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Antagonism of 5-hydroxytryptamine(4) receptors attenuates hyperactivity induced by cocaine: putative role for 5-hydroxytryptamine(4) receptors in the nucleus accumbens shell.
J Pharmacol Exp Ther. 1999 Oct; 291(1):300-7.JP

Abstract

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.

Authors+Show Affiliations

Department of Pharmacology and Toxicology, The University of Texas Medical Branch, Galveston, Texas, USA.No affiliation info available

Pub Type(s)

Journal Article
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

10490917

Citation

McMahon, L R., and K A. Cunningham. "Antagonism of 5-hydroxytryptamine(4) Receptors Attenuates Hyperactivity Induced By Cocaine: Putative Role for 5-hydroxytryptamine(4) Receptors in the Nucleus Accumbens Shell." The Journal of Pharmacology and Experimental Therapeutics, vol. 291, no. 1, 1999, pp. 300-7.
McMahon LR, Cunningham KA. Antagonism of 5-hydroxytryptamine(4) receptors attenuates hyperactivity induced by cocaine: putative role for 5-hydroxytryptamine(4) receptors in the nucleus accumbens shell. J Pharmacol Exp Ther. 1999;291(1):300-7.
McMahon, L. R., & Cunningham, K. A. (1999). Antagonism of 5-hydroxytryptamine(4) receptors attenuates hyperactivity induced by cocaine: putative role for 5-hydroxytryptamine(4) receptors in the nucleus accumbens shell. The Journal of Pharmacology and Experimental Therapeutics, 291(1), 300-7.
McMahon LR, Cunningham KA. Antagonism of 5-hydroxytryptamine(4) Receptors Attenuates Hyperactivity Induced By Cocaine: Putative Role for 5-hydroxytryptamine(4) Receptors in the Nucleus Accumbens Shell. J Pharmacol Exp Ther. 1999;291(1):300-7. PubMed PMID: 10490917.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Antagonism of 5-hydroxytryptamine(4) receptors attenuates hyperactivity induced by cocaine: putative role for 5-hydroxytryptamine(4) receptors in the nucleus accumbens shell. AU - McMahon,L R, AU - Cunningham,K A, PY - 1999/9/22/pubmed PY - 1999/9/22/medline PY - 1999/9/22/entrez SP - 300 EP - 7 JF - The Journal of pharmacology and experimental therapeutics JO - J. Pharmacol. Exp. Ther. VL - 291 IS - 1 N2 - 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. SN - 0022-3565 UR - https://www.unboundmedicine.com/medline/citation/10490917/Antagonism_of_5_hydroxytryptamine_4__receptors_attenuates_hyperactivity_induced_by_cocaine:_putative_role_for_5_hydroxytryptamine_4__receptors_in_the_nucleus_accumbens_shell_ L2 - http://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=10490917 DB - PRIME DP - Unbound Medicine ER -