Antagonism of 5-hydroxytryptamine(4) receptors attenuates hyperactivity induced by cocaine: putative role for 5-hydroxytryptamine(4) receptors in the nucleus accumbens shell.
The localization of 5-hydroxytryptamine(4) (5-HT(4)) receptors suggests their role in the regulation of dopamine (DA) neurotransmission, a speculation that has been supported by neurochemical studies. Mesolimbic DA systems play a prominent role in mediating the behavioral effects of the abused psychostimulant cocaine, and the intent of the present study was to assess the role of 5-HT(4) receptors in the control of spontaneous and cocaine-induced activity. Systemic administration of the 5-HT(4) receptor partial agonist 1-(4-amino-5-chloro-2-methoxyphenyl)-3-[1-butyl-4-piperidinyl]1-propa none hydrochloride (RS 67333; 0.0001-1 mg/kg) or the 5-HT(4) receptor antagonist 4-amino-5-chloro-2-methoxy-benzoic acid-(diethylamino)ethyl ester hydrochloride (SDZ 205,557; 0.0001-1 mg/kg) did not significantly alter spontaneous activity, whereas SDZ 205,557 significantly attenuated cocaine-induced horizontal activity and rearing. To test the hypothesis that cocaine-elicited behaviors were modulated by 5-HT(4) receptors in the nucleus accumbens (NAc) shell, two separate groups of male rats were implanted with bilateral cannulas aimed at the NAc shell. Intra-NAc shell microinjections of either RS 67333 (1 or 3 microgram/0.2 microliter/side) or SDZ 205,557 (1-5 microgram/0.2 microliter/side) did not alter spontaneous activity observed after a systemic saline injection but did significantly attenuate the hyperactivity induced by systemic cocaine injection (10 mg/kg). These results support an involvement of 5-HT(4) receptors, particularly those in the NAc shell, in the locomotor stimulatory effects of cocaine. Furthermore, these data suggest that 5-HT(4) receptors may regulate behavioral processes dependent on mesolimbic DA pathways and may provide a novel target for the development of medications useful in the treatment of both drug dependence and psychiatric disorders.
McMahon
L R
LR
Department of Pharmacology and Toxicology, The University of Texas Medical Branch, Galveston, Texas, USA.
Cunningham
K A
KA
D010129:4-Aminobenzoic Acid / Q000008:administration & dosage / Q000494:pharmacology; D000814:Aniline Compounds / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D003042:Cocaine / Q000494:pharmacology*; D008297:Male; D009714:Nucleus Accumbens / Q000187:drug effects* / Q000378:metabolism; D010880:Piperidines / Q000008:administration & dosage / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011985:Receptors, Serotonin / Q000187:drug effects / Q000378:metabolism*; D044422:Receptors, Serotonin, 5-HT4; D012702:Serotonin Antagonists / Q000494:pharmacology*; D017366:Serotonin Receptor Agonists / Q000008:administration & dosage / Q000494:pharmacology; D062366:para-Aminobenzoates
D000814:Aniline Compounds; D010880:Piperidines; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D062366:para-Aminobenzoates; C072790:2-methoxy-4-amino-5-chlorobenzoic acid 2-(diethylamino)ethyl ester; D044422:Receptors, Serotonin, 5-HT4; C107826:RS 67333; D003042:Cocaine; D010129:4-Aminobenzoic Acid