Discriminative stimulus properties of the "atypical" antidepressant, mirtazapine, in rats: A pharmacological characterization

Abstract

Rationale: Though interoceptive properties of antidepressants have been described, discriminative stimulus (DS) properties of mirtazapine, which does not affect monoamine reuptake, remain uncharacterized. Objectives: The objectives of the study are to train rats to recognize a mirtazapine DS, then perform substitution studies with other antidepressants and drugs acting at sites occupied by mirtazapine. Materials and methods: Using a two-lever, fixed-ratio 10 schedule, rats were trained to discriminate mirtazapine (2.5 mg/kg, i.p.) from saline. Results: Sessions, 63∈±∈8, were necessary to reach the criterion for 14 rats that all subsequently recognized (100%) mirtazapine at the training dose. Mirtazapine blocks serotonin (5-HT)2C receptors, and the 5-HT2C antagonists, SB242,084, SB243,213 and S32006, revealed dose-dependent and full (≥80%) substitution at doses of 2.5, 2.5, and 0.63 mg/kg, respectively. By contrast, the 5-HT 2A antagonists, MDL100,907 and SR46349-B, the 5-HT2B antagonist, SB204,741, and the 5-HT3 antagonist, ondansetron, showed no significant substitution. Though mirtazapine indirectly recruits 5-HT 1A receptors, the 5-HT1A agonists, buspirone and 8-OH-DPAT, did not substitute. Mirtazapine blocks α2- adrenoceptors, but several α2-adrenoceptor antagonists (yohimbine, RX821,002 and atipamezole) failed to substitute. Despite blockade by mirtazapine of histamine H1 receptors, no substitution was seen with the selective H1 antagonist, pyrilamine. Finally, the selective noradrenaline reuptake inhibitor, reboxetine (0.16), fully substituted for mirtazapine, whereas the 5-HT/noradrenaline reuptake inhibitors, duloxetine and S33005, several 5-HT reuptake inhibitors (citalopram, fluvoxamine, and paroxetine) and the dopamine reuptake inhibitors, bupropion and GBR12,935, did not substitute. Conclusion: Mirtazapine elicits a DS in rats for which selective antagonists at 5-HT2C receptors display dose-dependent substitution, whereas drugs acting at other sites recognized by mirtazapine are ineffective. © 2008 Springer-Verlag.