Long-term 5-HT reuptake blockade, but not monoamine oxidase inhibition, decreases the function of terminal 5-HT autoreceptors: an electrophysiological study in the rat brain

Abstract

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 × 14 days), a selective 5-HT reuptake blocker, or clorgyline (1 mg/kg/day × 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. The reduction of the function of the terminal 5-HT autoreceptor by the long-term fluoxetine treatment was further indicated by the decreased ratio of effectiveness of the 0.8 and 5 Hz stimulations as compared to that of control rats. To verify that the reuptake blockade per se could not account for the increased synaptic efficacy of 5-HT projections following long-term fluoxetine, the drug was administered acutely to naive rats. It did not increase the efficacy of the stimulation of the 5-HT pathway. Two conclusions are drawn from these results: 1) the increased efficacy of 5-HT synaptic transmission by long-term treatment with antidepressant 5-HT reuptake blockers is not directly due to 5-HT reuptake blockade, but rather, to a reduced function of the terminal 5-HT autoreceptor; 2) the latter phenomenon cannot be ascribed to an increased availability of 5-HT in the synaptic cleft as it was not produced by long-term clorgyline treatment. Hence, these results suggest that long-term occupation of the [³H]IMI site might result in a decreased function of terminal 5-HT autoreceptors.