Phenotypic analysis of dopamine receptor knockout mice; recent insights into the functional specificity of dopamine receptor subtypes

Neuropharmacology 47 (2004) 1117–1134 www.elsevier.com/locate/neuropharm

Review

Phenotypic analysis of dopamine receptor knockout mice; recent insights into the functional specificity of dopamine receptor subtypes Andrew Holmes a,
, Jean E. Lachowicz b, David R. Sibley c a

c

Section on Behavioral Science and Genetics, National Institute of Alcoholism and Alcohol Abuse, National Institutes of Health, Building 10, Room 3C217, Bethesda, MD 20892, USA b CNS/CV Biological Research, Schering Plough Research Institute, Kenilworth, NJ 07033, USA Molecular Neuropharmacology Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA Received 7 May 2004; received in revised form 20 June 2004; accepted 28 July 2004

Abstract The functional specificity of dopamine receptor subtypes remains incompletely understood, in part due to the absence of highly selective agonists and antagonists. Phenotypic analysis of dopamine receptor knockout mice has been instrumental in identifying the role of dopamine receptor subtypes in mediating dopamine’s effects on motor function, cognition, reward, and emotional behaviors. In this article, we provide an update of recent studies in dopamine receptor knockout mice and discuss the limitations and future promise of this approach. Published by Elsevier Ltd. Keywords: Dopamine; Receptor; Gene; Behavior; Knockout; Mouse

1. Introduction 1.1. Dopamine receptor subtypes and dopamine receptor ‘‘knockout’’ mice The brain dopamine system is organized into four anatomically distinct pathways (Lindvall and Bjorklund, 1978). Dopamine neurons in the substantia nigra project to the striatum to form the ‘‘nigrostriatal’’ pathway. A second major group of dopamine-containing neurons project from the ventral tegmental area to form the ‘‘mesolimbic’’ (innervating the nucleus accumbens, septum, olfactory tubercle, amygdala, and piriform cortex) and ‘‘mescocortical’’ (innervating medial prefrontal, cingulate and entorhinal cortices) pathways. A fourth, ‘‘tuberoinfundibular’’, pathway sends efferents from the arcuate nucleus of the hypothalamus to the intermediate lobe of the pituitary and the hypophyseal portal vessels of the median eminence. While these pathways are each associated with particular neural
Corresponding author. Tel.: +1-3014-203519; fax: +1-3014801952. E-mail address: [email protected] (A. Holmes).

0028-3908/$ - see front matter Published by Elsevier Ltd. doi:10.1016/j.neuropharm.2004.07.034

functions and disease states, such functional demarcation is far from absolute. Further separation and refinement of dopaminergic function is achieved, in part, via actions at different receptor subtypes. Dopamine mediates its neural effects via actions at both presynaptic and postsynaptic dopamine receptors. Five separate dopamine receptor subtypes have been identified, all belonging to the seven transmembrane G-protein coupled receptor family (Civelli et al., 1993; Gingrich and Caron, 1993; Sibley et al., 1993). Based on its pharmacological and signaling properties, the D1R-like subfamily, comprising D1R and D5R subtypes, is differentiated from the D2R-like subfamily, comprising D2R, D3R and D4R subtypes (Kebabian and Calne, 1979; Missale et al., 1998). D1R-like receptors stimulate signal transduction by coupling to Gs proteins and subsequent activation of adenylyl cyclase and cAMP production. D2R-like receptors couple to Gi/o-like proteins and suppress signal transduction via inhibition of adenylyl cyclase and cAMP production and modulation of ion channels. The divergent intracellular effects of dopamine receptors, together with their divergent neuroanatomical

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localization, strongly suggest that individual dopamine receptor subtypes mediate distinct functional properties of dopamine. There is no doubt that elucidating this functional specificity would represent a major advance in our understanding of how dopamine governs neural function and impacts a variety of debilitating neurological and neuropsychiatric diseases. Unfortunately, the majority of available dopamine receptor agonists or antagonists do not act with specificity at individual receptor subtypes within the D1R-like or D2R-like subfamilies, thereby limiting their utility as research tools. There are currently no ligands with greater than 10-fold selectivity for D1R vs. D5R. Within the D2R-like family, there are compounds with >100-fold selectivity for D4R vs. D2R, or D3R vs. D2R, but still no D2R-selective agonist and antagonists. D2RL and D2RS isoforms of the D2R cannot be selectively targeted with pharmacological agents. Gene targeting techniques in the mouse have evolved as a widely used approach to elucidate the functions of specific molecules found in the brain (Crawley, 2000; Bucan and Abel, 2002). Given the aforementioned limitations of a traditional behavioral pharmacological approach to study dopamine receptor subtype function, the ability to functionally ‘‘knockout’’ a dopamine receptor with great specificity has made it an attractive and fruitful strategy. Several authors have reviewed the many studies that have reported on neural and behavioral phenotypes in dopamine receptor knockout (KO) mice (Sibley, 1999; Glickstein and Schmauss, 2001; Waddington et al., 2001; Zhang and Xu, 2001; Tan et al., 2003; Viggiano et al., 2003). The goal of the present article is to provide an update of recent research in this rapidly moving field and attempt to place these developments within the context of prior findings.

2. D1R KO mice; movement, motivation and memory 2.1. General D1R KO mice were the first dopamine receptor KO mice to be generated. Two lines of D1R KO mice exist (Drago et al., 1994; Xu et al., 1994b). D1R KO mice show normal appearance and no obvious neurological defects, but exhibit growth retardation and low survival after weaning (Drago et al., 1994; Xu et al., 1994a, b). This failure to thrive can be rescued by providing KO mice with easy access to a palatable food, such as wet chow on the cage floor, suggesting that it may relate to a deficit in fine motor control (Drago et al., 1994; Xu et al., 1994a, b; see also Section 2). This contrasts with the apparent loss of the motivation to feed that is observed in mutant mice

