Cytisine, a partial agonist of high-affinity nicotinic acetylcholine receptors, has antidepressant-like properties in male C57BL/6J mice
Introduction
A number of observations suggest that smoking and nicotine can regulate mood in both human subjects and animal models. In clinical studies, depressed subjects have an approximately 50% higher incidence of smoking than the general population (Diwan et al., 1998, Glassman et al., 1990, Kessler, 1995). In addition, nicotine patch can reduce symptoms of depression in non-smokers (Salin-Pascual et al., 1995) whereas smoking cessation can exacerbate symptoms of depression (Glassman et al., 1990). Animal studies have also shown that chronic nicotine administration can elicit antidepressant-like effects in rats both in the learned helplessness (Semba et al., 1998) and the forced swim (Djuric et al., 1999, Tizabi et al., 1999) paradigms. Taken together, these studies suggest that the nicotine in tobacco modulates neuronal systems regulating mood.
Nicotine exerts its effects by binding to, activating and desensitizing nicotinic acetylcholine receptors (nAChRs) in the central nervous system and autonomic ganglia (Picciotto, 1998). α4/β2-containing (α4/β2*) nAChRs combined with the α5, α6 or β3 subunits are the most widely expressed nAChRs in the central nervous system, and also have the highest affinity for nicotine, whereas α7*nAChRs form functional homomers and are highly expressed in the hippocampus and cortex, but also found in most other brain regions (Zoli et al., 1998). The observation that increased acetylcholine levels results in depression (Janowsky et al., 1972) whereas nicotine administration can decrease depressive symptoms (Salin-Pascual et al., 1995) appears paradoxical, however, chronic administration of nicotine (particularly as delivered through nicotine patch) can desensitize rather than activate nAChRs (Reitstetter et al., 1999), resulting in functional antagonism (for reviews see Gentry and Lukas, 2002, Quick and Lester, 2002). This suggests that blockade rather than activation of nAChRs might have antidepressant effects. This hypothesis is supported by the fact that mecamylamine, a non-selective nAChR antagonist, decreased symptoms of depression in patients with Tourette's syndrome (Dursun and Kutcher, 1999, Mihailescu and Drucker-Colin, 2000, Salin-Pascual et al., 2003), and has antidepressant-like properties in mice (Caldarone et al., 2004, Rabenstein et al., 2006).
Studies in knockout mice have demonstrated that the absence of β2*nAChRs throughout development can lead to antidepressant-like phenotypes (Caldarone et al., 2004). Moreover, amitriptyline, a classical antidepressant, has no effect in these animals, strongly suggesting that β2*nAChRs are involved in the function of a classical antidepressant. This study also showed that subthreshold doses of the nicotinic antagonist mecamylamine and the tricyclic antidepressant amitriptyline could combine to result in antidepressant-like effects, supporting the idea that blockade of nAChRs might be antidepressant. We hypothesized that if blockade of nAChRs results in antidepressant-like behavior, interference with endogenous acetylcholine signaling though these nAChRs might also result in an antidepressant-like response. We therefore used cytisine, a partial agonist of β2*nAChRs and a full agonist at β4 nAChRs (Picciotto et al., 1995) in several tests of antidepressant efficacy. This is of particular interest since recent studies suggest that partial agonists of α4/β2*nAChRs may be useful in smoking cessation (Coe et al., 2005). Additionally, we furthered our behavioral analyses by testing locomotor activity and anxiety-like behaviors, because both could be major confounds in the different assessments we used in this study. Finally, we assessed c-fos expression, an immediate-early gene commonly considered to be a marker of neuronal activity, to identify neurobiological correlates of the antidepressant-like effects of cytisine.
Section snippets
Animals
Three-month-old C57BL/6J (B6) male mice were purchased from The Jackson Laboratory (Bar Harbor, ME, USA). Mice were immediately grouped 4 per cage under standard conditions (temperature 21 ± 2 °C, 12:12-h light/dark cycle, lights on at 07:00 h). Food and water were available ad libitum. After a 2-week rest period, mice were marked on their tail with a permanent marker for identification and were randomly assigned to one of the different treatment groups (saline, cytisine and mecamylamine; n =
Results
In the tail suspension test (Fig. 1A), mice injected with cytisine showed significantly less immobility at the 1.5 mg/kg dose compared to saline-treated animals (F1,14 = 13.15, p = 0.003), as did mice injected with mecamylamine (1 mg/kg; F1,14 = 19.28, p = 0.0006). Treatment with other cytisine doses showed a trend to induce decreased immobility but did not reach significance compared to saline treatment.
Similarly, in the forced swim test (Fig. 1B), mice treated with cytisine (1.5 mg/kg) spent
Discussion
The potential antidepressant-like effects of cytisine, a partial agonist of α4/β2*nAChRs and a full agonist at α3/β4*nAChRs, was investigated in several rodent models of antidepressant efficacy. Acute cytisine treatment had antidepressant-like effects in both the tail suspension and the forced swim tests. These effects did not appear connected to the full agonist properties of cytisine at α3/β4*receptors because similar results were obtained when animals were treated with the broad nAChR
Acknowledgements
This work was supported by NIH grants DA13334/AA15632, MH77681, DA00436 and the NARSAD Foster Bam award.
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