Effects of (-)-tertatolol, (-)-penbutolol and (+/-)-pindolol in combination with paroxetine on presynaptic 5-HT function: an in vivo microdialysis and electrophysiological study

Abstract

The antidepressant efficacy of selective serotonin reuptake inhibitors (SSRIs) might be enhanced by co-administration of 5-HT1A receptor antagonists. Thus, we have recently shown that the selective 5-HT1A receptor antagonist, WAY 100635, blocks the inhibitory effect of an SSRI on 5-HT cell firing, and enhances its ability to elevate extracellular 5-HT in the forebrain. Here we determined whether the beta-adrenoceptor/5-HT1A receptor ligands (+/-)-pindolol, (-)-tertatolol and (-)-penbutolol, interact with paroxetine in a similar manner. Both (-)-tertatolol (2.4 mg kg(-1) i.v.) and (-)-penbutolol (2.4 mg kg(-1) i.v.) enhanced the effect of paroxetine (0.8 mg kg(-1) i.v.) on extracellular 5-HT in the frontal cortex, whilst (+/-)-pindolol (4 mg kg(-1) i.v.) did not. (-)-Tertatolol (2.4 mg kg(-1) i.v.) alone caused a slight increase in 5-HT however, (-)-penbutolol (2.4 mg kg(-1) i.v.) alone had no effect. In electrophysiological studies (-)-tertatolol (2.4 mg kg(-1) i.v.) alone had no effect on 5-HT cell firing but blocked the inhibitory effect of paroxetine. In contrast, (-)-penbutolol (0.1-0.8 mg kg(-1) i.v.) itself inhibited 5-HT cell firing, and this effect was reversed by WAY 100635 (0.1 mg kg(-1) i.v.). We have recently shown that (+/-)-pindolol inhibits 5-HT cell firing via a WAY 100635-sensitive mechanism. Our data suggest that (-)-tertatolol enhances the effect of paroxetine on forebrain 5-HT via blockade of 5-HT1A autoreceptors which mediate paroxetine-induced inhibition of 5-HT cell firing. In comparison, the mechanisms by which (-)-penbutolol enhances the effect of paroxetine on extracellular 5-HT is unclear, since (-)-penbutolol itself appears to have agonist properties at the 5-HT1A autoreceptor. Indeed, the agonist action of (+/-)-pindolol at 5-HT1A autoreceptors probably explains its inability to enhance the effect of paroxetine on 5-HT in the frontal cortex. Overall, our data suggest that both (-)-tertatolol and (-)-penbutolol are superior to (+/-)-pindolol in terms of enhancing the effect of an SSRI on extracellular 5-HT. Both (-)-tertatolol and (-)-penbutolol are worthy of investigation for use as adjuncts to SSRIs in the treatment of major depression.

Figure 1

Time course of the effect of paroxetine (0.8 mg kg⁻¹ i.v.) on 5-HT levels in dialysates of the frontal cortex in vehicle- and (±)-pindolol (4 mg kg⁻¹) pretreated animals. The vehicle was acetic acid/glucose. Drugs were given as indicated by the arrows. Basal levels of 5-HT were 11±2 (5), 25±5 (4), 15±2 (6) and 23±5 (6) fmol sample⁻¹, in the groups of animals which received vehicle/vehicle, (±)-pindolol/vehicle, vehicle/paroxetine and (±)-pindolol/paroxetine, respectively.

Figure 2

Time course of the effect of paroxetine (0.8 mg kg⁻¹ i.v.) on 5-HT levels in dialysates of the frontal cortex in vehicle- and (−)-tertatolol- (2.4 mg kg⁻¹) pretreated animals. The vehicle was distilled water. Drugs were given as indicated by the arrows. Basal levels of 5-HT were 11±2 (5), 17±3 (4), 17±3 (5) and 19±3 (5), and fmol sample⁻¹, in the groups of animals which received vehicle/vehicle, (−)-tertatolol/vehicle, vehicle/paroxetine and (−)-tertatolol/paroxetine, respectively.

