1 The acute inhibitory effect of selective 5-hydroxytryptamine (serotonin) reuptake inhibitors (SSRIs) on 5-HT neuronal activity may offset their ability to increase synaptic 5-HT in the forebrain.2 Here, we determined the effects of the SSRI, paroxetine, and a novel selective 5-HTIA receptor antagonist, WAY 100635, on 5-HT cell firing in the dorsal 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 anaesthetized rats.

1 Selective 5-hydroxytryptamine (5-HT; serotonin) reuptake inhibitors (SSRIs) cause a greater increase in extracellular 5-HT in the forebrain when the somatodendritic 5-HT 1A autoreceptor is blocked. Here, we investigated whether blockade of the terminal 5-HT 1B autoreceptor in¯uences a selective 5-HT reuptake inhibitor in the same way, and whether there is an additional e ect of blocking both the 5-HT 1A and 5-HT 1B autoreceptors. 2 Extracellular 5-HT was measured in frontal cortex of the anaesthetized rat by use of brain microdialysis. In vivo extracellular recordings of 5-HT neuronal activity in the dorsal raphe nucleus (DRN) were also carried out. 6 Despite the lack of e ect of GR127935 on 5-HT under basal conditions, when 5-HT output was elevated about 3 fold (by adding 1 mM paroxetine to the perfusion medium), the drug caused a doserelated (1 and 5 mg kg 71 , i.v.) increase in 5-HT. 7 By itself, GR127935 slightly but signi®cantly decreased 5-HT cell ®ring in the DRN at higher doses (2.0 ± 5.0 mg kg 71 , i.v.), but did not prevent the inhibition of 5-HT cell ®ring induced by paroxetine. 8 In summary, our results suggest that selective 5-HT reuptake inhibitors may cause a large increase in 5-HT in the frontal cortex when 5-HT autoreceptors on both the somatodendrites (5-HT 1A ) and nerve terminals (5-HT 1B ) are blocked. This increase is greater than when either set of autoreceptors are blocked separately. The failure of a 5-HT 1B receptor antagonist alone to enhance the e ect of the selective 5-HT reuptake inhibitor in our experiments may be related to a lack of tone on the terminal 5-HT 1B autoreceptor due to a continued inhibition of 5-HT cell ®ring. These results are discussed in relation to the use of 5-HT autoreceptor antagonists to augment the antidepressant e ect of selective 5-HT reuptake inhibitors.

1 It has been hypothesized that 5-HT 1A autoreceptor antagonists may enhance the therapeutic ecacy of SSRIs and other antidepressants. Although early clinical trials with the b-adrenoceptor/5-HT 1 ligand, pindolol, were promising, the results of recent more extensive trials have been contradictory. Here we investigated the actions of pindolol at the 5-HT 1A autoreceptor by measuring its eect on 5-HT neuronal activity and release in the anaesthetized rat. 2 Pindolol inhibited the electrical activity of 5-HT neurones in the dorsal raphe nucleus (DRN). This eect was observed in the majority of neurones tested (10/16), was dose-related (0.2 ± 1.0 mg kg 71 , i.v.), and was reversed by the 5-HT 1A receptor antagonist, WAY 100635 (0.1 mg kg 71 , i.v.), in 6/7 cases tested. 3 Pindolol also inhibited 5-HT neuronal activity when applied microiontophoretically into the DRN in 9/10 neurones tested. This eect of pindolol was current-dependent and blocked by co-application of WAY 100635 (3/3 neurones tested). 4 In microdialysis experiments, pindolol caused a dose-related (0.8 and 4 mg kg 71 , i.v.) fall in 5-HT levels in dialysates from the frontal cortex (under conditions where the perfusion medium contained 1 mM citalopram). In rats pretreated with WAY 100635 (0.1 mg kg 71 , i.v.), pindolol (4 mg kg 71 , i.v.) did not decrease, but rather increased 5-HT levels. 5 We conclude that, under the experimental conditions used in this study, pindolol displays agonist eects at the 5-HT 1A autoreceptor. These data are relevant to previous and ongoing clinical trials of pindolol in depression which are based on the rationale that the drug is an eective 5-HT 1A autoreceptor antagonist.

Improved clinical antidepressant efficacy may result if the acute inhibition of 5-HT cell firing induced by antidepressants is prevented. Here we examined whether inhibition of 5-HT cell firing by non-selective 5-HT uptake inhibiting antidepressant drugs is reversed by a selective 5-HT1A receptor antagonist. In addition, we examined whether concomitant blockade of NA uptake offsets the inhibition of 5-HT cell firing resulting from 5-HT uptake blockade. Antidepressants which block 5-HT uptake (paroxetine, clomipramine, amitriptyline, venlafaxine), all caused dose-dependent and complete inhibition of 5-HT cell firing. Desipramine, a selective NA uptake blocker, caused a slight reduction in firing. The selective 5-HT1A receptor antagonist, WAY 100635, reversed the inhibition of 5-HT cell firing induced by clomipramine, amitriptyline, venlafaxine, and paroxetine, but not that induced by the alpha 1 adrenoceptor antagonist, prazosin. Desipramine, at a dose which increased extracellular NA in the DRN, reversed the effect of prazosin but did not alter the ability of paroxetine to inhibit 5-HT cell firing. Our data indicate that antidepressant drugs with 5-HT uptake blocking properties inhibit 5-HT cell firing via activation of 5-HT1A autoreceptors, and do so irrespective of their effects on NA uptake. These data are discussed in relation to the application of 5-HT1A receptor antagonists to enhance the clinical efficacy of antidepressant drugs.

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