with virtually no dopaminergic neurotransmission (Cannon and Palmiter, 2003). The D1R is abundant in the striatum, amygdala and olfactory tubercle, and is also found in the hippocampus, globus pallidus, hypothalamus, septum, substantia nigra, and throughout the cerebral cortex (Levey et al., 1993; Ariano and Sibley, 1994). Radioligand binding of D1R-like receptors is negligible in the brain of D1R KO mice, although some binding, presumably to D5R, is detectable in hippocampus (Friedman et al., 1997; Becker et al., 2001; Montague et al., 2001; Wong et al., 2003a). D2R-like binding and dopamine transporter binding also appear normal in D1R KO mice (Xu et al., 1994a; El-Ghundi et al., 1999; but see Wong et al., 2003a). However, there are fewer total dopamine (tyrosine hydroxylase-positive) neurons in D1R KO mice than wild type (WT) controls (Parish et al., 2002). In addition, midbrain levels of dopamine are elevated and dopamine metabolites are altered in D1R KO mice, suggesting that there may be a compensatory increase in dopamine synthesis and/or release following inactivation of the receptor (El-Ghundi et al., 1998; Parish et al., 2002). Lastly, striatal levels of dynorphin and substance P, both of which are synthesized in D1Rexpressing neurons, are reduced in D1R KO mice (Drago et al., 1994; Xu et al., 1994b; Wong et al., 2003a). Psychostimulant-induced increases in dynorphin, but not substance P, are also abolished in these mice (Drago et al., 1996; Moratalla et al., 1996). 2.2. Motor functions While D1R-like antagonists profoundly reduce locomotor activity, several laboratories have found that D1R KO mice exhibit increased locomotor activity and retarded locomotor habituation in an open field apparatus (Xu et al., 1994a, b, 2000b; Crawford et al., 1997; Clifford et al., 1998; Karasinska et al., 2000; Becker et al., 2001; Miyamoto et al., 2001; Centonze et al., 2003a; McNamara et al., 2003; Wong et al., 2003b). Additionally, D1R KO mice have been reported to show reduced orofacial movements and impaired motor coordination on the rotarod test, as well as reduced spontaneous grooming behavior and an absence of novelty- and neuropeptide-induced grooming (Cromwell et al., 1998; Drago et al., 1999; Karasinska et al., 2000; Tomiyama et al., 2002). The hyperactivity- and hypoactivity-inducing effects of D1R-like (but not D2R-like) agonists and antagonists are abolished in D1R KO mice (Xu et al., 1994a, b; Drago et al., 1996; Moratalla et al., 1996; Clifford et al., 1999; Miyamoto et al., 2001; Tomiyama et al., 2002; Centonze et al., 2003a; McNamara et al., 2003). In the context of dopamine’s putative role in schizophrenia (see Section 4.5), it is noteworthy that the hyperlocomotor-inducing effects of the psychotomimetic NMDA

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antagonist, ketamine, are also lost in the D1R KO mice (Miyamoto et al., 2001). Taken together, these findings suggest an important role for D1R in maintaining spontaneous motor behaviors, and appear to affirm the relative importance of D1R over D5R in mediating the motor effects of D1R-like agonists (see also Section 3.2). However, baseline hyperactivity, motor incoordination and absent locomotor responses to D1R-like agonists have not been found in all studies of D1R KO mice, and in some cases opposite (e.g., a hypoactive baseline), phenotypes have been observed (Drago et al., 1996; Smith et al., 1998; Clifford et al., 1999; El-Ghundi et al., 1999; Karasinska et al., 2000). The reason for these inconsistencies is not yet fully understood. One widely discussed possibility is that analysis of motoric phenotypes in D1R KO mice may have been confounded by the genetic background on which the mutation was present, such that genes contributed by one of the parental strains (i.e., a 129 substrain), rather than the loss of D1R, may underlie the observed locomotor abnormalities (for a fuller discussion, see Section 4.3). However, this explanation appears to be discounted by the recent finding that locomotor phenotypes, such as reduced locomotor habituation, were actually more prominent in D1R KO mice backcrossed onto a congenic (C57BL/6) genetic background than in mice on a mixed genetic background (McNamara et al., 2003). This study does nonetheless strongly emphasize the critical influence of genetic background on behavioral phenotypes in dopamine receptor KO mice. Another factor influencing variability in D1R locomotor phenotypes across studies is likely to stem from inter-laboratory differences in the methods used to assess these behaviors. It is increasingly accepted that variations in task parameters such as the size, material, shape, and illumination of the apparatus used, the test duration employed, and the prior experimental experience of the subject can strongly influence a variety of mouse behaviors, particularly in tasks based on exploratory locomotion (Holmes and Rodgers, 1998; Crabbe et al., 1999; Holmes, 2001; McIlwain et al., 2001). In this context, there is growing evidence that the dopamine system is acutely sensitive to psychological stressors (Arnsten and Goldman-Rakic, 1998). Thus, ostensibly subtle variations in task protocol and procedure, as well rearing and husbandry conditions, may produce marked variation in the level of stress/ dopamine challenge evoked by a behavioral task and, in doing so, modify the manifestation of abnormal D1R KO phenotypes (Clifford et al., 2000). This scenario may apply equally to the study of behavior in other dopamine receptor KO mice. Unfortunately, there are no easy solutions to this problem. The adoption of ‘‘standardized’’ methods of behavioral analysis is likely to be impractical beyond a

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rudimentary level (for relevant discussion, see Wahlsten et al., 2003). A valuable step forward would be to better understand the relationship between stress and the dopamine system. In addition, some authors have proposed that refining behavioral analysis may clarify the precise nature of phenotypic alterations in dopamine receptor KO mice (for review see Waddington et al., 2001). Indeed, the adoption of more sophisticated methods of assessment, that incorporate ethological measures of distinct components of the behavioral repertoire (Rodgers et al., 1997), has proved valuable to the phenotypic description of locomotor phenotypes in D1R (and other dopamine receptor) KO mice (Drago et al., 1996; Clifford et al., 1999). 2.3. Reward D1R KO mice have been instrumental in clarifying the role of the D1R subtype in dopaminergic mediation of reward-related behaviors. Consistent with the effects of D1R-like antagonist treatment (Kalivas and Stewart, 1991), deletion of the D1R KO either eliminates or markedly attenuates the hyperactivity-inducing and behavioral-sensitizing effects of acute and chronic treatment with psychostimulants or morphine (Drago et al., 1996; Xu et al., 1996, 2000b; Crawford et al., 1997; Becker et al., 2001, but see Karper et al., 2002). Psychostimulant treatment in D1R KO mice also fails to inhibit firing or induce expression of brain derived nerve growth factor (BDNF) and other genes in brain regions implicated in reward, such as the nucleus accumbens (Xu et al., 1994a, 2000b; Miner et al., 1995; Moratalla et al., 1996; Crawford et al., 1997; Zhang et al., 2002a,b), an issue which we return to later. Recent studies have complimented these observations by demonstrating that psychostimulant-induced phosphorylation of DARPP-32, an intracellular signaling molecule thought to mediate the neural effects of psychostimulants, is also compromised in D1R KO mice (Svenningsson et al., 2003). However, reward-related behaviors in D1R KO mice have yet to be thoroughly studied. An early investigation found that D1R KO mice demonstrated normal responses to the rewarding effects of cocaine in the conditioned place preference test (Miner et al., 1995). More recently, D1R KO mice have been found to show reduced voluntary ethanol consumption, as well as reduced operant responding for a sucrose reinforcer (El-Ghundi et al., 1998, 2003). The possibility, suggested by these findings, that deletion of the D1R may attenuate the reinforcing properties of rewarding stimuli, would be consistent with emerging clinical data; e.g., the euphoric effects of cocaine can be blunted by a D1R-like antagonist in cocaine addicts (Romach et al., 1999). Given the clinical implications of identifying novel dopamine receptor-based therapeutic targets for

