Effect of pindolol on the function of pre- and postsynaptic 5-HT1A receptors: in vivo microdialysis and electrophysiological studies in the rat brain.
In microdialysis studies, somatodendritic 5-HT1A receptors in the dorsal raphe nucleus (DRN) were activated by the local infusion of 50 microM citalopram, a selective 5-HT reuptake inhibitor (SSRI). This reduced extracellular 5-HT by about 50% in dorsal striatum, an area receiving 5-HT afferents exclusively from the DRN. (-)Pindolol dose-dependently attenuated this citalopram-induced reduction of striatal extracellular 5-HT. Consistent with its 5-HT reuptake blocking properties, single doses of the SSRI paroxetine (1 and 3 mg/kg IP) and citalopram (1 mg/kg IP) significantly elevated extracellular 5-HT in the dorsal striatum. Pretreatment with (-)pindolol (15 mg/kg IP) potentiated the effect of 3 mg/kg paroxetine and 1 mg/kg citalopram on striatal extracellular 5-HT. A 2-day treatment with 10 mg/kg/day (SC) of paroxetine reduced by 60% the spontaneous activity of 5-HT neurons of the DRN. However, 5-HT neurons displayed normal activity in rats treated with paroxetine and (-)pindolol for 2 days. The inhibitory effect of LSD on 5-HT neuronal firing activity was also markedly attenuated in (-)pindolol-treated rats, indicating that somatodendritic 5-HT1A receptors were blocked by (-)pindolol. To determine whether (-)pindolol also blocked postsynaptic 5-HT1A receptors in hippocampus, 5-HT and the prototypical 5-HT1A agonist 8-OH-DPAT were applied by microiontophoresis onto CA3 pyramidal neurons following the same treatment. (-)Pindolol did not modify the responsiveness of these neurons to 5-HT and 8-OH-DPAT. Taken together, these results indicate that (-)pindolol can potentiate the effects of an SSRI on extracellular 5-HT concentration by preventing the activation of somatodendritic 5-HT1A autoreceptors resulting from the blockade of the 5-HT transporter in the raphe. This presumably leads to enhanced 5-HT neurotransmission because (-)pindolol would not alter the responsiveness of certain postsynaptic 5-HT1A receptors, such as those located on hippocampal CA3 pyramidal neurons. These results provide a neurobiological basis for the reported potentiation of certain antidepressant drugs by pindolol in major depression.
Romero
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L
Department of Neurochemistry, CID, Consejo Superior de Investigaciones Cientificas (CSIC), Barcelona, Spain.
Bel
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N
Artigas
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de Montigny
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C
Blier
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P
D000818:Animals; D001921:Brain / Q000187:drug effects*; D003342:Corpus Striatum / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D008297:Male; D017551:Microdialysis; D010869:Pindolol / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D011985:Receptors, Serotonin / Q000187:drug effects*; D012701:Serotonin / Q000378:metabolism*
D011985:Receptors, Serotonin; D012701:Serotonin; D010869:Pindolol