Abstract
Drug-elicited head-twitch behavior is a useful model for studying hallucinogen activity at 5-HT2A receptors in the mouse. Chemically diverse compounds active in this assay yield biphasic dose-effect curves, but there is no compelling explanation for the “descending” portion of these functions. A set of experiments was designed to test the hypothesis that the induction of head-twitch behavior is mediated by agonist actions at 5-HT2A receptors, whereas the inhibition of head-twitch behavior observed at higher doses results from competing agonist activity at 5-HT2C receptors. The effects of the phenethylamine hallucinogen R(−)-2,5-dimethoxy-4-iodoamphetamine (DOI) on head-twitch behavior were studied over a range of doses in the mouse, generating a characteristic biphasic dose-response curve. Pretreatment with the selective 5-HT2A antagonist (+)-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenylethyl)]-4-piperidine-methanol (M100907) shifted only the ascending limb of the DOI dose-effect function, whereas pretreatment with the nonselective 5-HT2A/2C antagonist 3-{2-[4-(4-fluorobenzoyl)piperidin-1-yl]ethyl}quinazoline-2,4(1H,3H)-dione (ketanserin) produced a parallel shift to the right in the DOI dose-response curve. Administration of the 5-HT2C agonist S-2-(chloro-5-fluoro-indol-l-yl)-1-methylethylamine (Ro 60-0175) noncompetitively inhibited DOI-elicited head-twitch behavior across the entire dose-effect function. Finally, pretreatment with the selective 5-HT2C antagonists 6-chloro-5-methyl-1-[(2-[2-methylpyrid-3-yloxy]pyrid-5yl)carbamoyl]indoline (SB242084) or 8-[5-(2,4-dimethoxy-5-(4-trifluoromethylphenylsulfonamido)phenyl-5-oxopentyl]-1,3,8-triazaspiro[4,5]decane-2,4-dione hydrochloride (RS 102221) did not alter DOI-elicited head-twitch behavior on the ascending limb of the dose-response curve but shifted the descending limb of the DOI dose-response function to the right. The results of these experiments provide strong evidence that DOI-elicited head-twitch behavior is a 5-HT2A agonist-mediated effect, with subsequent inhibition of head-twitch behavior being driven by competing 5-HT2C agonist activity.
Footnotes
This work was supported in part by the Intramural Research program of the National Institutes of Health National Institute on Drug Abuse and National Institute on Alcohol Abuse and Alcoholism; the National Institutes of Health National Institute on Drug Abuse [Grant DA020645]; the National Institutes of Health National Center for Research Resources [Grants RR020146, RR00165]; the College on Problems of Drug Dependence; and the American Society for Pharmacology and Experimental Therapeutics [Summer Undergraduate Research Fellowship (to C.M.H.)].
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
doi:10.1124/jpet.110.172247.
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ABBREVIATIONS:
- 5-HT
- serotonin
- DOI
- R(−)-2,5-dimethoxy-4-iodoamphetamine
- HTR
- head-twitch response
- Ro 60-0175
- S-2-(chloro-5-fluoro-indol-l-yl)-1-methylethylamine
- SB242084
- 6-chloro-5-methyl-1-[(2-[2-methylpyrid-3-yloxy]pyrid-5yl)carbamoyl]indoline
- RS 102221
- 8-[5-(2,4-dimethoxy-5-(4-trifluoromethylphenylsulfonamido)phenyl-5-oxopentyl]-1,3,8-triazaspiro[4,5]decane-2,4-dione hydrochloride
- M100907
- (+)-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenylethyl)]-4-piperidine-methanol
- ketanserin
- 3-{2-[4-(4-fluorobenzoyl)piperidin-1-yl]ethyl}quinazoline-2,4(1H,3H)-dione
- SDZ-SER 082
- (+)-cis-4,5,7a,8,9,10,11,11a-octahydro-7H-10-methylindolo[1,7-bc][2,6]-naphthyridine fumarate
- 2C-T-7
- 2,5-dimethoxy-4-(n)-propylthiophenethylamine.
- Received June 29, 2010.
- Accepted September 16, 2010.
- U.S. Government work not protected by U.S. copyright
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