Modification of serotonergic neuron properties by long-term treatment with serotonin reuptake blockers.
The authors investigated the mechanism of action of the antidepressant serotonin (5-HT) reuptake blocker citalopram in the rat by means of an in vivo electrophysiologic paradigm. In control animals, the acute intravenous administration of citalopram reduced the firing rate of dorsal raphe nucleus serotonergic neurons with an ED50 of 230 micrograms/kg. Rats were treated with citalopram (20 mg/kg/day i.p.) for 2, 7, and 14 days. Two-day treatment was accompanied by a marked reduction of the firing activity of serotonergic neurons; there was a partial recovery after 7 days of treatment, and a complete one following 14-day citalopram administration. The response of serotonergic neurons to intravenously administered lysergic acid diethylamide (LSD), a somatodendritic 5-HT autoreceptor agonist, was reduced in rats treated with citalopram for 14 days, suggesting that such a treatment reduces the sensitivity of the somatodendritic autoreceptor. Fourteen-day citalopram treatment also markedly enhanced the efficacy of the stimulation of the afferent serotonergic pathway in suppressing the firing activity of postsynaptic CA3 dorsal hippocampus pyramidal neurons. This enhanced efficacy of serotonergic synaptic transmission was not the result of an increased sensitivity of postsynaptic neurons to serotonin, as the effect of the direct microiontophoretic application of serotonin onto these same neurons was not modified. That serotonin reuptake blockade per se was responsible for this enhancement could also be ruled out, as the acute intravenous administration of citalopram (1 mg/kg) in control rats failed to enhance the efficacy of the stimulation. To determine an involvement of the 5-HT terminal autoreceptor, methiothepin (1 mg/kg), a terminal autoreceptor antagonist, was injected intravenously in control and citalopram-treated rats.(ABSTRACT TRUNCATED AT 250 WORDS)
de Montigny
C
C
McGill University, Department of Psychiatry, Montreal, Quebec, Canada.
Chaput
Y
Y
Blier
P
P
D000818:Animals; D015283:Citalopram / Q000008:administration & dosage / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology; D006801:Humans; D007275:Injections, Intravenous; D008238:Lysergic Acid Diethylamide / Q000494:pharmacology; D008719:Methiothepin / Q000494:pharmacology; D011903:Raphe Nuclei / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D011985:Receptors, Serotonin / Q000187:drug effects / Q000502:physiology; D012701:Serotonin / Q000502:physiology*; D009435:Synaptic Transmission / Q000187:drug effects* / Q000502:physiology
D011985:Receptors, Serotonin; D015283:Citalopram; D012701:Serotonin; D008719:Methiothepin; D008238:Lysergic Acid Diethylamide