Citalopram (CIT), is a selective serotonin (5-HT) reuptake blocker and a clinically effective antidepressant. The present electrophysiological studies were undertaken to investigate in vivo the acute and long-term effects of CIT administration on 5-HT neurotransmission. In a first series of experiments, a single dose of CIT (0.05-0.5 mg/kg) was administered intravenously to naive rats while recording the activity of a 5-HT-containing neuron in the nucleus raphe dorsalis. A dose-response relationship of the inhibitory effect of CIT on the firing activity of 5-HT neurons was obtained with an ED50 of 0.23 +/- 0.03 mg/kg. In a second series of experiments, rats were treated with CIT (20 mg/kg/day, i.p.) for 2, 7 and 14 days. In rats treated for 2 days, there was a marked reduction in the firing activity of 5-HT neurons in the nucleus raphe dorsalis; there was a partial recovery after 7 days and a complete recovery after 14 days of treatment. The response of 5-HT neurons to intravenously administered LSD was decreased in rats treated for 14 days with CIT, indicating a desensitization of the somatodendritic 5-HT autoreceptor. In a third series of experiments, carried out in rats treated with CIT (20 mg/kg/day, i.p.) for 14 days, the suppression of firing activity of CA3 hippocampal pyramidal neurons produced by microiontophoretically-applied 5-HT and by the electrical activation of the ascending 5-HT pathway was measured. Long-term treatment with CIT did not modify the responsiveness of these neurons to microiontophoretically-applied 5-HT.(ABSTRACT TRUNCATED AT 250 WORDS)
The present in viva studies were undertaken to evaluate electrophysiologically the modulatory role of the terminal 5-HT autoreceptor on S-HT neurotransmission. In a first series of experiments, the effect of the electrical activation of the ascending 5-HT pathway on the firing activity of CA3 hippocampal pyramidal neurons was measured before and after the intravenous administration of methiothepin, a terminal 5-HT autoreceptor antagonist. Methiothepin significantly increased the duration of the suppression of firing activity of these neurons by the electrical stimulation of the 5-HT pathway, without modifying their responsiveness to microiontophoretically applied 5-HT. This suggests that endogenously released 5-HT activates the 5-HT terminal autoreceptor and that methiothepin enhances the efficacy of 5-HT synaptic transmission by blocking this activation. In a second series of experiments, further evidence for the activation of terminal 5-HT autoreceptors by 5-HT released by the electrical stimulation was sought by assessing the effectiveness of 2 series of stimulations of the ascending 5-HT pathway delivered at different frequencies while recording the same postsynaptic neuron. Increasing the frequency of stimulation (from 0.8 to 5 Hz) significantly reduced the duration of suppression of firing activity of the postsynaptic neurons. This difference between the 0.8 and 5 Hz stimulations was decreased by intravenous methiothepin, suggesting that the reduced effectiveness of the stimulations delivered at the higher frequency is attributable to a greater activation of the terminal 5-HT autoreceptor. These results provide direct electrophysiological evidence for the modulatory role of the 5-HT terminal autoreceptor on 5-HT neurotransmission.Most of the evidence supporting the existence of autoreceptors on 5-HT terminals has been derived from in vitro data on the release of 5-HT from rat brain synaptosomes and slices (for a review, see Moret, 1985). These studies have consistently demonstrated that exogenously applied agonists such as 5-HT itself and lysergic acid diethylamide (LSD) decrease the electrically or K+-evoked release of 3H-5-HT in a concentration-dependent manner (Baumann and Waldmeier, 1981;Cerrito and Raiteri, 1979;Chase et al., 1969;Cox and Ennis, 1982; Farnebo and Hamberger, 197 1, 1974;Gothert, 1980; Giithert and Weinheimer, 1979;Hamon et al., 1974;Katz and Kopin, 1969;Langer and Moret, 1982;Martin and Sanders-Bush, 1982;Mounsey et al., 1982). In such preparations, the antagonist property ofmethReceived Aug. 19, 1985; revised Jan. 27, 1986; accepted Mar. 24, 1986. This iothepin has been demonstrated by its ability to reduce the effect of exogenous 5-HT and LSD on the depolarization-induced 3H-5-HT release; the parallel rightward shift of the dose-response curves for the inhibition of )H-HT release by 5-HT and LSD suggests that methiothepin prevents the effect of these agonists by a steric interaction at the autoreceptor site (Cerrito and Raiteri, 1979;Cox and Ennis, 1982;Farnebo and Hamberger, 1974...
5-HT-containing terminals possess autoreceptors which modulate the release of 5-HT into the synaptic cleft. Tritiated imipramine ([3H]IMI), and more specifically [3H]citalopram and [3H]paroxetine, bind to a site associated with the 5-HT reuptake carrier on the 5-HT terminals. The function of terminal 5-HT autoreceptors is decreased following long-term treatment with the 5-HT reuptake blocker citalopram. The present study was undertaken to determine whether an increased synaptic availability of 5-HT or, the occupation of the [3H]IMI site, were responsible for this modification. Unitary extracellular recordings were obtained from CA3 dorsal hippocampus pyramidal neurons under chloral hydrate anesthesia in rats treated daily with fluoxetine (10 mg/kg/day X 14 days), a selective 5-HT reuptake blocker, or clorgyline (1 mg/kg/day X 21 days), an inhibitor of type A monoamine oxidase. The function of the terminal 5-HT autoreceptors was assessed by comparing the effectiveness of the electrical stimulation of the ascending 5-HT pathway on the firing activity of hippocampus pyramidal neurons prior to, and following, the administration of methiothepin, an antagonist of the terminal 5-HT autoreceptor, and, by determining the ratio of effectiveness of 0.8 Hz (S1) and 5 Hz (S2) stimulations. Long-term administration of fluoxetine or clorgyline both increased the efficacy of the stimulation of the 5-HT pathway. However, the enhancing effect of methiothepin on the efficacy of the stimulation was attenuated by the fluoxetine, but not by the clorgyline, treatment.(ABSTRACT TRUNCATED AT 250 WORDS)
Most visits to the psychiatric emergency service were made by frequent users who had distinctive profiles, which are potentially useful for developing clinical strategies to reduce the impact of this patient group on this service.
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