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The Journal of Neuroscience, April 1, 2002, 22(7):2977-2988
Role of Dopamine D2-like Receptors in Cocaine
Self-Administration: Studies with D2 Receptor Mutant Mice and Novel D2
Receptor Antagonists
S. Barak
Caine1,
S.
Stevens
Negus1,
Nancy K.
Mello1,
Smita
Patel2,
Linda
Bristow2,
Janusz
Kulagowski2,
Daniela
Vallone3,
Adolfo
Saiardi3, and
Emiliana
Borrelli3
1 Alcohol and Drug Abuse Research Center, McLean
Hospital, Harvard Medical School, Belmont, Massachusetts 02478, 2 Merck, Sharp and Dohme Neuroscience Research
Laboratories, Harlow, Essex CM20 2QR, United Kingdom, and
3 Institut de Génétique et de Biologie
Moléculaire et Cellulaire, 67404 Illkirch Cedex, Strasbourg,
France
Dopamine receptor subtypes have been classified generally as
D1-like (e.g., D1, D5) or D2-like (D2, D3, D4), and converging evidence
suggests that D2-like receptors may be especially important in
mediating the abuse-related effects of cocaine. However, it has been
difficult to differentiate the roles of the D2-like receptor subtypes
in the behavioral effects of cocaine because of the relatively low
selectivity of drugs for D2, D3, and D4 receptors in
vivo. The goal of the present series of studies was to
investigate the contributions of D2-like receptor subtypes in the
reinforcing effects of cocaine using new genetic and pharmacological
tools. First, we evaluated cocaine self-administration behavior, and related effects of nonselective D2-like drugs, in mutant mice that lack
the D2 receptor but express D3 and D4 receptors. When high doses of
cocaine on the descending limb of the cocaine dose-effect function
were available, D2 mutant mice self-administered at higher rates than
their heterozygous or wild-type littermates, but the ascending limb of
the cocaine dose-effect function did not differ between genotypes.
Elevated rates of drug intake were not attributable to nonspecific
increases in response rate, because response rates maintained by
presentation of a range of food concentrations were significantly lower
in D2 mutant mice than in wild-type mice. In wild-type mice,
pretreatment with the D2-like antagonist eticlopride increased rates of
self-administration of high doses of cocaine, and the D2-like agonist
quinelorane served as a positive reinforcer when substituted for
cocaine. However, these effects of eticlopride and quinelorane were not
observed in mice that lacked the D2 receptor. Next, we compared the
effects of novel antagonists selective for different D2 receptor
subtypes on cocaine self-administration behavior in outbred rats. In
rats, a D2 selective antagonist increased rates of self-administration
of high doses of cocaine and also combinations of cocaine and the
D2-like agonist quinelorane, whereas D3/D4 antagonists were
ineffective. Collectively, these findings suggest that the D2 receptor
is not necessary for cocaine self-administration, but this receptor
subtype is involved in mechanisms that limit rates of high-dose cocaine
self-administration. Our results also suggest that D3 and D4 receptors
do not play major roles in the modulation of cocaine
self-administration by D2-like drugs.
Key words:
dopamine; cocaine; D2; D3; D4; receptor
Copyright © 2002 Society for Neuroscience 0270-6474/02/2272977-12$05.00/0
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