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.
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.
Kleven
M S
MS
Centre de Recherche Pierre Fabre, Castres, France.
Assié
M B
MB
Koek
W
W
D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000378:metabolism / Q000494:pharmacology; D000662:Amphetamines / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D014151:Anti-Anxiety Agents / Q000378:metabolism / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects*; D001578:Benzopyrans / Q000378:metabolism / Q000494:pharmacology; D004192:Discrimination, Psychological / Q000187:drug effects*; D007650:Ketanserin / Q000494:pharmacology; D008238:Lysergic Acid Diethylamide / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D008297:Male; D009539:Nicotinic Acids / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology*; D010880:Piperidines / Q000378:metabolism / Q000494:pharmacology; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D011985:Receptors, Serotonin / Q000378:metabolism; D016713:Ritanserin / Q000494:pharmacology; D012702:Serotonin Antagonists / Q000494:pharmacology*; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*
D000662:Amphetamines; D014151:Anti-Anxiety Agents; D001578:Benzopyrans; C107691:FG 5974; D009539:Nicotinic Acids; D010879:Piperazines; D010880:Piperidines; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; C067554:CGS 18102A; D016713:Ritanserin; C086497:LEK 8804; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D008238:Lysergic Acid Diethylamide; D007650:Ketanserin; C015952:4-iodo-2,5-dimethoxyphenylisopropylamine