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

Abstract

These observations are consistent with a role of 5-HT2C receptors in mediation of the interoceptive properties of SSRIs and suggest that the DS effects of citalopram are not related to its "antidepressant" properties per se. Finally, they underline the distinctive nature of mirtazapine and mianserin as compared to antidepressant agents which interact with 5-HT uptake sites.

Discriminative stimulus properties of the “atypical” antidepressant, mirtazapine, in rats: a pharmacological characterization

“…It is instructive to consider substitution/antagonism profiles of mianserin compared to mirtazapine versus various training drugs (Table 5). First, despite its affinity for NA transporters, mianserin did not substitute for reboxetine, and neither mianserin nor mirtazapine generalize to citalopram (Dekeyne et al 2001b;Millan and Dekeyne 2007). Second, in line with a CTA study of Walker et al (2005), mirtazapine and mianserin block DS actions of 5-HT 2C receptor agonists (Gommans et al 1998;Bourson et al 1996;Dekeyne et al 1999).…”

“…However, since other agents that elevate NA levels do not substitute for reboxetine, this issue justifies additional exploration. The interoceptive actions of mirtazapine can unambiguously be differentiated from antidepressants increasing extracellular 5-HT, since no substitution was observed with three SSRIs, and mirtazapine itself did not substitute to DS induced by citalopram (Dekeyne et al 2001b). Moreover, inasmuch as the DARIs, bupropion and GBR12,935, failed to substitute for the mirtazapine DS, a role of increased DA availability does not contribute to its interoceptive effects.…”

“…A role of 5-HT 2C receptors is supported by the observation that mirtazapine blocks the DS properties of the selective 5-HT 2C agonist, Ro60,0175. Furthermore, it also abrogates the DS elicited by the SSRI, citalopram, which is mediated via 5-HT 2C receptors (Millan et al 2000a;Dekeyne et al 2001b). Interestingly, mirtazapine and S32006 both behave as inverse agonists at constitutively active 5-HT 2C receptors, and SB243,213 is an inverse agonist at 5-HT 2C receptors coupled to phospholipase A2, though not phospholipase C (Wood et al 2001;Berg et al 2006;Chanrion et al 2008;Dekeyne et al 2008).…”

“…This challenging procedure is reminiscent of difficulties confronted in training animals to recognize other antidepressants like SSRIs and NARIs employing a similar training procedure (Olivier et al 1993;Dekeyne et al 2001b;Dekeyne and Millan 2003). Nonetheless, a sufficient number of subjects did reliably achieve the criterion requisite for thorough testing, and the finding that mirtazapine provoked a "salient" interoceptive stimulus herein is consistent with its ability to elicit a CTA in mice, albeit over a far shorter exposure period of 5 days (Berendsen and Broekkamp 1997).…”

“…This is unfortunate since discriminative stimulus (DS) studies are potentially instructive in evaluating several interesting issues: first, in determining whether a training drug shares interoceptive effects with other classes of clinically active antidepressant; second, in characterizing mechanisms of action involved in the interoceptive effects of antidepressants using substitution tests with ligands selective for specific classes of receptor and transporter; third, in relating DS properties of antidepressants to their functional actions, including their influence upon mood. In fact, despite difficulties faced in training, these questions have been addressed in drug discrimination studies of the selective serotonin (5-HT) reuptake inhibitor (SSRI), citalopram, the selective noradrenaline (NA) reuptake inhibitor (NARI), reboxetine, and dopamine (DA) reuptake inhibitor, bupropion (Olivier et al 1993;Terry and Katz 1997;Millan et al 1999aMillan et al , 1999bDekeyne et al 2001aDekeyne et al , 2001bYoung and Glennon 2002;Millan and Dekeyne 2007; see Dekeyne and Millan 2003 for review). By contrast, the poor tolerance of tricyclic agents upon longterm administration, has complicated their use as training drugs (Zhang and Barrett 1991;Dekeyne and Millan 2003).…”