenberg, T.S., Heidbreder, C., 1995. Sensitization to the conditioned rewarding effects of cocaine: pharmacological and temporal characteristics. Journal of Pharmacology and Experimental Therapeutics 273, 808–815. Siegel, J., Sisson, D.F., Driscoll, P., 1993. Augmenting and reducing of visual evoked potentials in Roman high- and low-avoidance rats. Physiology & Behavior 54, 707–711. Spanagel, R., Almeida, O.F., Shippenberg, T.S., 1993. Long lasting changes in morphine-induced mesolimbic dopamine release after chronic morphine exposure. Synapse 14, 243–245. Stark, H., Rothe, T., Wagner, T., Scheich, H., 2004. Learning a new behavioural strategy in the shuttle-box increases prefrontal dopamine. Neuroscience 25, 21–29. Steimer, T., Driscoll, P., 2003. Divergent stress responses and coping styles in psychogenetically selected Roman high-(RHA) and low-(RLA) avoidance rats: behavioural, neuroendocrine and developmental aspects. Stress 6, 87–100. Steimer, T., la Fleur, S., Schulz, P.E., 1997. Neuroendocrine correlates of emotional reactivity and coping in male rats from the Roman high(RHA/Verh) and low-(RLA/Verh) avoidance lines. Behavior Genetics 27, 503–512. Swanson, C.L., Heath, S., Stratford, T.R., Kelley, A.E., 1997. Differential behavioral responses to dopaminergic stimulation of nucleus accumbens subregions in the rat. Pharmacology Biochemistry and Behavior 58, 933–945. Taylor, J.R., Horger, B.A., 1999. Enhanced responding for conditioned reward produced by intra-accumbens amphetamine is potentiated after cocaine sensitization. Psychopharmacology 142, 31–40. Thomas, M.J., Beurrier, C., Bonci, A., Malenka, R.C., 2001. Longterm depression in the nucleus accumbens: a neural correlate of behavioural sensitization to cocaine. Nature Neuroscience 4, 1217–1223. Tjon, G.H., Voorn, P., Vanderschuren, L.J., de Vries, T.J., Michiels, N.H., Jonker, A.J., Klop, H., Nestby, P., Mulder, A.H., Schoffelmeer, A.N., 1997. Delayed occurrence of enhanced striatal preprodynorphin gene expression in behaviorally sensitized rats: differential long-term effects of intermittent and chronic morphine administration. Neuroscience 76, 167–176. Todtenkopf, M.S., Carreiras, T., Melloni Jr., R.H., Stellar, J.R., 2002a. The dorsomedial shell of the nucleus accumbens facilitates cocaineinduced locomotor activity during the induction of behavioral sensitization. Behavioural Brain Research 131, 9–16. Todtenkopf, M.S., Stellar, J.R., Melloni Jr., R.H., 2002b. Neither ibotenic acid nor volkensin lesions of the nucleus accumbens shell affect the expression of cocaine sensitization. European Journal of Neuroscience 16, 541–546. Uhl, G.R., Liu, Q.R., Naiman, D., 2002. Substance abuse vulnerability loci: converging genome scanning data. Trends in Genetics 18, 420–425. Vanderschuren, L.J., Kalivas, P.W., 2000. Alterations in dopaminergic and glutamatergic transmission in the induction and expression of behavioral sensitization: a critical review of preclinical studies. Psychopharmacology 151, 99–120. Vanderschuren, L.J., Tjon, G.H., Nestby, P., Mulder, A.H., Schoffelmeer, A.N., De Vries, T.J., 1997. Morphine-induced long-term sensitization to the locomotor effects of morphine and amphetamine depends on the temporal pattern of the pretreatment regimen. Psychopharmacology 131, 115–122. Vanderschuren, L.J., Schoffelmeer, A.N., Mulder, A.H., De Vries, T.J., 1999. Lack of cross-sensitization of the locomotor effects of morphine in amphetamine-treated rats. Neuropsychopharmacology 21, 550–559. Vanyukov, M.M., Tarter, R.E., 2000. Genetic studies of substance abuse. Drug and Alcohol Dependence 59, 101–123.

ARTICLE IN PRESS O. Giorgi et al. / Neuroscience and Biobehavioral Reviews 31 (2007) 148–163 Verheul, R., van den Brink, W., 2000. The role of personality pathology in the aetiology and treatment of substance use disorders. Current Opinion in Psychiatry 13, 163–169. Vorel, S.R., Liu, X., Hayes, R.J., Spector, J.A., Gardner, E.L., 2001. Relapse to cocaine-seeking after hippocampal theta burst stimulation. Science 292, 1175–1178. Wise, R.A., 2004. Dopamine, learning and motivation. Nature Reviews Neuroscience 5, 483–494. Wolf, M.E., White, F.J., Nassar, R., Brooderson, R.J., Khansa, M.R., 1993. Differential development of autoreceptor subsensitivity and enhanced dopamine release during amphetamine sensitization.

163

Journal of Pharmacology and Experimental Therapeutics 264, 249–255. Zahm, D.S., 2000. An integrative neuroanatomical perspective on some subcortical substrates of adaptive responding with emphasis on the nucleus accumbens. Neuroscience and Biobehavioral Reviews 24, 85–105. Zeier, H., Baettig, K., Driscoll, P., 1978. Acquisition of DRL-20 behavior in male and female Roman high- and low-avoidance rats. Physiology & Behavior 20, 791–793. Zuckerman, M., 1996. The psychobiological model for impulsive unsocialized sensation seeking: a comparative approach. Neuropsychobiology 34, 125–129.