Enhancement of the anticonvulsant effect of fluoxetine following blockade of 5-HT1A receptors

• Published in: European journal of pharmacology Vol. 336; no. 1; pp. 1 - 6
• Main Authors: BROWNING, R. A, WOOD, A. V, MERRILL, M. A, DAILEY, J. W, JOBE, P. C
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier 01.10.1997
• Subjects: Acoustic Stimulation; Animals; Anticonvulsants - therapeutic use; Anticonvulsants. Antiepileptics. Antiparkinson agents; Biological and medical sciences; Brain - drug effects; Brain - metabolism; Cyclohexylamines - therapeutic use; Drug Interactions; Female; Fenclonine - pharmacology; Fluoxetine - therapeutic use; Medical sciences; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Norepinephrine - metabolism; Pharmacology. Drug treatments; Pindolol - therapeutic use; Rats; Receptors, Serotonin - drug effects; Receptors, Serotonin, 5-HT1; Seizures - drug therapy; Serotonin - metabolism; Serotonin Antagonists - therapeutic use; Serotoninergic system; Nervous system diseases; Rat; Serotonin; Fluoxetine; Psychotropic; Epilepsy; Rodentia; Anticonvulsant; Reuptake inhibitor; Extracellular; Cerebral disorder; Vertebrata; Experimental disease; Mammalia; 5-HT1A Serotonine receptor; Animal; Central nervous system disease; Neurotransmitter; Antidepressant agent; Mechanism of action
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/s0014-2999(97)01215-6

Serotonin reuptake inhibitors, such as fluoxetine, have been shown to exert anticonvulsant effects in several animal models of epilepsy. In view of recent studies showing that 5-HT1A receptor antagonists (somatodendritic autoreceptor antagonists) enhance the increase in extracellular 5-hydroxytryptamine (5-HT, serotonin) produced by serotonin reuptake inhibitors, it was of interest to determine if these antagonists also enhance the anticonvulsant effect of fluoxetine in Genetically Epilepsy-Prone Rats (GEPRs). The 5-HT1A receptor antagonists (-)-pindolol and LY 206130 (1-[1-H-indol-4-yloxy]-3-[cyclohexylamino]-2-propanol maleate) were examined in the present study and both enhanced the anticonvulsant action of fluoxetine in severe seizure GEPRs (GEPR-9s). The latter effect of LY 206130 was found to be dose- and 5-HT-dependent. These findings provide further evidence that the increase in extracellular serotonin observed after administering fluoxetine in combination with a 5-HT1A receptor antagonist is physiologically important and that the anticonvulsant effect of fluoxetine in the GEPR is mediated through an increase in extracellular 5-HT.