Deletion of the 5-HT(3A)-receptor subunit blunts the induction of cocaine sensitization.
Serotonin (5-HT) receptors are classified into seven groups (5-HT(1-7)), comprising at least 14 structurally and pharmacologically distinct receptor subtypes. Pharmacological antagonism of ionotropic 5-HT(3) receptors has been shown to modulate both behavioral and neurochemical aspects of the induction of sensitization to cocaine. It is not known, however, if specific molecular subunits of the 5-HT(3) receptor influence the development of cocaine sensitization. To address this question, we studied the effects of acute and chronic intermittent cocaine administration in mice with a targeted deletion of the gene for the 5-HT(3A)-receptor subunit (5-HT(3A)-/-). 5-HT(3A) (-/-) mice showed blunted induction of cocaine-induced locomotor sensitization as compared with wild-type littermate controls. 5-HT(3A) (-/-) mice did not differ from wild-type littermate controls on measures of basal motor activity or response to acute cocaine treatment. Enhanced locomotor response to saline injection following cocaine sensitization was observed equally in 5-HT(3A) (-/-) and wild-type mice suggesting similar conditioned effects associated with chronic cocaine treatment. These data show a role for the 5-HT(3A)-receptor subunit in the induction of behavioral sensitization to cocaine and suggest that the 5-HT(3A) molecular subunit modulates neurobehavioral adaptations to cocaine, which may underlie aspects of addiction.
Hodge
C W
CW
Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. chodge@med.unc.edu
Bratt
A M
AM
Kelley
S P
SP
D000818:Animals; D000697:Central Nervous System Stimulants / Q000494:pharmacology*; D002872:Chromosome Deletion; D003042:Cocaine / Q000494:pharmacology*; D019970:Cocaine-Related Disorders / Q000235:genetics* / Q000523:psychology; D003213:Conditioning, Psychological / Q000187:drug effects; D003433:Crosses, Genetic; D006580:Genetic Carrier Screening; D005838:Genotype; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects* / Q000235:genetics*; D009154:Mutation / Q000235:genetics; D044406:Receptors, Serotonin, 5-HT3 / Q000235:genetics*; D011995:Recombination, Genetic / Q000235:genetics
D000697:Central Nervous System Stimulants; D044406:Receptors, Serotonin, 5-HT3; D003042:Cocaine