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addiction, further studies of reward-related behavior in D1R KO mice will be of considerable importance. 2.4. Cognition Dopamine is known to play an important role in cognition (Robbins, 2000). Interestingly, a number of studies have reported deficits on hippocampal-mediated behavioral tasks, such as the Morris water maze, in D1R KO mice (El-Ghundi et al., 1998; Smith et al., 1998; Karasinska et al., 2000). Moreover, D1R KO mice exhibit impaired long-term potentiation, a molecular correlate of learning and memory, in both hippocampal and corticostriatal neurons (Matthies et al., 1997; Centonze et al., 2003a). However, performance on other hippocampal-mediated tests such as contextual fear conditioning and passive avoidance appears normal in D1R KO mice, and more work is required to ascertain the precise nature of hippocampal function in these mice (El-Ghundi et al., 1999, 2001). A growing literature implicates the prefrontal cortex in the mediation of behaviors including working memory and cognitive flexibility, response inhibition, and extinction of learned fear responses (Goldman-Rakic, 1995; Milad and Quirk, 2002; Chudasama and Robbins, 2003). In this context, recent findings demonstrating deficits in fear extinction and reversal learning in D1R KO mice suggest that prefrontal cortex function may be impaired (El-Ghundi et al., 1999, 2001, 2003). This is supported by the demonstration that long-term potentiation in prefrontal cortex neurons is abnormal in D1R deficient mice (Huang et al., 2004). Indeed, a prefrontal deficit in D1R KO mice would also be highly congruent with (1), the rich localization of D1R in the prefrontal cortex (Levey et al., 1993; Ariano and Sibley, 1994), (2), D1R-like modulation of prefrontal cortex synaptic plasticity (Otani et al., 1998; Gurden et al., 2000; Huang et al., 2004) and (3), evidence that D1R-like agonists and antagonists administered directly into the prefrontal cortex affect cognitive performance in rodents and non-human primates (Williams and Goldman-Rakic, 1995; Granon et al., 2000; Robbins, 2000; Lidow et al., 2003). Thus, the existing data suggest that D1R KO mice could provide an interesting model to study the role of this subtype in prefrontal cortex-mediated behaviors.

3. D5R KO mice; still an enigma? 3.1. General D5R KO mice are viable, healthy and develop without the growth retardation seen in D1R KO mice (Holmes et al., 2001; Hollon et al., 2002). Moreover, despite evidence that antisense knockdown of the D5R

in the ventromedial hypothalamus inhibits lordosis in female rats (Apostolakis et al., 1996), D5R KO mice are fertile and reproduce normally. D5R KO mice do, however, develop abnormally high blood pressure (Hollon et al., 2002) and show increased vulnerability to cysteamine-induced gastric lesions (Hunyady et al., 2001). Across species, the neural expression of the D5R is distinct from and more limited than D1R; in the rodent brain, the D5R is found in the hippocampus, prefrontal cortex and basal ganglia, as well as thalamic and hypothalamic nuclei (Ciliax et al., 2000). Confirming the preponderance of the D1R relative to the D5R in the mouse brain, D1R-like autoradiographic binding in D5R KO mice is almost indistinguishable from WT controls (Montague et al., 2001; Hollon et al., 2002; Laplante et al., 2004). To date, possible changes in brain D2R-like receptors in D5R KO have not been demonstrated. 3.2. Motor functions Consistent with a relatively specialized role for the D5R, phenotypic analysis of D5R KO mice has revealed fewer behavioral abnormalities than observed in D1R KO. Basal locomotor activity, motor coordination, prepulse inhibition, and anxiety-like behaviors all appear normal in D5R KO mice (Holmes et al., 2001; Elliot et al., 2003). Operant responding for cocaine was also recently shown to be normal in these mice (Elliot et al., 2003). Preliminary data have indicated a gender-specific antidepressant-like phenotype in D5R KO mice tested in a mouse model of ‘‘behavioral despair’’ (Holmes et al., 2001). If robust, this phenotype may provide a novel insight into the role of D5R in stress-related behavior, and could relate to the aforementioned localization of D5R in the hippocampus, a brain region implicated in depression (MacQueen et al., 2003). The hyperactivity-inducing effects of D1R-like agonist and, in a separate study, cocaine, were found to be mildly attenuated in D5R KO (Holmes et al., 2001; Elliot et al., 2003). These findings extend studies showing a near complete loss of the same effects of D1R-like agonists in D1R KO mice (see Section 2). Because there is no evidence of altered D1R binding in D5R KO mice, the most parsimonious explanation for these findings is that D5R normally contributes to the hyperactivity-inducing effects of dopamine agonists (Centonze et al., 2003a). This hypothesis is supported by other recent findings. First, while dopaminergic excitation of striatal interneurons is blocked by treatment with a D1R-like antagonist in WT mice, this response is retained in D1R KO mice (Centonze et al., 2003b). Second, D1R-like agonists are still able to modulate neuronal activity in the subthalamic nucleus

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(a major region controlling basal ganglia output) in the absence of the D1R (Baufreton et al., 2003). These emerging findings have led to the proposal that D1R and D5R exert synergistic control over locomotor activity when the subtypes are expressed on the same striatal neuronal type (medium spiny) via a common signal transduction mechanism (Centonze et al., 2003a). Ultrastructural differentiation of D1R and D5R within corticostriatal neurons also raises the possibility of mutually opposing actions of the subtypes (Bergson et al., 1995; Centonze et al., 2003b). 3.3. Cognition A notable exception to the higher expression of the D1R vs. D5R in the brain is in the hippocampus, where the pattern is reversed (Ciliax et al., 2000). Recent research in D5R KO mice has begun to shed light on the function of hippocampal D5R. D5R KO mice display reduced extracellular levels of acetylcholine in the hippocampus as well as significantly blunted acetylcholine-releasing responses to D1R-like agonist treatment in this region (Laplante et al., 2004). These findings concur with previous evidence indicating that the antisense knockdown of hippocampal D5R attenuates D1R-like agonist stimulation of hippocampal acetylcholine release in rats (Hersi et al., 2000). Given the well-established role of cholinergic neurotransmission in mediating learning and memory (Everitt and Robbins, 1997), combined with evidence of dopamine D1R-like facilitation of hippocampal long-term potentiation and memory function (Bach et al., 1999; Li et al., 2003), these findings suggest an important modulatory role for the D5R in hippocampal-mediated cognition. However, to date, behavioral studies have found little evidence of impaired learning and memory on various hippocampal-mediated tasks in D5R KO mice (Holmes et al., 2001). More detailed studies of cognitive function in D5R KO mice are awaited.

