PHARMACOLOGICAL CHARACTERIZATION OF IN-VIVO PROPERTIES OF PUTATIVE MIXED 5-HT1A AGONIST 5-HT2A/2C ANTAGONIST ANXIOLYTICS .2. DRUG DISCRIMINATION AND BEHAVIORAL OBSERVATION STUDIES IN RATS/

To characterize their in vivo 5-hydroxytryptamine (5-HT)(2A) antagonis t properties, the ability of the putative mixed 5-HT1A agonists/5-HT2A /2C antagonists -(2-pyrimidinyl)-1-piperazinyl)ethyl)tricyclo(3.3. 1.1 (3,7)) decane-1-carboxamide (WY-50,324), ophenyl)butyl)-1-piperazinyl) -3-pyridinecarboxylic acid hydrochloride (FG5974), dro-N-(2-propynyl)- 6-methylergoline-8b-carboxamide (LEK-8804) and trans-1,3,4,a5,10b-hexa hydrol methoxy-4-propyl-2H-(1)benzopyranol[3,4-b]pyridine (CGS 18102A) to antagonize both head twitches and discriminative stimulus (DS) eff ects produced by (+/-)-2,5-dimethoxy-4-iodoamphetamine (DOI) in rats w ere compared with those of the 5-HT2 antagonists ketanserin and ritans erin, and the 5-HT2 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-HT1A antagonist zinyl]ethyl]-N-(2-pyridinyl)cyclohexanecarboxamide ( WAY-100635) failed to alter the ability of ritanserin, ketanserin or C GS 18102A to attenuate DOI-induced head twitches. In contrast, WAY-100 635 completely blocked the effects of 8-OH-DPAT, buspirone and WY-50,3 24, and partially blocked the effects of LEK-8804, demonstrating that 5-HT1A agonist properties are involved in the effects of all of the mi xed compounds except CGS 18102A. In rats trained to discriminate DOI ( 0.63 mg/kg) from saline in a two-lever, FRIO drug discrimination parad igm, ketanserin, ritanserin and CGS 18102A blocked the DS effects of t he 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 effe cts of DOI. In vivo 5-HT1A agonist effects were demonstrated by the fi nding that relatively selective-and mixed-5-HT1A agonists produced one or more elements of the ''serotonin syndrome,'' i.e., flat-body postu re, forepaw treading, or lower-lip retraction, and produced high level s 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 effec ts are thought to be mediated by 5-HT2A receptors, the results demonst rate that the putative mixed compound, CGS 18102A has prominent 5-HT2A antagonist properties in vivo, whereas 5-HT2A antagonist effects of W Y-50,324, FG5974 and LEK-8804 could not be clearly identified.