Very little is known about constitutive activity in vivo. This study examined whether constitutive activity and inverse agonism contribute to discriminative stimulus effects of drugs acting at serotonin (5-HT)2A receptors. Rats were trained to discriminate between saline and either 0.56 mg/kg 5-HT2 receptor agonist 1-(2,5-dimethoxy-4-methylphenyl)-2- aminopropane (DOM), 1.0 mg/kg 5-HT2A receptor antagonist ketanserin, or 0.1 mg/kg purported 5-HT2A receptor inverse agonist (R)-(+)-α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl] -4-pipidinemethanol (MDL100907). Discriminative control was established with each drug after 33 to 35 sessions. MDL100907 and ketanserin did not occasion DOM lever responding but attenuated the discriminative stimulus effects of DOM. DOM did not occasion responding on the drug-associated lever in rats discriminating MDL100907 or ketanserin, but attenuated the discriminative stimulus effects of both drugs. Ketanserin and ritanserin occasioned MDL100907-lever responding, whereas rats discriminating ketanserin responded only partially on the drugassociated lever after receiving MDL100907, ritanserin, or the α1-adrenergic antagonist prazosin. Combining prazosin with MDL100907 or ritanserin resulted in near-complete ketanserinlever responding, indicating that the ketanserin stimulus involves both 5-HT2A and α1-adrenergic receptors. Administration of p- chlorophenylalanine methyl ester, then fenfluramine, significantly decreased cortical 5-HT, enhanced sensitivity to the discriminative stimulus effects of DOM, and occasioned partial MDL100907-lever responding. Collectively, these results show that DOM and MDL100907 discriminative stimulus effects are mediated by 5-HT2A receptors and that ketanserin discriminative stimulus effects involve both 5-HT2A and α1-adrenergic receptors. Results in 5-HT-depleted rats further suggest that the discriminative stimulus effects of MDL100907 might involve antagonism of endogenous 5-HT and/or inverse agonism at 5-HT2A receptors.
|Original language||English (US)|
|Number of pages||9|
|Journal||Journal of Pharmacology and Experimental Therapeutics|
|State||Published - Nov 2009|
ASJC Scopus subject areas
- Molecular Medicine