Document Detail

Antagonism of 5-hydroxytryptamine(4) receptors attenuates hyperactivity induced by cocaine: putative role for 5-hydroxytryptamine(4) receptors in the nucleus accumbens shell.
MedLine Citation:
PMID:  10490917     Owner:  NLM     Status:  MEDLINE    
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.
L R McMahon; K A Cunningham
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Publication Detail:
Type:  Journal Article; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  The Journal of pharmacology and experimental therapeutics     Volume:  291     ISSN:  0022-3565     ISO Abbreviation:  J. Pharmacol. Exp. Ther.     Publication Date:  1999 Oct 
Date Detail:
Created Date:  1999-10-12     Completed Date:  1999-10-12     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  0376362     Medline TA:  J Pharmacol Exp Ther     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  300-7     Citation Subset:  IM    
Department of Pharmacology and Toxicology, The University of Texas Medical Branch, Galveston, Texas, USA.
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MeSH Terms
4-Aminobenzoic Acid / administration & dosage,  analogs & derivatives,  pharmacology
Aniline Compounds / administration & dosage,  pharmacology
Cocaine / pharmacology*
Nucleus Accumbens / drug effects*,  metabolism
Piperidines / administration & dosage,  pharmacology
Rats, Sprague-Dawley
Receptors, Serotonin / drug effects,  metabolism*
Receptors, Serotonin, 5-HT4
Serotonin Agonists / administration & dosage,  pharmacology
Serotonin Antagonists / pharmacology*
Grant Support
Reg. No./Substance:
0/Aniline Compounds; 0/Piperidines; 0/Receptors, Serotonin; 0/Serotonin Agonists; 0/Serotonin Antagonists; 137196-67-9/SDZ 205-557; 150-13-0/4-Aminobenzoic Acid; 158165-40-3/Receptors, Serotonin, 5-HT4; 160845-95-4/RS 67333; 50-36-2/Cocaine

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