4. D2R; splice variants enrich the picture 4.1. General Three separate lines of D2R KO mice have been generated (Baik et al., 1995; Kelly et al., 1997; Jung et al., 1999). To date, these mice have been the most well studied of the dopamine receptor KO mice. Consistent with the D2R’s role as an inhibitory mediator of pituitary hormone synthesis and secretion (Sibley and Creese, 1983) D2R KO mice exhibit reduced pituitary growth hormone release, develop pituitary tumors and, as a result of elevated glucocorticoid levels, adrenal hypertrophy (Kelly et al., 1997; Saiardi et al., 1997; Saiardi and Borrelli, 1998; Asa et al., 1999; Diaz-Torga

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et al., 2002). As pituitary hormone function is normal in D2RL KO mice (see Section 4.6), D2R mediation of this function appears to occur through the D2RS isoform (Xu et al., 2002). D2R KO mice also show increased blood pressure and susceptibility to sodiuminduced hypertension (Li et al., 2001, 2002; Ozono et al., 2003; Ueda et al., 2003). Otherwise, and despite some reports of growth retardation, D2R KO mice appear healthy. The D2R is expressed at much higher levels in brain than the other D2R-like subtypes. The D2R is especially prominent in the vicinity of the mesencephalic dopamine cell body regions, as well as in the dorsal and ventral striatum and the olfactory tubercle (Meador-Woodruff et al., 1989). The loss of the D2R in KO mice is associated with reduced levels of neurotrophins and fewer total striatal dopamine (i.e., tyrosine hydroxylase-positive) neurons (Bozzi and Borrelli, 1999; Parish et al., 2002). In addition, D2R KO mice exhibit significantly increased striatopallidal enkephalin and reduced striatonigral substance P mRNA, as well increased cytochrome oxidase expression in the subthalamic nucleus (Murer et al., 2000). D2R KO mice show a transient postnatal increase in D3R, and in some reports, a decrease in D1R-like binding (Baik et al., 1995; Xu et al., 1997; Kelly et al., 1998; Jung et al., 1999). Although the motoric effects of D1R-like agonists and antagonists are largely normal in D2R KO mice (Kelly et al., 1998; Phillips et al., 1998; Boulay et al., 1999a; Tomiyama et al., 2004), D1R-like agonist-induced stereotypical behavior is exaggerated (Glickstein and Schmauss, 2001, 2004). Moreover, D2R KO mice show significantly blunted striatum and prefrontal cortex activation (as assayed by c-fos expression) in response to D1R-like agonists (Jung et al., 1999; Schmauss, 2000; Schmauss et al., 2002; Glickstein and Schmauss, 2004). These alterations in D2R KO cortical responsivity are associated with deficits in working memory performance, and can be reversed by treatment with methamphetamine (Schmauss, 2000; Glickstein et al., 2002). Parenthetically, transgenic overexpression of D1R in extrastriatal regions does not significantly alter behavioral abnormalities in D2R KO mice (Dracheva et al., 1999; Dracheva and Haroutunian, 2001). Taken together, the available evidence indicates certain D1R functional alterations in D2R KO mice, although the precise nature of these alterations is yet to be fully elucidated. 4.2. Autoreceptor function D2R-like receptors are localized both postsynaptically and presynaptically on dopamine terminals and soma. Consistent with a major functional role of the D2R in regulating dopaminergic neuronal activity (Roth, 1984), the ability of dopamine to inhibit the fir-

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ing of neurons in the substantia nigra or ventral tegmental area, or inhibit dopamine release in striatal projections areas, is lost in D2R KO mice (Mercuri et al., 1997; Rouge-Pont et al., 2002). In addition, deletion of the D2R (but not D3R) abolishes the ability of D2Rlike agonists to inhibit striatal dopamine synthesis and release, activate G-protein-gated inwardly rectifying potassium channels and increase locomotor activity (Kelly et al., 1998; Koeltzow et al., 1998; L’Hirondel et al., 1998; Boulay et al., 1999a, 2000; Benoit-Marand et al., 2001; Clifford et al., 2001; McNamara et al., 2002; Schmitz et al., 2002; Davila et al., 2003; Lindgren et al., 2003; Tomiyama et al., 2004). Thirdly, the capacity of striatal dopamine neurons to attenuate amphetamine-induced dopamine release is disrupted in D2R KO mice (Schmitz et al., 2001). Taken together, these findings confirm that the D2R serves as the principal autoreceptor on dopamine neurons. However, despite the loss of this function, neither synaptic dopamine levels nor tissue concentrations of dopamine or its metabolites are markedly altered in D2R KO mice (Benoit-Marand et al., 2001; Rouge-Pont et al., 2002; but see Koeltzow et al., 1998; Jung et al., 1999; Parish et al., 2002). This profile indicates that either the D2R does not exert strong tonic control of dopamine activity or, more likely, that compensatory mechanisms have fulfilled this role in D2R KO mice. In this context, there is some evidence that the other major regulator of extracellular striatal dopamine, the dopamine transporter, is upregulated in the striatum of D2R KO mice (Parish et al., 2002). Functional changes in dopamine transporter-mediated striatal dopamine reuptake have also been found in D2R KO mice, although the magnitude and direction of the changes have varied across studies (Dickinson et al., 1999; Schmauss et al., 2002). 4.3. Motor functions D2R KO mice exhibit significantly lower levels of locomotor activity than WT controls (Baik et al., 1995; Kelly et al., 1998; Boulay et al., 1999a, 2000; Jung et al., 1999; Aoyama et al., 2000; Clifford et al., 2000; Zahniser et al., 2000; Dracheva and Haroutunian, 2001; Chausmer et al., 2002; McNamara et al., 2002; Tran et al., 2002; Vallone et al., 2002; Palmer et al., 2003). Moreover, profound deficits in gait, posture and motor coordination in D2R KO mice suggested a fundamental role for the receptor in mediating dopaminergic control of these behaviors (Baik et al., 1995; Jung et al., 1999; Aoyama et al., 2000). However, gait and motor coordination deficits in D2R KO mice have not been found in all investigations. As noted in Section 2.2, genetic background has been found to be a significant influence on motor phenotypes in D1R KO mice. There are marked strain

