title: The antiaggressive potency of (-)-penbutolol involves both 5-HT1A and 5-HT1B receptors and beta-adrenoceptors.
abstract: The relative importance of 5-HT1A and beta-adrenergic activities in the antiaggressive effects of (-)-penbutolol was studied in male mice. (-)-Penbutolol had high affinity for 5-HT1A receptors and beta-adrenoceptors, and antagonized the 5-methoxy-N,N-dimethyltryptamine (5-MeODMT)-induced 5-HT syndrome and the 8-hydroxy-2-(di-n-propylamin)tetralin (8-OH-DPAT)-induced discriminatory stimulus in rats. (-)-Penbutolol abolished aggressive behaviour (ED50 = 56 mumol/kg), and reversed the antiaggressive effects of 8-OH-DPAT and 1-(3-trifluoromethylphenyl)piperazine (TFMPP) (ED50 = 8.1 and 2.1 mumol/kg, respectively). (N-[2-[4-(2-Methoxyphenyl)-1-piperazinyl]ethyl-N-(2-pyridinyl) cyclohexanecarboxamide (WAY 100635) reversed the antiaggressive effects of 8-OH-DPAT (ED50 = 0.012 mumol/kg), but did not affect the antiaggressive effects of TFMPP. The antiaggressive effect of a submaximal dose of 8-OH-DPAT was markedly potentiated by beta-adrenoceptor antagonists without 5-HT1A receptor affinity, whereas (-)-penbutolol was effective at only one dose (4.5 mumol/kg). In conclusion, the 5-HT1A receptor antagonistic potency of (-)-penbutolol in aggressive mice is attenuated by beta-adrenoceptor-induced facilitation of serotonergic neurotransmission.
authors.affiliation: Pharmacological Research, H. Lundbeck A/S, Copenhagen-Valby, Denmark.
authors.forename: C
authors.initials: C
authors.lastname: Sánchez
authors.forename: J
authors.initials: J
authors.lastname: Arnt
authors.forename: E K
authors.initials: EK
authors.lastname: Moltzen
mesh_terms: D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000378:metabolism; D000319:Adrenergic beta-Antagonists / Q000493:pharmacokinetics / Q000494:pharmacology*; D000374:Aggression / Q000187:drug effects*; D000818:Animals; D008297:Male; D008732:Methoxydimethyltryptamines / Q000378:metabolism; D008790:Metoprolol / Q000494:pharmacology; D051379:Mice; D010394:Penbutolol / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D011943:Receptors, Adrenergic, beta / Q000187:drug effects* / Q000378:metabolism; D011985:Receptors, Serotonin / Q000187:drug effects* / Q000378:metabolism; D012701:Serotonin / Q000494:pharmacology; D012702:Serotonin Antagonists / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000378:metabolism; D012934:Social Isolation
chemical_list: D000319:Adrenergic beta-Antagonists; D008732:Methoxydimethyltryptamines; D010879:Piperazines; D011725:Pyridines; D011943:Receptors, Adrenergic, beta; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; C018406:1-(3-trifluoromethylphenyl)piperazine; D012701:Serotonin; C090413:N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D010394:Penbutolol; D008790:Metoprolol