Cytisine, a partial agonist of high-affinity nicotinic acetylcholine receptors, has antidepressant-like properties in male C57BL/6J mice

Abstract

The nicotine in tobacco is thought to modulate neuronal systems regulating mood. Moreover, it appears possible that blockade rather than activation of beta2-containing (beta2*) nicotinic acetylcholine receptors (nAChRs) may lead to antidepressant-like effects. We used cytisine, a partial agonist of alpha4/beta2*nAChRs and a full agonist at alpha3/beta4*nAChRs, in several tests of antidepressant efficacy. Further, we used c-fos expression to identify potential neurobiological correlates of the antidepressant-like effects of cytisine. Cytisine had antidepressant-like effects in several animal models of antidepressant efficacy. In addition, immunohistochemical analyses indicated that cytisine could reduce c-fos immunoreactivity in the basolateral amygdala by approximately 50%. These data show that cytisine acts like classical antidepressants in rodent models of antidepressant efficacy. In addition, cytisine's ability to block alpha4/beta2*nAChRs may be responsible for its antidepressant-like properties, and these may be mediated through a reduction of neuronal activity in the basolateral amygdala. These studies also suggest that both antagonists and partial agonists of alpha4/beta2*nAChRs would be interesting targets for the development of novel antidepressant drugs.

Figure 1

Total time spent immobile in the tail suspension (A) and in the forced swim (B) tests by C57BL/6J male mice treated with saline, cytisine and mecamylamine. Error bars represent SEM. * P< 0.05, ** P< 0.01. N=8 for each treatment group.

Figure 2

Latency to initiate a feeding episode in the novelty-suppressed feeding test in male C57BL/6 mice. Effects of acute cytisine treatment is represented on the right. Error bars represent SEM. ** P<0.01, *** P<0.001. N=8 for each treatment group.

Figure 3

Total time spent in the dark compartment of the light/dark box test after acute cytisine or saline treatment in male C57BL/6 mice (A). Total number of beam breaks in an open-field for 20 minutes after acute injection of cytisine of cytisine or saline in male C57BL/6 mice (B). Error bars represent SEM. * P<0.05. N=8 for each treatment group.

Figure 4

A. c-fos immunostaining in brain areas of C57BL/6J male mice, following 24-days of treatment with saline, cytisine or mecamylamine. BLA: basolateral amygdala; Hypoth: hypothalamus; Nacc: nucleus accumbens; PVA: paraventricular nucleus; Sch: suprachiasmatic nucleus. Errors bars represent SEM. * p<0.05; ** p<0.01; *** p<0.001. N=8 for each treatment group. B, C, D. Examples of c-fos immunostaining in the (baso)lateral amygdala in saline-, cytisine-, and mecamylamine-treated animals.