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Research ArticleBEHAVIORAL PHARMACOLOGY

Contribution of Serotonin (5-Hydroxytryptamine; 5-HT) 5-HT2 Receptor Subtypes to the Hyperlocomotor Effects of Cocaine: Acute and Chronic Pharmacological Analyses

Malgorzata Filip, Marcy J. Bubar and Kathryn A. Cunningham
Journal of Pharmacology and Experimental Therapeutics September 2004, 310 (3) 1246-1254; DOI: https://doi.org/10.1124/jpet.104.068841
Malgorzata Filip
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Marcy J. Bubar
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Kathryn A. Cunningham
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Abstract

The role of serotonin (5-hydroxytryptamine; 5-HT) 5-HT2 receptor subtypes (5-HT2AR, 5-HT2BR, and 5-HT2CR) in acute cocaine-evoked hyperactivity was compared with their contribution to the development and expression of locomotor sensitization upon repeated, intermittent treatment with cocaine (10 mg/kg/day for 5 days) in male Wistar rats. Cocaine-evoked hyperactivity was significantly enhanced by pretreatment with the preferential 5-HT2AR agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) and the 5-HT2CR antagonist SDZ SER-082 [(+)-cis-4,5,7a,8,9,10,11,11a-octahydro-7H-10-methylindolo(1,7-BC)(2,6) naphthyridine fumarate]. The 5-HT2AR antagonist SR 46349B [1(Z)-[2-(dimethylamino)ethoxyimino]-1(2-fluorophenyl)-3-(4-hydroxyphenyl)-2(E)-propene] and the preferential 5-HT2CR agonist MK 212 [6-chloro-2-(1-piperazinyl)pyrazine HCl] (2 mg/kg) significantly attenuated acute cocaine-evoked hyperactivity; however, a lower dose of MK 212 (0.3 mg/kg) enhanced cocaine-evoked hyperactivity. The 5-HT2BR agonist BW 723C86 (1-[5-(2-thienylmethoxy)-1H-3-indolyl]propan-2-amine HCl) and the 5-HT2BR antagonist SB 204741 [N-(1-methyl-5-indolyl)-N′-(3-methyl-5-isothiazolyl) urea] had no effect on cocaine-evoked hyperactivity. Repeated treatment with cocaine alone resulted in a 2-fold increase in hyperactivity upon challenge with cocaine 5 days after termination of the cocaine regimen (sensitization). The 5-HT2AR antagonist SR 46349B also blocked cocaine-evoked hyperactivity following repeated cocaine treatment, whereas the other 5-HT2R ligands were ineffective. When any of the 5-HT2R ligands was coadministered with cocaine during the treatment regimen (10 mg/kg/day for 5 days), the development of sensitization was unchanged as measured by the level of cocaine-evoked hyperactivity upon challenge 5 days after termination of the treatment. The present study implies that 5-HT2AR and 5-HT2CR exert oppositional influence upon hyperactivity evoked by acute administration of cocaine; this balance is altered following repeated cocaine administration.

Footnotes

  • This research was supported by grants from the U.S.-Poland Joint Commission Maria Sklodowska Curie Fund, the National Institute on Drug Abuse [DA 06511 (K.A.C.), DA 00260 (K.A.C.), DA 15259 (M.J.B.)], and the statutory activity of the Institute of Pharmacology Polish Academy of Sciences in Krakow.

  • doi:10.1124/jpet.104.068841.

  • ABBREVIATIONS: DA, dopamine; 5-HT, 5-hydroxytryptamine, serotonin; 5-HT2R, serotonin2 receptor; SR 46349B, 1(Z)-[2-(dimethylamino)ethoxyimino]-1(2-fluorophenyl)-3-(4-hydroxyphenyl)-2(E)-propene; MK 212, 6-chloro-2-(1-piperazinyl)pyrazine HCl; DOI, 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane; SDZ SER-082, (+)-cis-4,5,7a,8,9,10,11,11a-octahydro-7H-10-methylindolo(1,7-BC)(2,6) naphthyridine fumarate; BW 723C86, 1-[5-(2-thienylmethoxy)-1H-3-indolyl]propan-2-amine HCl; SB 204741, N-(1-methyl-5-indolyl)-N′-(3-methyl-5-isothiazolyl) urea; ANOVA, analysis of variance; M100907, R-(+)-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenylethyl)]-4-piperidine-methanol; SB 242084, 6-chloro-5-methyl-1-[[2-(2-methylpyridyl-3-oxy)-pyrid-5-yl]carbamoyl]indoline; SB 206553, N-3-pyridinyl-3,5-dihydro-5-methyl-benzo(1,2-b:4,5-b′)dipyrrole-1(2H)carboxamide hydrochloride; GABA, γ-aminobutyric acid; NAc, nucleus accumbens; PFC, prefrontal cortex; VTA, ventral tegmental area.

    • Received March 24, 2004.
    • Accepted May 6, 2004.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 310 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 310, Issue 3
1 Sep 2004
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Research ArticleBEHAVIORAL PHARMACOLOGY

Contribution of Serotonin (5-Hydroxytryptamine; 5-HT) 5-HT2 Receptor Subtypes to the Hyperlocomotor Effects of Cocaine: Acute and Chronic Pharmacological Analyses

Malgorzata Filip, Marcy J. Bubar and Kathryn A. Cunningham
Journal of Pharmacology and Experimental Therapeutics September 1, 2004, 310 (3) 1246-1254; DOI: https://doi.org/10.1124/jpet.104.068841

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Research ArticleBEHAVIORAL PHARMACOLOGY

Contribution of Serotonin (5-Hydroxytryptamine; 5-HT) 5-HT2 Receptor Subtypes to the Hyperlocomotor Effects of Cocaine: Acute and Chronic Pharmacological Analyses

Malgorzata Filip, Marcy J. Bubar and Kathryn A. Cunningham
Journal of Pharmacology and Experimental Therapeutics September 1, 2004, 310 (3) 1246-1254; DOI: https://doi.org/10.1124/jpet.104.068841
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