Electrophysiological and neurochemical evidence that pindolol has agonist properties at the 5‐HT_1A autoreceptor in vivo

Abstract

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.

Potentiation by (-)Pindolol of the Activation of Postsynaptic 5-HT1A Receptors Induced by Venlafaxine

“…This effect appears to be mediated by an agonistic action of pindolol on somatodendritic 5-HT 1A receptors as, in both studies, it was reversed by the subsequent acute intravenous administration of WAY 100635. Moreover, the intravenous administration of pindolol, as well as its microiontophoretic application directly onto dorsal raphe 5-HT neurons, have been reported to induce a suppression of firing activity (Clifford et al 1998). Overall, these results suggesting an agonistic activity of pindolol at somatodendritic 5-HT 1A receptors are in apparent discrepancy with the present ones showing that a twoday treatment of (-)pindolol produces an efficient antagonism on this population of receptors ( Figure 6).…”

Differential Occupancy of Somatodendritic and Postsynaptic 5HT1A Receptors by Pindolol A Dose-Occupancy Study with [11C]WAY 100635 and Positron Emission Tomography in Humans

“…Recent preclinical studies show that pindolol is a weak agonist at the pre-synaptic receptors, since pindolol by itself reduces the firing rate of DRN 5-HT neurons, an effect antagonized by WAY 100635 (Clifford et al 1998;Haddjeri et al 1999). In cells transfected with the human 5-HT 1A receptor, pindolol induces an increase in [ 35 S]GTP␥S binding, a prototypical agonist response (Newman-Tancredi et al 1998).…”

“…It is currently assumed that silent 5-HT 1A antagonists would be the optimal pharmacological agents for this application: WAY 100635 or other silent antagonists provide superior potentiation of he acute effects of SSRIs on 5-HT transmission compared to pindolol, a difference attributed to the fact that pindolol is a partial agonist (Sharp et al 1993;Clifford et al 1998;Gartside et al 1999). However, if DRN selectivity is a unique feature of partial agonists, a weak and DRN selective partial agonist might still be the drug of choice for this application.…”

Genetic variation in cortico-amygdala serotonin function and risk for stress-related disease

“…Activation of 5-HT1A-R autoreceptors located on the soma and dendrites of serotonin cells (Sotelo et al, 1990;Verge et al, 1986) inhibits DRN neuronal firing and consequent forebrain release (Clifford et al, 1998;Sprouse and Aghajanian, 1986). This provides an essential mechanism by which the serotonin system can self-regulate its activity under conditions of stimulation, such as stress exposure.…”