Elsevier

Neuropharmacology

Volume 47, Issue 8, December 2004, Pages 1117-1134
Neuropharmacology

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

https://doi.org/10.1016/j.neuropharm.2004.07.034Get rights and content

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.

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.

References (222)

  • J.J. Clifford et al.

    Conservation of behavioural topography to dopamine D1-like receptor agonists in mutant mice lacking the D1A receptor implicates a D1-like receptor not coupled to adenylyl cyclase

    Neuroscience

    (1999)
  • J.J. Clifford et al.

    Topographical evaluation of behavioural phenotype in a line of mice with targeted gene deletion of the D2 dopamine receptor

    Neuropharmacology

    (2000)
  • J.J. Clifford et al.

    Comparative, topographically-based evaluation of behavioural phenotype and specification of D(1)-like:D(2) interactions in a line of incipient congenic mice with D(2) dopamine receptor ‘knockout’

    Neuropsychopharmacology

    (2001)
  • W.E. Crusio

    Gene-targeting studies: new methods, old problems

    Trends in Neuroscience

    (1996)
  • C.L. Cunningham et al.

    Ethanol-conditioned place preference is reduced in dopamine D2 receptor-deficient mice

    Pharmacology, Biochemistry and Behavior

    (2000)
  • S. Dracheva et al.

    Locomotor behavior of dopamine D1 receptor transgenic/D2 receptor deficient hybrid mice

    Brain Research

    (2001)
  • S. Dracheva et al.

    Paradoxical locomotor behavior of dopamine D1 receptor transgenic mice

    Experimental Neurology

    (1999)
  • J. Drago et al.

    D1 dopamine receptor-deficient mouse: cocaine-induced regulation of immediate-early gene and substance P expression in the striatum

    Neuroscience

    (1996)
  • F. Drago et al.

    The expression of neuropeptide-induced excessive grooming behavior in dopamine D1 and D2 receptor-deficient mice

    European Journal of Pharmacology

    (1999)
  • M. El-Ghundi et al.

    Disruption of dopamine D1 receptor gene expression attenuates alcohol-seeking behavior

    European Journal of Pharmacology

    (1998)
  • M. El-Ghundi et al.

    Spatial learning deficit in dopamine D(1) receptor knockout mice

    European Journal of Pharmacology

    (1999)
  • M. El-Ghundi et al.

    Prolonged fear responses in mice lacking dopamine D1 receptor

    Brain Research

    (2001)
  • L.A. Fetsko et al.

    Alterations in D1/D2 synergism may account for enhanced stereotypy and reduced climbing in mice lacking dopamine D2L receptor

    Brain Research

    (2003)
  • R. Gerlai

    Gene-targeting studies of mammalian behavior: is it the mutation or the background genotype?

    Trends in Neuroscience

    (1996)
  • S.B. Glickstein et al.

    Dopamine receptor functions: lessons from knockout mice [corrected]

    Pharmacology and Therapeutics

    (2001)
  • A.I. Hersi et al.

    Dopamine D-5 receptor modulates hippocampal acetylcholine release

    Brain Research Molecular Brain Research

    (2000)
  • A. Holmes

    Targeted gene mutation approaches to the study of anxiety-like behavior in mice

    Neuroscience and Biobehavioral Reviews

    (2001)
  • A. Holmes et al.

    Responses of Swiss-Webster mice to repeated plus-maze experience: further evidence for a qualitative shift in emotional state?

    Pharmacology, Biochemistry and Behavior

    (1998)
  • B. Hunyady et al.

    Susceptibility of dopamine D5 receptor targeted mice to cysteamine

    Journal of Physiology (Paris)

    (2001)
  • M.Y. Jung et al.

    Decreased c-fos responses to dopamine D(1) receptor agonist stimulation in mice deficient for D(3) receptors

    Journal of Biological Chemistry

    (1999)
  • M.Y. Jung et al.

    Potentiation of the D2 mutant motor phenotype in mice lacking dopamine D2 and D3 receptors

    Neuroscience

    (1999)
  • M.Y. Jung et al.

    Targeted disruption of the dopamine D(2) and D(3) receptor genes leads to different alterations in the expression of striatal calbindin-D(28k)

    Neuroscience

    (2000)
  • D. Accili et al.

    A targeted mutation of the D3 dopamine receptor gene is associated with hyperactivity in mice

    Proceedings of the National Academy of Sciences USA

    (1996)
  • O. Aizman et al.

    Anatomical and physiological evidence for D1 and D2 dopamine receptor colocalization in neostriatal neurons

    Nature Neuroscience

    (2000)
  • S. Aoyama et al.

    Rescue of locomotor impairment in dopamine D2 receptor-deficient mice by an adenosine A2A receptor antagonist

    The Journal of Neuroscience

    (2000)
  • E.M. Apostolakis et al.

    Dopaminergic regulation of progesterone receptors: brain D5 dopamine receptors mediate induction of lordosis by D1-like agonists in rats

    The Journal of Neuroscience

    (1996)
  • A.F. Arnsten et al.

    Noise stress impairs prefrontal cortical cognitive function in monkeys: evidence for a hyperdopaminergic mechanism

    Archives of General Psychiatry

    (1998)
  • S.L. Asa et al.

    Pituitary lactotroph adenomas develop after prolonged lactotroph hyperplasia in dopamine D2 receptor-deficient mice

    Endocrinology

    (1999)
  • L.D. Asico et al.

    Disruption of the dopamine D3 receptor gene produces renin-dependent hypertension

    Journal of Clinical Investigation

    (1998)
  • M.E. Bach et al.

    Age-related defects in spatial memory are correlated with defects in the late phase of hippocampal long-term potentiation in vitro and are attenuated by drugs that enhance the cAMP signaling pathway

    Proceedings of the National Academy of Sciences USA

    (1999)
  • J.H. Baik et al.

    Parkinsonian-like locomotor impairment in mice lacking dopamine D2 receptors

    Nature

    (1995)
  • J. Baufreton et al.

    D5 (not D1) dopamine receptors potentiate burst-firing in neurons of the subthalamic nucleus by modulating an L-type calcium conductance

    The Journal of Neuroscience

    (2003)
  • A. Becker et al.

    Loss of locomotor sensitisation in response to morphine in D1 receptor deficient mice

    Naunyn Schmiedebergs Archives of Pharmacology

    (2001)
  • M. Benoit-Marand et al.

    Inhibition of dopamine release via presynaptic D2 receptors: time course and functional characteristics in vivo

    The Journal of Neuroscience

    (2001)
  • S.C. Benoit et al.

    Altered feeding responses in mice with targeted disruption of the dopamine-3 receptor gene

    Behavioral Neuroscience

    (2003)
  • C. Bergson et al.

    Characterization of subtype-specific antibodies to the human D5 dopamine receptor: studies in primate brain and transfected mammalian cells

    Proceedings of the National Academy of Sciences USA

    (1995)
  • Y. Bozzi et al.

    Absence of the dopamine D2 receptor leads to a decreased expression of GDNF and NT-4 mRNAs in restricted brain areas

    European Journal of Neuroscience

    (1999)
  • Y. Bozzi et al.

    Neuroprotective role of dopamine against hippocampal cell death

    The Journal of Neuroscience

    (2000)
  • D.L. Braff et al.

    Human studies of prepulse inhibition of startle: normal subjects, patient groups, and pharmacological studies

    Psychopharmacology (Berlin)

    (2001)
  • M. Bucan et al.

    The mouse: genetics meets behaviour

    Nature Reviews Genetics

    (2002)
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