differences in motor performance on the rotarod, open field and other motor tasks (Tarantino et al., 2000; Holmes et al., 2002). Therefore, the fact that the motor incoordination phenotype in D2R KO mice resembles that of the 129 parental strain is consistent with the possibility that this phenotype is a false-positive caused by 129 parental genes (Crusio, 1996; Gerlai, 1996). This explanation is supported by the finding that repeated backcrossing of the D2R null mutation onto a C57BL/6 genetic background effectively ‘‘rescued’’ motor coordination deficits in these mice (Kelly et al., 1998). An alternative possibility is that when the mutation is backcrossed into the C57BL/6J genetic strain, epistasis interactions between the null mutation and C57BL/6J background gene(s) protect against motor coordination deficits in D2R KOs (for discussion, see Holmes et al., 2003). Irrespective of the underlying reasons, the significant influence of genetic background on both D2R KO and D1R KO locomotor phenotypes strongly advises the use of congenic backgrounds in future studies of these and other dopamine receptor KO mice. There is growing evidence of the importance of functional interactions between the D2R and A2A adenosine receptor subtype in the pathophysiology and treatment of dopamine-related movement disorders, such as Parkinson’s disease (Kase et al., 2003). The D2R KO mouse has recently proven to be a useful tool for studying D2R–A2AR interactions. While A2AR binding density is normal in D2R KO mice, there is evidence of functional uncoupling of the A2AR in these mice (Aoyama et al., 2000; Zahniser et al., 2000). Behaviorally, the hyperactivity-inducing effects of A2AR antagonists are reduced, but not completely abolished, in D2R KOs (Aoyama et al., 2000; Zahniser et al., 2000; Chen et al., 2001). These and related findings have led to the hypothesis that the D2R and A2AR likely exert their effects on motor function via opposing, yet semi-independent mechanisms, and encourage further delineation of these interactions in search of novel therapeutic approaches to the treatment of movement disorders. 4.4. Reward Reward-related responses to a number of drugs of abuse are abnormal in D2R KO mice. Independent studies have shown that voluntary ethanol consumption, ethanol-induced conditioned place preference, operant responding for ethanol, ethanol-induced sedation and ataxia are all reduced in D2R KO mice, while the locomotor stimulating and sensitizing effects of ethanol are increased (Phillips et al., 1998; Cunningham et al., 2000; Risinger et al., 2000; Palmer et al., 2003). Extending these findings and demonstrating that the influence of genetic background on D2R KO

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behavioral phenotypes extends to ethanol responses (see Section 4.3), a recent study has shown that augmented locomotor stimulant effects of ethanol are observed when the mutation is on a C57BL/6J, but not 129, genetic background, while reduced ethanolinduced ataxia occurs independently of background strain (Palmer et al., 2003). Notwithstanding, these data in D2R KO mice extend evidence that the mouse D2R (Drd2) is a major candidate gene underlying variation in ethanol-related behaviors (Phillips et al., 1994). D2R KO mice do not self-administer morphine and fail to develop conditioned place preference to morphine, while morphine-induced hyperactivity and morphine withdrawal (as well as brain l-opioid receptor levels) are normal in D2R KOs (Maldonado et al., 1997; Elmer et al., 2002; see also Smith et al., 2002). Further studies have suggested that the role of the D2R in opiate reward may be restricted to conditions in which the incentive to obtain the drug is especially high, as during dependence and withdrawal, while (Dockstader et al., 2001). Electrophysiological data also indicate that abnormal nucleus accumbens responses to reward in D2R KO mice may be highly specific to particular phases of reward processing and, more generally, that striatal synaptic plasticity is grossly abnormal in these mice (Calabresi et al., 1997; Tran et al., 2002). D2R KO responses to psychostimulants are similarly complex. The locomotor stimulant effects of cocaine are diminished in D2R KO mice (Chausmer and Katz, 2001; Chausmer et al., 2002), while selfadministration of moderate–high doses of cocaine is increased in D2R KO mice; an effect mimicked by D2R-, but not D3R- or D4R-, preferring antagonists (Caine et al., 2002). However, unlike normal mice treated with D2R-like antagonists, D2R KOs are fully able to discriminate cocaine from saline (Chausmer and Katz, 2001; Chausmer et al., 2002). These somewhat disparate findings concur with emerging clinical data pointing to a critical, but complex, role for D2R in reward and addition (Volkow et al., 2002). 4.5. Sensorimotor gating Startle responses to sudden high-intensity sensory stimuli (e.g., a loud noise) are inhibited when closely preceded by a low-intensity stimulus (a weaker sound). This ‘‘prepulse inhibition’’ (PPI) response is impaired in schizophrenia and certain other neuropsychiatric disorders (Braff et al., 2001), and has proven a valuable assay to delineate the actions of antipsychotics in mutant mouse models (Geyer et al., 2002). Rodent behavioral pharmacological data have established a significant role for D2R in mediating the PPI-impairing effects of psychotomimetic drugs such as amphetamine (Geyer et al., 2002). In agreement with these findings, D2R KO mice fail to show amphetamine-induced

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disruption of PPI (Ralph et al., 1999). Demonstrating the specificity of these effects, amphetamine-induced deficits were not found in D3R KO mice or D4R KO mice, and the PPI-deficits caused by treatment with a NMDA receptor antagonist were unaltered in D2R KO mice (Ralph et al., 1999; Ralph-Williams et al., 2002). Further work has demonstrated that amphetamine-induced disruption of PPI is not altered in D1R KO, while responses to D1R-like agonists are abolished in D1R KO and mildly attenuated in D5R KO mice (Holmes et al., 2001; Ralph-Williams et al., 2002). Thus, these data suggest that an essential role for the D2R in mediating sensorimotor gating deficits caused by amphetamine, but probably not all PPI-impairing drugs. In view of the long-standing hypothesis that the dopamine system is central to the pathophysiology and treatment schizophrenia, more work in this area utilizing dopamine receptor KO mice is expected. 4.6. Splice variants Across species the D2R mRNA is alternatively spliced to produce short (D2RS) and long (D2RL) isoforms, the latter containing an additional 29 amino acid insertion in the third cytoplasmic loop of the receptor (Giros et al., 1989; Mack et al., 1991). The 29 amino acid insertion sequence in the D2L isoform is encoded by an 87 bp cassette exon in the D2R gene (Monsma et al., 1989). In the mouse brain, the D2RL isoform is much more highly expressed and shows partially discrete neuroanatomical localization compared to the D2RS isoform, suggesting functional specificity (Mack et al., 1991; Neve et al., 1991). D2RL KO mice have been generated to explore this by selectively targeting the 87 bp exon which encodes the 29 amino acid sequence defining the D2RL isoform, thereby producing mice in which the D2R gene is only capable of generating the D2RS isoform (Usiello et al., 2000; Wang et al., 2000). D2R binding is normal in D2RL KO mice, presumably via increased D2RS binding (Wang et al., 2000). However, behavioral analysis has shown that D2RL KO mice exhibit a number of behavioral abnormalities. These phenotypes include diminished conditioned place preference to morphine, reduced aggression and impaired avoidance learning (Vukhac et al., 2001; Smith et al., 2002). D2RL KO mice also demonstrate reduced basal open field locomotor activity in some studies (Wang et al., 2000; but see Usiello et al., 2000; Xu et al., 2002; Fetsko et al., 2003). A more consistent finding has been that D2RL KO mice exhibit blunted hypoactive/cataleptic responses to D2R-like antagonists and reduced stereotypical responses to psychostimulants (Usiello et al., 2000; Wang et al., 2000; Xu et al., 2002; Fetsko et al., 2003). The baseline locomotor hypoactivity and the reduced

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responsivity to treatment with D2R-like ligands observed in D2RL KO mice resemble the phenotypic alterations found in D2R KO mice (see Section 4.3). However, there are clear phenotypic differences between D2R KO and also D2RL KO mice. D2R-like agonist-induced stereotypical behavior and D2R-like agonist activation of postsynaptic phosphoproteins, such as DARPP-32, which are both absent in D2R KO mice, are maintained in D2RL KO mice (Fetsko et al., 2003; Lindgren et al., 2003). Moreover, D2R autoreceptor-mediated inhibition of dopamine synthesis and release in response to D2R-like agonists or psychostimulants remain intact in D2RL KO mice (Usiello et al., 2000; Rouge-Pont et al., 2002). Lastly, in contrast to the loss of PPI-impairing effects of psychostimulants in D2R KO mice discussed in the preceding section, these responses are extant in D2RL KO mice (Xu et al., 2002). Taken together, these diverse data demonstrate that the D2RS and D2RL isoforms are responsible for discrete functions of the D2R. The available evidence suggests that D2RL is the isoform responsible for postsynaptic D2R effects, while D2RS may mediate D2R autoreceptor control of dopamine release. Clearly, such functional dissociation has major implications for developing novel pharmacotherapeutics targeting the D2R.

5. D3R; reward and cooperativity 5.1. General Three lines of mutant mice lacking functional D3R have been generated (Accili et al., 1996; Xu et al., 1997; Jung et al., 1999). D3R KO mice show normal appearance, growth, fertility, and no gross neurological dysfunctions, but develop renin-dependent hypertension (Asico et al., 1998; Jose et al., 1998). Brain binding density of other dopamine receptors, including the D1R and D2R, also appears normal in D3R KO mice (Accili et al., 1996; Xu et al., 1997; Wong et al., 2003a). While basal feeding and body weight are normal in D3R KOs, these mice deposit greater amounts of fat when maintained on a high-fat diet and show blunted hyperphagic responses to treatments such as leptin and insulin (Benoit et al., 2003; McQuade et al., 2004). These novel data suggest a potential specific role for D3R in body weight regulation. D2R-like receptors are known to be important regulators of body temperature, and D3R KO mice have helped clarify the role of D3R in these effects. Early pharmacological studies showing that hypothermia induction by mixed D2R/D3R agonists correlated highly with affinity for D3R implied that these effects were D3R-mediated (Millan et al., 1995). However, the hypothermia-inducing effects of D2R/D3R agonists are

normal in D3R KO mice but absent in D2R KOs, strongly suggesting that it is principally the D2R, rather than the D3R, that mediates these effects (Boulay et al., 1999a; Xu et al., 1999; Perachon et al., 2000). As discussed earlier, studies of D2R KO mice have provided evidence supporting the primacy of the D2R subtype as the major presynaptic autoreceptor on dopamine neurons (see Section 4.2). An auxiliary role for D3R in controlling dopamine release via postsynaptically mediated negative feedback has been proposed (Schwartz et al., 1993). While most measures of dopamine content, uptake and neuronal firing are normal in D3R KO mice, some reports note higher basal striatal extracellular dopamine (Xu et al., 1997; Koeltzow et al., 1998; but see Zapata et al., 2001). In addition, stereotypical and striatal responses (i.e., c-fos and dynorphin expression) to chronic cocaine treatment are exaggerated in D3R KOs (Xu et al., 1997; Carta et al., 2000). Lastly, a recent study has shown that D1R and D2R-mediated G-protein activation and calcium influx is enhanced in cultured forebrain neurons from D3R KO mice (Mizuo et al., 2004). Taken together, these findings are consistent with an inhibitory influence of D3R, at least in striatal neurons. However, there are also reports that locomotor responses to psychostimulants are unaltered in D3R KO mice and that their striatal responsivity to D1R-like agonist and chronic cocaine treatment is diminished rather than increased (Jung and Schmauss, 1999; Betancur et al., 2001). Moreover, while D3R-preferring agonists fail to inhibit striatal dopamine release in D3R KO mice, the locomotor effects of putatively selective D3R agonists and antagonists are maintained in D3R KO mice, but lost in D2R KOs, suggesting that the D2R rather than D3R is the principle receptor mediating these behavioral changes (Boulay et al., 1999a, b, 2000; Xu et al., 1999; Betancur et al., 2001; Zapata et al., 2001; Pritchard et al., 2003). 5.2. Locomotion, emotion and reward D3R KO mice exhibit locomotor hyperactivity in some studies, but not others (Xu et al., 1997; Boulay et al., 1999a,b, 2000; Depoortere, 1999; Jung and Schmauss, 1999; Jung et al., 1999; Carta et al., 2000; Karasinska et al., 2000; Betancur et al., 2001; McNamara et al., 2002; Vallone et al., 2002; Boyce-Rustay and Risinger, 2003; Pritchard et al., 2003; Wong et al., 2003b). A possible cause of this variability is that the increase in activity in D3R KOs may be transient and restricted to the early phase of open field testing (Accili et al., 1996; Xu et al., 1997; Vallone et al., 2002). One interpretation of an exaggerated locomotor response during initial exposure to a novel environment is that it indicates reduced neophobia/anxiety-like behavior

