ELECTROPHYSIOLOGICAL AND NEUROCHEMICAL EVIDENCE THAT PINDOLOL HAS AGONIST PROPERTIES AT THE 5-HT1A AUTORECEPTOR IN-VIVO

1 It has been hypothesized that 5-HT1A autoreceptor antagonists may en hance the therapeutic efficacy of SSRIs and other antidepressants. Alt hough early clinical trials with the beta-adrenoceptor/5-HT1 ligand, p indolol, were promising, the results of recent more extensive trials h ave been contradictory. Here we investigated the actions of pindolol a t the 5-HT1A autoreceptor by measuring its effect on 5-HT neuronal act ivity and release in the anaesthetized rat. 2 Pindolol inhibited the e lectrical activity of 5-HT neurones in the dorsal raphe nucleus (DRN). This effect was observed in the majority of neurones tested (10/16), was dose-related (0.2-1.0 mg kg(-1), i.v.), and was reversed by the 5- HT1A receptor antagonist, WAY 100635 (0.1 mg kg(-1), i.v.), in 6/7 cas es tested. 3 Pindolol also inhibited 5-HT neuronal activity when appli ed microiontophoretically into the DRN in 9/10 neurones tested. This e ffect of pindolol was current-dependent and blocked by co-application of WAY 100635 (3/3 neurones tested). 4 In microdialysis experiments, p indolol caused a dose-related (0.8 and 4 mg kg(-1), i.v.) fall in 5-HT levels in dialysates from the frontal cortex (under conditions where the perfusion medium contained 1 mu M citalopram). In rats pretreated with WAY 100635 (0.1 mg kg(-1), i.v.), pindolol (4 mg kg(-1), i.v.) di d not decrease, but rather increased 5-HT levels. 5 We conclude that, under the experimental conditions used in this study, pindolol display s agonist effects at the 5-HT1A autoreceptor. These data are relevant to previous and ongoing clinical trials of pindolol in depression whic h are based on the rationale that the drug is an effective 5-HT1A auto receptor antagonist.