Discriminative stimulus properties of the atypical antidepressant, mirtazapine, in rats: a pharmacological characterization.
BACKGROUND
Though interoceptive properties of antidepressants have been described, discriminative stimulus (DS) properties of mirtazapine, which does not affect monoamine reuptake, remain uncharacterized.


OBJECTIVE
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.


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-HT(2C) antagonists, SB242,084, SB243,213 and S32006, revealed dose-dependent and full (> or =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-HT(2B) antagonist, SB204,741, and the 5-HT(3) antagonist, ondansetron, showed no significant substitution. Though mirtazapine indirectly recruits 5-HT(1A) receptors, the 5-HT(1A) agonists, buspirone and 8-OH-DPAT, did not substitute. Mirtazapine blocks alpha(2)-adrenoceptors, but several alpha(2)-adrenoceptor antagonists (yohimbine, RX821,002 and atipamezole) failed to substitute. Despite blockade by mirtazapine of histamine H(1) receptors, no substitution was seen with the selective H(1) 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.


CONCLUSIONS
Mirtazapine elicits a DS in rats for which selective antagonists at 5-HT(2C) receptors display dose-dependent substitution, whereas drugs acting at other sites recognized by mirtazapine are ineffective.
Dekeyne
Anne
A
Department of Neuropharmacology, Institut de Recherches Servier, Centre de Recherches de Croissy 125 Chemin de Ronde, 78290, Croissy-sur-Seine, Paris, France. anne.dekeyne@fr.netgrs.com
Millan
Mark J
MJ
D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000818:Animals; D000929:Antidepressive Agents, Tricyclic / Q000494:pharmacology*; D004192:Discrimination, Psychological / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D006634:Histamine H1 Antagonists / Q000494:pharmacology; D008297:Male; D008803:Mianserin / Q000031:analogs & derivatives* / Q000494:pharmacology; D000078785:Mirtazapine; D051381:Rats; D017208:Rats, Wistar; D012054:Reinforcement, Psychology; D012702:Serotonin Antagonists / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000494:pharmacology
D000317:Adrenergic alpha-Antagonists; D000929:Antidepressive Agents, Tricyclic; D006634:Histamine H1 Antagonists; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D008803:Mianserin; D000078785:Mirtazapine