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(Holmes, 2001). Supporting this possibility, some, but not all, studies D3R KO mice show a reduced anxietylike phenotype on the elevated plus-maze and open field (Steiner et al., 1997; Xu et al., 1997; Karasinska et al., 2000; Vallone et al., 2002). However, these data in KO mice are seemingly at odds with the anxiolyticlike effects of, albeit non-selective, D3R-preferring agonists (Rogers et al., 2000; Rogoz et al., 2003). Therefore, an alternative explanation for these changes is that they reflect a more general failure to inhibit behavior responses to novelty (see also Section 6.2). Indeed, indicating that D3R KO mice may harbor dysfunctions at the level of the prefrontal cortex, a brain region mediating in response inhibition, these mice exhibit working memory deficits and blunted prefrontal neuronal responses to D1R-like agonist treatment (Glickstein et al., 2002). In the rodent brain the D3R and D4R are expressed at much lower levels than the D2R (see also Section 6.1). In comparison to D2R, the D3R shows a highly restricted expression in limbic regions, including the nucleus accumbens (Sokoloff et al., 1990; Bouthenet et al., 1991; Levesque et al., 1992). This dense localization of D3R in the mescocortical circuit suggests that the receptor may play a prominent role in mediating reward-related behavior (for review, see Everitt et al., 1999). Indeed, drugs acting at the D3R are potent modulators of the reinforcing effects of psychostimulants and functional changes in D3R function are associated with altered responses to these drugs (Caine and Koob, 1993; Pilla et al., 1999; Xu et al., 2000a; Vorel et al., 2002). Further supporting a role for the D3R in reward, D3R KO mice show increased conditioned place preference to amphetamine and morphine (Xu et al., 1997; Narita et al., 2003). Moreover, suggesting D3R contribution to the reinforcing effects of cannabinoids, the ability of a cannabinoid CB1 receptor antagonist to activate nucleus accumbens neurons is diminished in D3R KO mice, but not D2R KOs (Duarte et al., 2003). Finally, one report has demonstrated reduced voluntary ethanol consumption, coupled with exaggerated ethanol-withdrawal and increased sensitivity to the hypnotic effects of ethanol in D3R KO mice (Narita et al., 2002). However, neither altered ethanol consumption, nor ethanol-induced conditioned place preference could be replicated in separate studies of D3R KO mice (Benoit et al., 2003; McQuade et al., 2003). Clearly, while additional research is needed, recent findings identify the D3R as an important component of the neural circuitry of reward and encourage further research in rewardrelated phenotypes in D3R KO mice.

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5.3. Supporting D1R-like/D2R-like cooperativity? D1R and D2R are present on the same striatal neurons, and while generally having mutually opposing effects on signal transduction, demonstrate cooperative/ synergistic effects under certain conditions (Walters et al., 1987; LaHoste et al., 1993, 2000 Xu et al., 1994a; Aizman et al., 2000). A supporting role for the D3R in modulating D1R/D2R cooperativity has been proposed (for discussion, see Glickstein and Schmauss, 2001). In this context, D3R KO mice show normal locomotor responses to treatment with either D1R-like or D2Rlike agents administered alone, but exaggerated hyperactivity responses to combined D1R-like/D2R-like agonist treatment (Accili et al., 1996; Xu et al., 1997; Betancur et al., 2001; Wong et al., 2003b; Yarkov et al., 2003). These findings are congruent with the idea that the D3R may normally inhibit the synergistic effects of D1R/D2R co-activation. However, a full picture of these processes is yet to emerge. For example, the synergistic hypoactive/cataleptic effects of D1R-likeþ D2R-like antagonist co-administration appear to be unaltered in D3R KO mice (Boulay et al., 2000). The ability of combined D1R-like þ D2R-like agonist administration to synergistically activate striatal neurons is also normal in D3R KO mice (Xu et al., 1997). Another approach to try and clarify the nature of functional interactions between the D1R, D2R and D3R has been to generate KO mice lacking the D3R and either the D1R or the D2R. Studies of D1Rþ D3R double KO mice are currently inconclusive, with reports showing that locomotor activity in double KOs is either no different from that seen in D1R KO mice, or that the hyperactivity observed in D1R KOs is further potentiated in mice lacking both D1R and D3R (Karasinska et al., 2000; Wong et al., 2003b). There is also some evidence that deletion of the D3R potentiates locomotor hypoactivity in D2R KO mice (Jung et al., 1999; but see Vallone et al., 2002). Elevations in striatal dopamine turnover and calbindin found in D2R KO mice have also been found to be augmented in D2R þ D3R double KO mice (Jung et al., 1999, 2000). These data suggest that the D2R and D3R normally mediate striatal function in a cooperative manner. This hypothesis would be consistent with the finding that striatal c-fos responses to D1R-like agonist stimulation are more effectively blocked by a combination of D3R gene deletion and D2R-antagonist treatment than either manipulation alone (Jung and Schmauss, 1999; Schmauss, 2000; Glickstein et al., 2002).

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6. D4R KO mice; losing (and gaining) their inhibitions 6.1. General In the only line of D4R KO mice currently available, mutant mice are viable, reproduce normally and show no gross morphological or neurological abnormalities (Rubinstein et al., 1997). Demonstrating an important role for the D4R in the regulation of adaptive retinal responses to changing levels of illumination, both basal and D2R-like agonist-induced photoreceptor responsivity is compromised in D4R KO mice (Nir et al., 2002). The D4R is expressed in the rodent striatum, albeit at significantly lower levels than the D2R (Van Tol et al., 1991; Primus et al., 1997; Khan et al., 1998). There is also a high density of D4R in rodent corticolimbic regions, including the prefrontal cortex, hippocampus, amygdala, and hypothalamus (MeadorWoodruff et al., 1996; Mrzljak et al., 1996; Ariano et al., 1997). Consistent with this relatively low abundance of the D4R, D2R-like binding is not demonstrably reduced in D4R KO mice (Rubinstein et al., 1997). However, D4R KO mice have been less extensively studied than other dopamine receptor KO mice and possible functional changes at other levels of the dopaminergic system, or in non-dopaminergic systems are yet to be thoroughly explored. A recent study has shown that both D1R and NMDA receptor binding is significantly increased in striatal regions on the D4R KO brain (Gan et al., 2004). Other work has demonstrated that a D4R-preferring agonist blocks the activity of GABAergic medium spiny neurons in the globus pallidus (via suppression of protein kinase A) and, conversely, that dopaminergic inhibition of these neurons is absent in D4R KO mice (Shin et al., 2003). This novel latter finding suggests that D4R may normally disinhibit basal ganglia output. 6.2. Behavior D4R KO mice show rotarod motor coordination superior to that of WT controls, exhibit exaggerated hyperactivity responses to both psychostimulants and ethanol, and are better at discriminating cocaine from saline than WTs (Rubinstein et al., 2001; Katz et al., 2003). One simplistic interpretation of these findings is that D4Rs may normally exert a generally inhibitory action on dopaminergic neurotransmission in certain brain regions. In agreement with this possibility, dopamine synthesis and turnover have been shown to be increased in the striatum, but not nucleus accumbens or frontal cortex, of D4R KO mice (Rubinstein et al., 1997, 2001). Moreover, electrophysiological studies

