Chronic coadministration of carbamazepine together with imipramine produces antidepressant-like effects in an ACTH-induced animal model of treatment-resistant depression: involvement of 5-HT(2A) receptors?

The use of carbamazepine has been reported to be an effective treatment for severe depression. We have already shown that the antidepressant-like effects of tricyclic antidepressants in the rat forced swim test (FST) are blocked by chronic treatment with adrenocorticotropic hormone (ACTH). In the present study, we examined the effect of the chronic administration of carbamazepine on the FST and the wet-dog shakes induced by (+/-) -1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI), a 5-HT(2A) receptor agonist, in ACTH-treated rats. Chronic administration of carbamazepine did not affect the duration of immobility in saline-treated and ACTH-treated rats. The reduction of immobility, induced by chronic administration of imipramine, was blocked by treatment with ACTH. When carbamazepine was administered concurrently with imipramine, we observed a significant decrease in immobility in rats treated with ACTH. Chronic ACTH treatment increased the number of the wet-dog shakes induced by DOI. This effect of ACTH was significantly increased by the coadministration of carbamazepine and imipramine. These results suggest that the use of carbamazepine together with tricyclic antidepressants had the effect of reducing immobility time in the FST in a tricyclic antidepressant-treatment-resistant depressive model induced by chronic ACTH treatment.

Effects of imipramine on extracellular serotonin and noradrenaline concentrations in ACTH-treated rats.

We investigated the effect of imipramine on extracellular serotonin (5-HT) and noradrenaline concentrations in the medial prefrontal cortex of rats treated with adrenocorticotropic hormone (ACTH) for 14 days using in vivo microdialysis. Chronic ACTH treatment did not affect basal extracellular 5-HT and noradrenaline concentrations compared with chronic saline treatment. Acute imipramine treatment plus chronic ACTH treatment significantly increased extracellular 5-HT concentrations, compared with imipramine treatment alone. 8-hydroxy-2-di-n-propylamino tetralin (8-OH-DPAT), a 5-HT1A receptors full agonist, caused a significant decrease in extracellular 5-HT concentrations. However, its inhibitory effect was attenuated by the treatment with ACTH for 14 days. These findings suggest that chronic treatment with ACTH enhances the increasing effect release of 5-HT by imipramine through the desensitization of somatodendritic 5-HT1A autoreceptors.

Increased DOI-induced wet-dog shakes in adrenocorticotropic hormone-treated rats are not affected by chronic imipramine treatment: possible involvement of enhanced 5-HT(2A)-receptor expression in the frontal cortex.

We examined the influence of imipramine, a traditional tricyclic antidepressant, on the binding to serotonin (5-HT)(2) receptors and levels of 5-HT(2A)-receptor mRNA in the frontal cortex of rats treated with adrenocorticotropic hormone (ACTH). Chronic treatment with ACTH significantly increased the binding of [(3)H]-ketanserin to 5-HT(2) receptors and the expression of 5-HT(2A)-receptor mRNA in the frontal cortex. However, it did not alter the concentration of 5-HT or 5-hydroxyindole acetic acid. The effect of chronic ACTH treatment on 5-HT(2) receptor and 5-HT(2A)-receptor mRNA levels was not altered by the chronic administration of imipramine. Also, imipramine did not affect the hyperfunction of 5-HT(2A) receptors caused by chronic ACTH treatment. These findings suggest that chronic treatment with ACTH acts to increase 5-HT(2A)-receptor synthesis through increased gene transcription, without modulating presynaptic serotonergic neurotransmission.