Following long-term training with citalopram, both mirtazapine and mianserin block its discriminative stimulus properties in rats

Rationale: The discriminative stimulus (DS) properties of the selective ser otonin (5-MT) uptake inhibitor (SSRI), citalopram, are mediated by 5-MT2C r eceptors. Interestingly, the "atypical" antidepressants, mianserin and mirt azapine, behave as antagonists at 5-HT2C receptors. Objective: Herein, we e valuated the influence of mianserin and mirtazapine upon the DS effects of citalopram. Methods: In a two-lever drug discrimination procedure, rats ini tially trained to discriminate citalopram (2.5 mg/kg, i.p.) from saline wer e retrained with a lower dose of citalopram (0.63 mg/kg, i.p.). Subsequentl y, generalization and antagonist studies were conducted with mianserin and mirtazapine. Results: Both dose-dependently blocked, but did not generalize to, the DS properties of citalopram without markedly disrupting response r ates. Their effective dose(50)s were 0.1 and 1.4 mg/kg, s.c., respectively. Conclusion: These observations are consistent with a role of 5-HT2C recept ors in mediation of the interoceptive properties of SSRIs and suggest that the DS effects of citalopram are not related to its "antidepressant" proper ties per se. Finally, they underline the distinctive nature of mirtazapine and mianserin as compared to antidepressant agents which interact with 5-HT uptake sites.