TY - JOUR
T1 - Interaction of 5-HT2Aand 5-HT2C receptors in R(-)-2,5-dimethoxy-4-iodoamphetamine-elicited head twitch behavior in mice
AU - Fantegrossi, William E.
AU - Simoneau, J.
AU - Cohen, M. S.
AU - Zimmerman, S. M.
AU - Henson, C. M.
AU - Rice, K. C.
AU - Woods, J. H.
PY - 2010/12
Y1 - 2010/12
N2 - 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-HT 2C 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.
AB - 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-HT 2C 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.
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U2 - 10.1124/jpet.110.172247
DO - 10.1124/jpet.110.172247
M3 - Article
C2 - 20858706
AN - SCOPUS:78649549071
VL - 335
SP - 728
EP - 734
JO - Journal of Pharmacology and Experimental Therapeutics
JF - Journal of Pharmacology and Experimental Therapeutics
SN - 0022-3565
IS - 3
ER -