INTERACTION BETWEEN A SELECTIVE 5-HT1A RECEPTOR ANTAGONIST AND AN SSRI IN-VIVO - EFFECTS ON 5-HT CELL FIRING AND EXTRACELLULAR 5-HT

1 The acute inhibitory effect of selective 5-hydroxytryptamine (seroto nin) reuptake inhibitors (SSRIs) on 5-HT neuronal activity may offset their ability to increase synaptic 5-HT in the forebrain. 2 Here, we d etermined the effects of the SSRI, paroxetine, and a novel selective 5 -HT1A receptor antagonist, WAY 100635, on 5-HT cell firing in the dors al raphe nucleus (DRN), and on extracellular 5-HT in both the DRN and the frontal cortex (FCx). Extracellular electrophysiological recording and brain microdialysis were used in parallel experiments, in anaesth etized rats. 3 Paroxetine dose-dependently inhibited the firing of 5-H T neurones in the DRN, with a maximally effective dose of approximatel y 0.8 mg kg(-1), i.v. WAY 100635 (0.1 mg kg(-1), i.v.) both reversed t he inhibitory effect of paroxetine and, when used as a pretreatment, c aused a pronounced shift to the right of the paroxetine dose-response curve. 4 Paroxetine (0.8 mg kg(-1), i.v.), doubled extracellular 5-HT in the DRN, but did not alter extracellular 5-HT in the FCx. A higher dose of paroxetine (2.4 mg kg(-1), i.v.) did increase extracellular 5- HT in the FCx, but to a lesser extent than in the DRN. Whereas 0.8 mg kg(-1), i.v. paroxetine alone had no effect on extracellular 5-HT in t he FCx, in rats pretreated with WAY 100635 (0.1 mg kg(-1)), paroxetine (0.8 mg kg(-1), i.v.) markedly increased extracellular 5-HT in the FC x. 5 In conclusion, pretreatment with the selective 5-HT1A receptor an tagonist, WAY 100635, blocked the inhibitory effect of paroxetine on 5 -HT neuronal activity in the DRN and, at the same time, markedly enhan ced the effect of paroxetine on extracellular 5-HT in the FCx. These r esults may be relevant to recent clinical observations that 5-HT1A rec eptor antagonists in combination with SSRIs have a rapid onset of anti depressant effect.