In vivo microdialysis evidence for central serotonin1A and serotonin1B autoreceptor blocking properties of the beta adrenoceptor antagonist (-)penbutolol.
Recently, we found that the beta 1/beta 2 adrenoceptor blocking agent (-)penbutolol prevents behavioral and biochemical actions of the specific serotonin (5-HT)1A agonist (+/-)-8-hydroxy-2-(di-n-propylamino)tetralin. The putative 5-HT1 receptor antagonist profile of (-)penbutolol was further explored in the present study, using in vivo microdialysis methods to assess its effects on central 5-HT release. (+)Penbutolol and (-)pindolol were included for comparison purposes. In contrast to (-)pindolol (8.0 mg/kg s.c.), administration of (-)penbutolol (2.0 or 8.0 mg/kg s.c.) increased hippocampal 5-HT output. The (-)penbutolol-induced 5-HT response was dose-related, stereoselective and Ca(++)-dependent. In addition, the 5-HT response to (-)penbutolol was abolished by omitting the 5-HT reuptake blocker citalopram from the perfusion medium, suggesting the need for endogenous 5-HT tone. Local (-)penbutolol (1 microM) perfusion increased the 5-HT output per se, and also blocked 5-HT release suppression caused by the 5-HT1B receptor agonist CP-93,129. Furthermore, (-)penbutolol, but not its (+)antipode, prevented the decrease of 5-HT release induced by the 5-HT1A receptor agonist (+/-)-8-hydroxy-2-(di-n-propylamino)tetralin. By comparison, the 5-HT1 receptor inactive beta adrenoceptor blockers metoprolol (beta 1) and ICI 118,551 (beta 2), given alone or in combination, did not increase 5-HT output and were ineffective in antagonizing the (+/-)-8-hydroxy-2-(di-n-propylamino)tetralin response. The data indicate that (-)penbutolol possesses 5-HT1A and 5-HT1B autoreceptor antagonist properties, and may be a useful tool in studies of central 5-HT receptor-mediated function.
Hjorth
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S
Department of Pharmacology, University of Göteborg, Sweden.
Sharp
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T
D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000494:pharmacology; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000818:Animals; D015283:Citalopram / Q000494:pharmacology; D003956:Dialysis; D006624:Hippocampus; D008297:Male; D008790:Metoprolol / Q000494:pharmacology; D010394:Penbutolol / Q000008:administration & dosage / Q000494:pharmacology*; D010477:Perfusion; D010869:Pindolol / Q000494:pharmacology; D011412:Propanolamines / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000378:metabolism; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D013237:Stereoisomerism
D000319:Adrenergic beta-Antagonists; D011412:Propanolamines; D011725:Pyridines; D011758:Pyrroles; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D015283:Citalopram; C065046:3-(1,2,5,6-tetrahydropyrid-4-yl)pyrrolo(3,2-b)pyrid-5-one; D012701:Serotonin; C026777:ICI 118551; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D010394:Penbutolol; D010869:Pindolol; D008790:Metoprolol