cgs-12066b and tianeptine

The effect of long term treatment with two tricyclic antidepressants on the sensitivity of 5-HT1B presynaptic heteroreceptors inhibiting acetylcholine (ACh) release was investigated. Groups of male rats received during 14 days either saline, citalopram (20 mg/kg), a serotonin (5-HT) uptake blocker, or tianeptine (2 x 10 mg/kg), an antidepressant that enhances 5-HT uptake. The efficacy of the 5-HT1B selective agonist 7-trifluoromethyl-4-(4-1-piperazinyl)-pyrrolo[1,2-a]quinoxaline (CGS 12066B) in reducing K(+)-evoked [3H]acetylcholine release from hippocampal synaptosomes was determined 24 hr after the last administration. The chronic treatment with citalopram or tianeptine modified neither the basal nor the K(+)-evoked release of [3H]acetylcholine. In contrast, these treatments significantly reduced the efficacy of CGS 12066B to inhibit the release of [3H]acetylcholine induced by K+ depolarization. These data suggest that chronic antidepressant treatment desensitizes 5-HT1B presynaptic heteroreceptors through a mechanism which seems to be independent of the synaptic availability of 5-HT.

Topics: Acetylcholine; Animals; Antidepressive Agents; Antidepressive Agents, Tricyclic; Citalopram; Hippocampus; In Vitro Techniques; Male; Potassium; Quinoxalines; Rats; Rats, Wistar; Receptors, Presynaptic; Receptors, Serotonin; Synaptosomes; Thiazepines

The interactions of citalopram and tianeptine, two antidepressants having opposite effects on serotonin (5-HT) uptake, with 5-HT1B presynaptic heteroreceptors located on cholinergic terminals were investigated. In rat hippocampal synaptosomes, citalopram (0.01 or 0.1 microM) or tianeptine (0.01-10 microM) did not modify the basal or the K(+)-evoked release of [3H]acetylcholine. Only at the concentration of 100 microM did tianeptine significantly decrease (-18%) the K(+)-evoked release of [3H]acetylcholine without affecting the spontaneous outflow of radioactivity. The inhibitory effect of 7-trifluoromethyl-4-(4-1-piperazinyl)-pyrrolo[1,2-a]quinoxaline (CGS 12066B), a 5-HT1B receptor agonist, on the stimulation-induced release of [3H]acetylcholine was reduced in a concentration-dependent manner by citalopram and tianeptine. Both drugs completely reversed the inhibitory effects of CGS 12066B at concentrations that did not modify by themselves the release of [3H]acetylcholine. In contrast, tianeptine, up to a concentration of 1 microM, failed to antagonise the inhibitory effect of the muscarinic receptor agonist carbachol on K(+)-evoked [3H]acetylcholine release. Finally, the administration of tianeptine ex vivo (10 or 20 mg/kg) modified neither the depolarisation-induced release of [3H]acetylcholine nor the inhibitory effect of CGS 12066B on this presynaptic process. These findings further confirm that antidepressants interact in vitro with presynaptic 5-HT1B heteroreceptors.

Topics: Acetylcholine; Animals; Antidepressive Agents, Tricyclic; Citalopram; Hippocampus; Male; Potassium; Quinoxalines; Rats; Rats, Wistar; Receptors, Serotonin; Synaptosomes; Thiazepines