Pierre Blier

Effects of a selective 5-HT reuptake blocker, citalopram, on the sensitivity of 5-HT autoreceptors: Electrophysiological studies in the rat brain

SummaryCitalopram (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; however, the effect of the electrical activation of the ascending 5-HT pathway on these same neurons was enhanced. To determine if 5-HT reuptake blockade could be responsible for this enhancement, CIT (1 mg/kg) was injected intravenously in naive rats while stimulating the ascending 5-HT pathway; it failed to modify the effectiveness of the stimulation. To assess the involvement of the 5-HT terminal autoreceptor, methiothepin, a 5-HT autoreceptor antagonist, was injected intravenously (1 mg/kg) in naive rats and in rats treated for 14 days with CIT while stimulating the ascending 5-HT pathway. Methiothepin enhanced the effect of the stimulation in naive rats but failed to do so in the CIT-treated rats. It is concluded that long-term CIT treatment enhances 5-HT neurotransmission by desensitizing both the somatodendritic and terminal 5-HT autoreceptors.

Short-term lithium administration enhances serotonergic neurotransmission: electrophysiological evidence in the rat CNS

Rats received lithium-containing chow for 48 h. Brain and plasma lithium concentrations ranged from 0.4 to 1.0 mEq/l. A first series of experiments served to assess the responsiveness of CA3 hippocampal pyramidal neurons to microiontophoretically applied serotonin (5-HT) and norepinephrine (NE). The response of the same neurons to electrical stimulation of the ventro-medial 5-HT pathway was measured after lithium treatment. The responsiveness to 5-HT and NE was not modified whereas the effect of activation of the ascending 5-HT pathway was increased two-fold by the lithium treatment. These neurons were activated to their physiological firing rate by means of small ejection currents of acetylcholine. A pretreatment with the 5-HT neurotoxin 5,7-dihydroxytryptamine abolished the response to the electrical stimulation in lithium-treated rats. In a second series of experiments, unitary recordings of 5-HT neurons were obtained from the dorsal raphe nucleus. The lithium treatment modified neither the number of spontaneously active 5-HT neurons nor their mean firing rate. These results provide direct electrophysiological evidence for the enhancement of 5-HT neurotransmission by short-term lithium treatment through its presynaptic action on 5-HT terminals.

Effects of the two antidepressant drugs mianserin and indalpine on the serotonergic system: single-cell studies in the rat

Several antidepressant treatments enhance serotonergic neurotransmission. The present electrophysiological studies were undertaken to assess the effect of mianserin and indalpine, two antidepressant drugs with different pharmacological profiles, on serotonergic neurotransmission. In a first series of experiments, the responsiveness of hippocampal pyramidal neurons to microiontophoretic applications of serotonin (5-HT), norepinephrine (NE) and γ-aminobutyric acid (GABA) was assessed following mianserin, imipramine (5 mg/kg/day IP) or saline administration for 14 days. At 48 h after the last dose of mianserin, responsiveness to 5-HT was increased whereas that to NE and GABA was not modified. The degree of sensitization to 5-HT was the same as that produced by imipramine. Acute IV administration of mianserin (up to 10 mg/kg) did not decrease the firing rate of dorsal raphe 5-HT neurons. In a second series of experiments, long-term administration of indalpine (5 mg/kg/day IP for 14 days) did not modify the responsiveness of hippocampal pyramidal neurons to microiontophoretically applied 5-HT, NE and GABA whereas imipramine treatment (5 mg/kg/day IP) increased selectively their sensitivity to 5-HT when compared to indalpine-treated rats. In keeping with its potent reuptake-blocking property, acute IV indalpine produced a marked decrease in the firing rate of dorsal raphe 5-HT neurons (ED50 0.33 mg/kg). The firing rate of dorsal raphe 5-HT neurons was assessed following 2-, 7- and 14-day treatments with indalpine (5 mg/day IP). After 2 days, the firing rate of 5-HT neurons was greatly reduced, after 7 days it had recovered partially and after 14 days it had returned to normal. At this point, the responsiveness of 5-HT neurons to IV LSD, an agonist of the 5-HT autoreceptor, and to microiontophoretically-applied 5-HT was decreased twofold, indicating desensitization of the autoreceptor. In conclusion, it is proposed that long-term treatment with mianserin, as with tricyclic antidepressant drugs and electroconvulsive shocks, increases 5-HT neurotransmission via sensitization of postsynaptic neurons to 5-HT whereas long-term treatment with indalpine, as with zimelidine, results in the same final effect via its presynaptic effect on 5-HT neurons presumably by blocking 5-HT reuptake. These data further support the notion that enhancing 5-HT neurotransmission might have an antidepressant effect.

Pre- and postsynaptic effects of zimelidine and norzimelidine on the serotoninergic system: single cell studies in the rat.