Figure 3

Time course of the effect of paroxetine (0.8 mg kg⁻¹ i.v.) on 5-HT levels in dialysates of the frontal cortex in vehicle- and (−)- penbutolol- (2.4 mg kg⁻¹) pretreated animals. The vehicle was distilled water. Drugs were given as indicated by the arrows. Basal levels of 5-HT were 11±2 (5), 10±1 (5), 14±2 (6) and 9±1 (6) fmol sample⁻¹, in the groups of animals which received vehicle/vehicle, (−)-penbutolol/vehicle, vehicle/paroxetine and (−)-penbutolol/paroxetine, respectively. Data for the vehicle/vehicle treated group are taken from Figure 2.

Figure 4

Effect of increasing doses of (−)-tertatolol and (−)-penbutolol on the firing rate of 5-HT cells in the DRN. Basal firing rates were 16.3±2.5 (9) and 8.7±2.0 (9) spikes 10 s⁻¹ in the groups treated with (−)-tertatolol and (−)-penbutolol respectively.

Figure 5

Rate meter recordings showing the effects of (−)-tertatolol and (−)-penbutolol on the firing rate of individual 5-HT cells in the DRN. Drugs were given as indicated by the arrows. (a) Shows a cell in which (−)-tertatolol did not influence the firing rate. (b), (c) and (d) show cells which were inhibited by (−)-penbutolol. Note that the cell shown in (c) is much less sensitive to inhibition by (−)-penbutolol than those in (b) and (d). Note also the reversal of the inhibitory effect of (−)-penbutolol by WAY 100635 shown in (b) and (d).

Figure 6

Effect of increasing doses of paroxetine on the firing rate of 5-HT cells in the DRN in naïve animals (control) and animals pretreated with (−)-tertatolol (2.4 mg kg⁻¹). Basal firing rates were 7.7±0.9 (6) 19.7±4.7 (4) spikes 10 s⁻¹ in the control and (−)-tertatolol pretreated groups respectively.

Figure 7

Rate meter recordings showing the effect of paroxetine on the firing rate of individual 5-HT cells in the DRN. Drugs were given as indicated by the arrows. (a) Shows the effect of paroxetine in a control cell. (b) Shows the effect of paroxetine in a (−)-tertatolol-pretreated cell.

Figure 7

Rate meter recordings showing the effect of paroxetine on the firing rate of individual 5-HT cells in the DRN. Drugs were given as indicated by the arrows. (a) Shows the effect of paroxetine in a control cell. (b) Shows the effect of paroxetine in a (−)-tertatolol-pretreated cell.

Figure 8

Rate meter recordings showing the effect of (−)-tertatolol and WAY 100635 on the inhibitory response to paroxetine in individual 5-HT cells in the DRN. Drugs were given as indicated by the arrows. (a) Shows a cell in which (−)-tertatolol caused near complete reversal of the effect of paroxetine. (b) Shows a cell in which the reversal by (−)-tertatolol was partial whilst (c) shows a cell in which (−)-tertatolol was ineffective. Note that subsequent administration of WAY 100635 reversed the inhibitory effect of paroxetine in the cells shown in (b) and (c).

Figure 8

Rate meter recordings showing the effect of (−)-tertatolol and WAY 100635 on the inhibitory response to paroxetine in individual 5-HT cells in the DRN. Drugs were given as indicated by the arrows. (a) Shows a cell in which (−)-tertatolol caused near complete reversal of the effect of paroxetine. (b) Shows a cell in which the reversal by (−)-tertatolol was partial whilst (c) shows a cell in which (−)-tertatolol was ineffective. Note that subsequent administration of WAY 100635 reversed the inhibitory effect of paroxetine in the cells shown in (b) and (c).

Figure 8

Rate meter recordings showing the effect of (−)-tertatolol and WAY 100635 on the inhibitory response to paroxetine in individual 5-HT cells in the DRN. Drugs were given as indicated by the arrows. (a) Shows a cell in which (−)-tertatolol caused near complete reversal of the effect of paroxetine. (b) Shows a cell in which the reversal by (−)-tertatolol was partial whilst (c) shows a cell in which (−)-tertatolol was ineffective. Note that subsequent administration of WAY 100635 reversed the inhibitory effect of paroxetine in the cells shown in (b) and (c).