ReviewPhenotypic analysis of dopamine receptor knockout mice; recent insights into the functional specificity of dopamine receptor subtypes
Introduction
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 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 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.
Section snippets
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, Xu et al., 1994b). 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
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
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
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
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
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 preexisting ideas about
Acknowledgements
DRS and AH are supported by the NIH Intramural Research Program.
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