The pre‐ and postsynaptic effects of zimelidine and norzimelidine were studied in adult male Sprague‐Dawley rats. The potency of the presynaptic effect was estimated from their ability to depress the rate of firing of serotonin (5‐HT)‐containing raphe neurons. Chronic administration of tricyclic antidepressant drugs has been shown to sensitize forebrain postsynaptic 5‐HT receptors. The effect of zimelidine on these receptors was compared to that of saline and chlorimipramine by assessing the responsiveness of hippocampal pyramidal cells to microiontophoretic applications of 5‐HT, norepinephrine (NE) and γ‐aminobutyric acid (GABA).

Effect of repeated amiflamine administration on serotonergic and noradrenergic neurotransmission: electrophysiological studies in the rat CNS

SummaryAmiflamine is a selective and reversible inhibitor of monoamine oxidase (MAO) type A which exerts a preferential effect on serotonin (5-HT) catabolism. The present studies were undertaken to compare the effects of repeated administration of amiflamine (2 mg/kg, twice daily) on several aspects of the functioning of the 5-HT and norepinephrine (NE) systems in the rat CNS. The activity of MAO-A and B was assessed in forebrain slices and the whole brain contents of the neurotransmitters and their metabolites were determined by HPLC after 2-, 7- and 21-day treatments. MAO-A was inhibited by about 50% 2 h after the last dose and its activity was back to normal in rats sacrificed 12 h after the last dose. The activity of MAO-B was unaffected two or 12 h after the last dose. Whole brain concentration of 5-HT was increased to a greater degree than that of NE following repeated administration of amiflamine. These increases in 5-HT and NE were accompanied by decreased levels of their respective metabolites 5-hydroxy-indoleacetic acid and 3-methoxy-4-hydroxyphenylethyleneglycol. The firing activity of dorsal raphe 5-HT neurons, but not that of NE neurons, was markedl decreased 2–6 h after the last dose of a 2-day treatment. However, 2–6 h after a 21-day treatment, the firing activity of 5-HT neurons was back to normal, whereas that of NE neurons was decreased by 30%. The recovery of firing activity of 5-HT neurons following long-term amiflamine is attributable to a desensitization of the somatic 5-HT autoreceptor as indicated by the decreased responsiveness of 5-HT neurons to intravenous LSD. In contrast, the sensitivity of the somatic NE autoreceptor was not modified, as verified by the unchanged responsiveness of NE neurons to clonidine, an α2 agonist. The duration of the suppression of firing activity of hippocampus pyramidal neurons produced by the electrical activation of the ascending 5-HT pathway was prolonged in amiflamine-treated rats as compared to controls. This increased synaptic efficacy was attributable to a presynaptic modification since the responsiveness of the same neurons to microiontophoretically-applied 5-HT was not changed. The efficacy of the stimulation of the dorsal NE bundle, as well as that of the microiontophoretic applied of NE, were unchanged in the same rats. Since the efficacy of the stimulation of the 5-HT pathway is increased at the time 5-HT neurons have regained their normal firing rate, it is concluded that 5-HT neurotransmission is enhanced following the long-term treatment with amiflamine.

Effects of quipazine on pre- and postsynaptic serotonin receptors: single cell studies in the rat CNS.

Many behavioural and biochemical studies have pointed to an agonistic activity of quipazine on serotonin (5-HT) receptors. In the present electrophysiological study, the effect of quipazine on pre- and postsynaptic 5-HT receptors in the rat was studied. Quipazine, administered intravenously, depressed the firing rate of 5-HT-containing dorsal raphe neurones (ED50 = 0.82 mg/kg). Microiontophoretic applications of quipazine on 5-HT-containing neurones in the dorsal raphe and on neurones of two forebrain regions receiving a 5-HT input (the ventral lateral geniculate nucleus and the dorsal hippocampus) consistently depressed neuronal firing rate as did 5-HT and D-lysergic acid diethylamide (LSD). Quipazine was more potent on 5-HT neurones than on the ventral lateral geniculate nucleus and hippocampal neurones: the post/presynaptic efficacy ratio for quipazine was similar to that of LSD. Following a selective denervation of 5-HT neurones with intraventricular injection of 5,7-di-hydroxy-tryptamine in desipramine-pretreated rats, the responsiveness of neurones in the ventral lateral geniculate nucleus to quipazine, applied microiontophoretically, was increased as was that to 5-HT and to LSD. These results provide direct evidence for the agonistic activity of quipazine on both pre- and postsynaptic 5-HT receptors.

Antidepressant Monoamine Oxidase Inhibitors Enhance Serotonin but not Norepinephrine Neurotransmission

Monoamine oxidase inhibitors (MAOIs) were the first effective drugs in the treatment of major depression (Klein et al. 1980). Given their inhibiting action on the catabolism of monoaminergic neurotransmitters, they constitute unique tools for investigating the neurobiological basis of the antidepressant response.