title: 5-HT1A receptor activation and anti-cataleptic effects: high-efficacy agonists maximally inhibit haloperidol-induced catalepsy.
abstract: Studies have shown that 5-HT1A receptor ligands modulate antipsychotic-induced catalepsy. Here, we further examined the role of intrinsic activity at 5-HT1A receptors in these effects. The anti-cataleptic effects of 5-HT(1A) receptor ligands with positive intrinsic activity [from high to low: 3-chloro-4-fluorophenyl-(4-fluoro-4-[[(5-methyl-6-methylamino-pyridin-2-ylmethyl)-amino]-methyl]-piperidin-1-yl-methanone fumaric acid salt (F 13714), eptapirone, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), 2-[4-[4-(7-methoxy-1-naphtyl) piperazino]butyl]-4-methyl-2H,4H-1,2,4-triazin-3,5-dione maleic acid salt (F 11461), buspirone, 2-[4-[4-(7-benzofuranyl)piperazino]butyl]-4-methyl-2H,4H-1,2,4-triazin-3,5-dione (F 12826), ipsapirone, and (s)-N-tert-butyl-3-(4-(2-methoxyphenyl)piperazine-1-yl)-2-phenylpropanamide hydrochloride (WAY 100135)] and negative intrinsic activity [N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl)cyclohexanecarboxamide dihydrochloride (WAY 100635)] were examined. Catalepsy was induced by the classical antipsychotic haloperidol (0.63 mg/kg) and measured in the cross-legged position test and in the bar test. All 5-HT1A receptor agonists, except WAY 100135, significantly attenuated the effects of haloperidol in the cross-legged position test. All agonists had similar effects in the bar test, except ipsapirone, which failed to attenuate haloperidol-induced catalepsy. In contrast to the effects observed with the agonists, the inverse agonist WAY 100635 appeared to enhance haloperidol-induced catalepsy in both tests, in agreement with earlier findings. The maximal effects of the 5-HT1A receptor ligands to attenuate catalepsy correlated positively with the rank order of their intrinsic activity at 5-HT1A receptors (either catalepsy test: r(S)=0.92, P<0.001). F 13714, which had the highest intrinsic activity, maximally inhibited haloperidol-induced catalepsy in the cross-legged position and bar tests (100% and 99% inhibition, respectively). Because the magnitude of the anti-cataleptic effects of 5-HT1A receptor ligands correlates positively with their intrinsic activity, it is likely that F 13714 has marked anti-cataleptic effects because of its high intrinsic activity at 5-HT1A receptors.
authors.affiliation: Centre de Recherche Pierre Fabre, 17 Avenue Jean Moulin, F-81106 cedex, Castres, France. frans.colpaert@pierre-fabre.com
authors.forename: Eric P M
authors.initials: EP
authors.lastname: Prinssen
authors.forename: Francis C
authors.initials: FC
authors.lastname: Colpaert
authors.forename: Wouter
authors.initials: W
authors.lastname: Koek
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000009:adverse effects*; D001522:Behavior, Animal / Q000187:drug effects; D002375:Catalepsy / Q000139:chemically induced / Q000517:prevention & control*; D004305:Dose-Response Relationship, Drug; D006220:Haloperidol / Q000009:adverse effects*; D008024:Ligands; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D011985:Receptors, Serotonin / Q000187:drug effects*; D044263:Receptors, Serotonin, 5-HT1; D012702:Serotonin Antagonists / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000494:pharmacology
chemical_list: D014150:Antipsychotic Agents; D008024:Ligands; D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D006220:Haloperidol