Pharmacological Characterization of In Vivo Properties of Putative Mixed 5-HT_1AAgonist/5-HT_2A/2C Antagonist Anxiolytics. II. Drug Discrimination and Behavioral Observation Studies in Rats

Abstract

To characterize their in vivo 5-hydroxytryptamine (5-HT)_2A antagonist properties, the ability of the putative mixed 5-HT_1Aagonists/5-HT_2A/2C antagonists (N-(29(4-(2-pyrimidinyl)-1-piperazinyl)ethyl)tricyclo(3.3.1.1(3,7)) decane-1-carboxamide (WY-50,324), (2-(4-(4,4-bis(4-fluorophenyl)butyl)-1-piperazinyl)-3-pyridinecarboxylic acid hydrochloride (FG5974), 9,10-didehydro-N-(2-propynyl)-6-methylergoline-8b-carboxamide (LEK-8804) and trans-1,3,4,a5,10b-hexahydro10-methoxy-4-propyl-2H-(1)benzopyranol[3,4-b]pyridine (CGS 18102A) to antagonize both head twitches and discriminative stimulus (DS) effects produced by (±)-2,5-dimethoxy-4-iodoamphetamine (DOI) in rats were compared with those of the 5-HT₂ antagonists ketanserin and ritanserin, and the 5-HT_1A agonists 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) and buspirone. All of these compounds produced dose-related decreases in DOI-induced head twitches; however pretreatment with the 5-HT_1Aantagonist N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl)cyclohexanecarboxamide (WAY-100635) failed to alter the ability of ritanserin, ketanserin or CGS 18102A to attenuate DOI-induced head twitches. In contrast, WAY-100635 completely blocked the effects of 8-OH-DPAT, buspirone and WY-50,324, and partially blocked the effects of LEK-8804, demonstrating that 5-HT_1A agonist properties are involved in the effects of all of the mixed compounds except CGS 18102A. In rats trained to discriminate DOI (0.63 mg/kg) from saline in a two-lever, FR10 drug discrimination paradigm, ketanserin, ritanserin and CGS 18102A blocked the DS effects of the training dose by more than 50%. In contrast, WY-50,324, FG5974, LEK-8804, buspirone and 8-OH-DPAT, up to doses that completely suppressed responding, failed to produce more than a 33% blockade of the DS effects of DOI. In vivo5-HT_1A agonist effects were demonstrated by the finding that relatively selective- and mixed-5-HT_1A agonists produced one or more elements of the “serotonin syndrome,” i.e., flat-body posture, forepaw treading, or lower-lip retraction, and produced high levels of drug-lever selection in rats trained to discriminate 8-OH-DPAT (0.16 mg/kg) from saline. Because DOI-induced head twitches and DS effects are thought to be mediated by 5-HT_2A receptors, the results demonstrate that the putative mixed compound, CGS 18102A has prominent 5-HT_2A antagonist properties in vivo, whereas 5-HT_2A antagonist effects of WY-50,324, FG5974 and LEK-8804 could not be clearly identified.