Enhanced locomotor, reinforcing, and neurochemical effects of cocaine in serotonin 5-hydroxytryptamine 2C receptor mutant mice.
Brain serotonin [5-hydroxytryptamine (5-HT)] systems substantially influence the effects of cocaine; however, the contributions of individual 5-HT receptor subtypes to the regulation of cocaine responses are unclear. A line of mutant mice devoid of 5-HT2C receptors was used to examine the contribution of this receptor subtype to the serotonergic modulation of cocaine responses. Mutants display enhanced exploration of a novel environment and increased sensitivity to the locomotor stimulant effects of cocaine. In an operant intravenous self-administration model under a progressive ratio schedule of reinforcement, mutants display elevated levels of lever pressing for cocaine injections, indicating that the drug is more reinforcing in these mice. Moreover, mutants exhibit enhanced cocaine-induced elevations of dopamine (DA) levels in the nucleus accumbens, a brain region implicated in the stimulant and rewarding properties of cocaine. In contrast, phenotypic differences in dorsal striatal DA levels were not produced by cocaine treatment. These findings strongly implicate 5-HT2C receptors in the serotonergic suppression of DA-mediated behavioral responses to cocaine and as a potential therapeutic target for cocaine abuse.
Rocha
Beatriz A
BA
National Institute on Drug Abuse/Intramural Research Program, Baltimore, Maryland 21224, USA.
Goulding
Evan H
EH
O'Dell
Laura E
LE
Mead
Andy N
AN
Coufal
Nicole G
NG
Parsons
Loren H
LH
Tecott
Laurence H
LH
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001923:Brain Chemistry / Q000187:drug effects; D003042:Cocaine / Q000008:administration & dosage / Q000494:pharmacology*; D019970:Cocaine-Related Disorders / Q000235:genetics / Q000378:metabolism*; D003216:Conditioning, Operant / Q000187:drug effects; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D004298:Dopamine / Q000032:analysis / Q000378:metabolism; D004351:Drug Resistance / Q000235:genetics; D005106:Exploratory Behavior / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D017551:Microdialysis; D009043:Motor Activity / Q000187:drug effects*; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism; D044405:Receptor, Serotonin, 5-HT2C; D011985:Receptors, Serotonin / Q000172:deficiency* / Q000235:genetics; D012054:Reinforcement, Psychology; D012646:Self Administration
D044405:Receptor, Serotonin, 5-HT2C; D011985:Receptors, Serotonin; D003042:Cocaine; D004298:Dopamine