Potentiation by (-)Pindolol of the activation of postsynaptic 5-HT(1A) receptors induced by venlafaxine.
The increase of extracellular 5-HT in brain terminal regions produced by the acute administration of 5-HT reuptake inhibitors (SSRI's) is hampered by the activation of somatodendritic 5-HT(1A) autoreceptors in the raphe nuclei. The present in vivo electrophysiological studies were undertaken, in the rat, to assess the effects of the coadministration of venlafaxine, a dual 5-HT/NE reuptake inhibitor, and (-)pindolol on pre- and postsynaptic 5-HT(1A) receptor function. The acute administration of venlafaxine and of the SSRI paroxetine (5 mg/kg, i.v.) induced a suppression of the firing activity of dorsal hippocampus CA(3) pyramidal neurons. This effect of venlafaxine was markedly potentiated by a pretreatment with (-)pindolol (15 mg/kg, i.p.) but not by the selective beta-adrenoceptor antagonist metoprolol (15 mg/kg, i.p.). That this effect of venlafaxine was mediated by an activation of postsynaptic 5-HT(1A) receptors was suggested by its complete reversal by the 5-HT(1A) antagonist WAY 100635 (100 microg/kg, i.v.). A short-term treatment with VLX (20 mg/kg/day x 2 days) resulted in a ca. 90% suppression of the firing activity of 5-HT neurons in the dorsal raphe nucleus. This was prevented by the coadministration of (-)pindolol (15 mg/kg/day x 2 days). Taken together, these results indicate that (-)pindolol potentiated the activation of postsynaptic 5-HT(1A) receptors resulting from 5-HT reuptake inhibition probably by blocking the somatodendritic 5-HT(1A) autoreceptor, but not its postsynaptic congener. These results support and extend previous findings providing a biological substratum for the efficacy of pindolol as an accelerating strategy in major depression.
Béïque
J C
JC
Neurobiological Psychiatry Unit, Department of Psychiatry, McGill University, Montréal, Québec, Canada.
Blier
P
P
de Montigny
C
C
Debonnel
G
G
D015116:5,7-Dihydroxytryptamine / Q000494:pharmacology; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000818:Animals; D003511:Cyclohexanols / Q000008:administration & dosage / Q000494:pharmacology*; D004357:Drug Synergism; D004594:Electrophysiology; D005110:Extracellular Space / Q000187:drug effects / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D007275:Injections, Intravenous; D008297:Male; D017374:Paroxetine / Q000494:pharmacology; D010869:Pindolol / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology; D017966:Pyramidal Cells / Q000187:drug effects / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D011903:Raphe Nuclei / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017981:Receptors, Neurotransmitter / Q000187:drug effects* / Q000378:metabolism; D011985:Receptors, Serotonin / Q000187:drug effects*; D044263:Receptors, Serotonin, 5-HT1; D018490:Serotonin Agents / Q000494:pharmacology; D012702:Serotonin Antagonists / Q000494:pharmacology; D017367:Selective Serotonin Reuptake Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D000069470:Venlafaxine Hydrochloride
D015116:5,7-Dihydroxytryptamine; D000319:Adrenergic beta-Antagonists; D003511:Cyclohexanols; D017374:Paroxetine; D010869:Pindolol; D010879:Piperazines; D011725:Pyridines; D017981:Receptors, Neurotransmitter; D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; D018490:Serotonin Agents; D012702:Serotonin Antagonists; D017367:Selective Serotonin Reuptake Inhibitors; D000069470:Venlafaxine Hydrochloride; C090413:N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide