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Electrophysiological and neurochemical evidence that pindolol has agonist properties at the 5‐HT 1A autoreceptor in vivo
Author(s) -
Clifford Elizabeth M,
Gartside Sarah E,
Umbers Valerie,
Cowen Philip J,
Hajós Mihály,
Sharp Trevor
Publication year - 1998
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0701796
Subject(s) - pindolol , autoreceptor , dorsal raphe nucleus , chemistry , agonist , microdialysis , 5 ht1a receptor , 5 ht receptor , raphe nuclei , pharmacology , neurochemical , antagonist , serotonin , medicine , endocrinology , receptor , serotonergic , biochemistry , extracellular
It has been hypothesized that 5‐HT 1A autoreceptor antagonists may enhance the therapeutic efficacy of SSRIs and other antidepressants. Although early clinical trials with the β‐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 effect on 5‐HT neuronal activity and release in the anaesthetized rat. Pindolol inhibited the electrical 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‐HT 1A receptor antagonist, WAY 100635 (0.1 mg kg −1 , i.v.), in 6/7 cases tested. Pindolol also inhibited 5‐HT neuronal activity when applied microiontophoretically into the DRN in 9/10 neurones tested. This effect of pindolol was current‐dependent and blocked by co‐application of WAY 100635 (3/3 neurones tested). In microdialysis experiments, pindolol 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 μ M citalopram). In rats pretreated with WAY 100635 (0.1 mg kg −1 , i.v.), pindolol (4 mg kg −1 , i.v.) did not decrease, but rather increased 5‐HT levels. We conclude that, under the experimental conditions used in this study, pindolol displays agonist effects 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 effective 5‐HT 1A autoreceptor antagonist.