5-HT(1A) agonist potential of pindolol: electrophysiologic studies in the dorsal raphe nucleus and hippocampus

The ability of pindolol to block 5-HT(1A) autoreceptors on serotonin-containing neurons in the raphe nuclei is thought to underlie the clinical reports of enhanced efficacy and rate of improvement in depressed patients treated with pindolol/selective serotonin reuptake inhibitor (SSRI) combinations. Selectivity for somatodendritic 5-HT(1A) autoreceptors is a crucial requirement, as blockade of postsynaptic 5-HT(1A) sites may jeopardize the therapeutic response. Previous investigators have probed the effects of pindolol on serotonergic dorsal raphe cell firing in animal species; here we confirm their findings and extend them to include observations on postsynaptic 5-HT(1A) receptors in the hippocampus.

Extracellular single-unit recordings were made in rats using standard electrophysiologic techniques. Firing rates of serotonin-containing neurons in the dorsal raphe nucleus and CA3 hippocampal pyramidal neurons were monitored and the effects of pindolol given alone or in combination with an SSRI (fluoxetine) or a 5-HT(1A) antagonist (WAY-100,635) were determined.

Pindolol inhibited the firing rates of serotonergic dorsal raphe neurons in a dose-dependent manner. Recovery to baseline firing rates was gradual, but this inhibition could be acutely reversed by WAY-100,635. A range of pindolol doses failed to block the inhibitory effects of fluoxetine on dorsal raphe cell firing. In the hippocampus, pindolol also inhibited cell firing as a function of dose, although these effects were insensitive to WAY-100,635 treatment.

The ability of pindolol to inhibit serotonergic dorsal raphe cell firing is indicative of its agonist potential and is consistent with previous studies. The lack of observable antagonism of the SSRI-induced slowing of raphe unit activity casts doubt on the suitability of this mechanism of action to account for the positive findings in clinical studies utilizing pindolol/SSRI combinations. The 5-HT(1A)-independent inhibition of hippocampal CA3 cell firing by pindolol suggests that this compound invokes multiple pharmacologic actions, all of which need to be assimilated into any proposed mechanism of action.