have demonstrated increased excitability of glutamatergic pyramidal neurons in the prefrontal cortex (but not striatum) of D4R KOs (Cepeda et al., 2001; Rubinstein et al., 2001). Finally, D4R KO mice exhibit increased susceptibility to the pro-convulsant effects of GABAA receptor antagonism (Rubinstein et al., 2001). This latter finding resembles the increased susceptibility to the epileptogenic and excitotoxic effects of glutamatergic or muscarinic receptor-challenge in D2R KO mice (Bozzi et al., 2000; Bozzi and Borrelli, 2002), and further supports a significant role for both the D2R and D4R in mediating neuronal excitability. While absence of the D4R may lead to a disinhibition of neural responses and increased sensitivity to stimulant drugs, research in both humans and D4R KO mice suggests a link between reduced D4R gene function and an abnormally high aversion to novelty. As noted above, across species, the D4R is densely expressed in the frontal cortex and limbic regions governing responses to novel and emotionally provocative stimuli (Meador-Woodruff et al., 1996; Mrzljak et al., 1996; Ariano et al., 1997). There is some evidence that individuals carrying a D4R gene variant that encodes for diminished ligand sensitivity show abnormally low levels of novelty-seeking (for review, see Paterson et al., 1999). In D4R KO mice, there are reports of moderately diminished open field locomotor activity, which may reflect an attenuated response to environmental novelty (Rubinstein et al., 1997; Katz et al., 2003). More saliently, specific investigation of novelty-seeking behavior in D4R KO mice has demonstrated heightened behavioral inhibition in high-novelty exploratory situations in mutant mice (Dulawa et al., 1999). Given that D4R KO mice were found to be normal in lownovelty, high-anxiety-provoking situations in this study, these phenotypic abnormalities appear to be specific to novelty, rather than anxiety (Dulawa et al., 1999). However, a subsequent study has found that D4R KO mice do display behavioral alterations consistent with increased anxiety-like behavior (Falzone et al., 2002). Therefore, the nature of changes in novelty-seeking, emotionality and behavioral inhibition in D4R KO mice is yet to be fully resolved.

7. Conclusions and future directions Phenotypic analysis of dopamine receptor KO mice has undoubtedly added to our understanding of how dopamine receptors function in the nervous system. In some cases this research has reinforced existing hypotheses regarding subtype function, for example, that the D2R is the prepotent autoreceptor controlling dopamine release and the D1R is integral to the behavioral and neural effects of psychostimulants. In other cases, dopamine receptor KO phenotypes appear to challenge

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preexisting ideas about subtype function, largely based on data from imperfect pharmacological tools (e.g., the D2R, rather than the D3R, mediates dopamineinduced hypothermia). Findings in dopamine receptor KO mice have also nurtured new avenues of research. KO mice have provided uniquely valuable tools for dissecting the functional specificity of the D2RS and D2RL isoforms, and the distinct role of the D5R. The various successes advocate the continued use of dopamine receptor KO mice. Research on dopamine receptor KO mice has been at the forefront of the debate regarding the utility of the gene targeting approach to study the brain. Since the first dopamine receptor KO mice were reported on in 1994, limitations of this approach have become apparent. As discussed earlier, variability in behavioral phenotypic abnormalities observed across laboratories has been linked to the influences of genetic background and variations in testing procedure (see Sections 2, 4.3 and 4.4). Perhaps an even thornier issue is the reason for discrepancies between the effects of genetic vs. pharmacological inactivation of a dopamine receptor. There are a number of examples where phenotypic alterations in dopamine receptor KO mice differ from the predicted effects of pharmacological antagonists. These differences can be quantitative, as in the modest decrease in basal locomotor activity in D2R KO mice relative to the profound hypoactivity/catalepsyinducing effects of D2R-like antagonists in normal mice, and they can be qualitative, as in the hyperactive phenotype in D1R KO mice that is opposite to the hypoactivity/catalepsy-inducing effects of D1R-like antagonists. The fact that the locomotor effects of D2R-like and D1R-like antagonists are effectively abolished in D2R mice and D1R KO mice, respectively, makes it unlikely that they are normally mediated through other subtypes in each sub-family. Rather, these discrepancies suggest that adaptive changes have occurred in KO mice as a result of lifelong deletion of a receptor. In hindsight, the extent of these changes is perhaps not surprising given the significant plasticity of the brain, especially during development. Indeed, identifying the nature of compensatory processes could itself provide valuable insight into the plasticity and functional interconnectivity of the dopamine system. However, adaptive changes are clearly undesirable when the goal is to understand how a receptor subtype normally functions ceteris paribus. Because of the potential for the recruitment of compensatory changes to occlude or otherwise alter the normal function of a dopamine receptor subtype, it is now widely accepted that phenotypic abnormalities in KO mice must be interpreted with this caveat in mind. There are also a number of emerging approaches that can help mitigate the problem of compensation in dopamine receptor KO mice. One powerful approach is to restrict

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inactivation of dopamine receptor genes to specific brain regions or cell types. Induction of such ‘‘conditional’’ inactivation can also be withheld until after development to further limit the occurrence of adaptive changes (Heyer et al., 2002). Alternatives to gene targeting are also available, including antisense knockdown of dopamine receptors (Sibley, 1999) and, more recently, viral-mediated RNA interference of dopamine function (Hommel et al., 2003). Lastly, the development of novel highly selective dopamine receptor subtype agonists and antagonists will have a major impact on the field. Even with these important advances, researchers now recognize that KO mice are no research panacea. Dopamine receptor KO mice are most effectively utilized when employed in conjunction with other techniques, where available, to generate converging lines of evidence regarding dopamine receptor function. Understanding functional specification of dopamine receptor subtypes remains a fundamental question in neuroscience. Progress in this field of research has profound implications for the improved understanding and treatment of many common neurological and neuropsychiatric diseases. There is still much to accomplish to define the role of dopamine receptor subtypes in these disorders using KO mice. Of particular note, the role of specific dopamine receptor subtypes localized in the prefrontal cortex in mediating a variety of behaviors including cognition and reward is currently under-explored, as is the role of cortical and limbic dopamine receptors in the regulation of emotion and stress. These studies could contribute significantly to the development of novel pharmacotherapies for schizophrenia, addiction and mood disorders. Likewise, there are still significant advances to be made in understanding the nature of striatal dopamine dysfunction in Parkinson’s disease and other neurodegenerative movement disorders. We envision that dopamine receptor KO mice will continue to contribute a major component to research directed at meeting these objectives.

Acknowledgements DRS and AH are supported by the NIH Intramural Research Program.

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