Pharmacological characterization of in vivo properties of putative mixed 5-HT1A agonist/5-HT(2A/2C) antagonist anxiolytics. II. Drug discrimination and behavioral observation studies in rats. Export

@article{citeulike:3771941, abstract = {To characterize their in vivo 5-hydroxytryptamine (5-HT)2A antagonist properties, the ability of the putative mixed 5-HT1A agonists/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-pyridinecarboxy lic acid hydrochloride (FG5974), 9,10-didehydro-N-(2-propynyl)-6-methylergoline-8b-carboxamid e (LEK-8804) and trans-1,3,4,a5,10b-hexahydro10-methoxy-4-propyl-2H-(1)benzopyra nol[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-HT1A 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 N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl)cyclohe xanecarboxamide (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-HT1A 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 vivo 5-HT1A agonist effects were demonstrated by the finding that relatively selective- and mixed-5-HT1A 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-HT2A receptors, the results demonstrate that the putative mixed compound, CGS 18102A has prominent 5-HT2A antagonist properties in vivo, whereas 5-HT2A antagonist effects of WY-50,324, FG5974 and LEK-8804 could not be clearly identified.}, author = {Kleven, M. S. and Assi\'{e}, M. B. and Koek, W.}, citeulike-article-id = {3771941}, citeulike-linkout-0 = {http://view.ncbi.nlm.nih.gov/pubmed/9262338}, citeulike-linkout-1 = {http://www.hubmed.org/display.cgi?uids=9262338}, issn = {0022-3565}, journal = {The Journal of pharmacology and experimental therapeutics}, keywords = {5ht, 5ht-2a, 5ht-2c, anxiety, anxiolytic, doi, ketanserin, ritanserin}, month = {August}, number = {2}, pages = {747--759}, posted-at = {2008-12-11 00:29:40}, priority = {2}, title = {Pharmacological characterization of in vivo properties of putative mixed 5-HT1A agonist/5-HT(2A/2C) antagonist anxiolytics. II. Drug discrimination and behavioral observation studies in rats.}, url = {http://view.ncbi.nlm.nih.gov/pubmed/9262338}, volume = {282}, year = {1997} }

TY - JOUR ID - citeulike:3771941 L3 - citeulike-article-id:3771941 N2 - To characterize their in vivo 5-hydroxytryptamine (5-HT)2A antagonist properties, the ability of the putative mixed 5-HT1A agonists/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-pyridinecarboxy lic acid hydrochloride (FG5974), 9,10-didehydro-N-(2-propynyl)-6-methylergoline-8b-carboxamid e (LEK-8804) and trans-1,3,4,a5,10b-hexahydro10-methoxy-4-propyl-2H-(1)benzopyra nol[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-HT1A 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 N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl)cyclohe xanecarboxamide (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-HT1A 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 vivo 5-HT1A agonist effects were demonstrated by the finding that relatively selective- and mixed-5-HT1A 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-HT2A receptors, the results demonstrate that the putative mixed compound, CGS 18102A has prominent 5-HT2A antagonist properties in vivo, whereas 5-HT2A antagonist effects of WY-50,324, FG5974 and LEK-8804 could not be clearly identified. IS - 2 JF - The Journal of pharmacology and experimental therapeutics SN - 0022-3565 EP - 759 TI - Pharmacological characterization of in vivo properties of putative mixed 5-HT1A agonist/5-HT(2A/2C) antagonist anxiolytics. II. Drug discrimination and behavioral observation studies in rats. VL - 282 SP - 747 KW - 5ht KW - 5ht-2a KW - 5ht-2c KW - anxiety KW - anxiolytic KW - doi KW - ketanserin KW - ritanserin AU - Kleven, MS AU - Assié, MB AU - Koek, W PY - 1997/08// UR - http://view.ncbi.nlm.nih.gov/pubmed/9262338 ER -