Besides the regulation of the
Besides the regulation of the stress responses, CRF and the urocortins have been implicated in drug addiction (Bruijnzeel and Gold, 2005, Sarnyai et al., 2001). For instance nicotine, the addictive substance of tobacco, can activate the HPA axis, just like any other stressor may do, although its impact on behavior depends on the dose and the time of administration. On the one hand, acute administration of low doses of nicotine promotes anxiolytic and antidepressant behavior (Andreasen and Redrobe, 2009, Balerio et al., 2005, Varani and Balerio, 2012). On the other hand, acute or chronic administration of higher doses of nicotine provokes anxiety and depression (Bura et al., 2010, Hayase, 2007, Hayase, 2011). In addition, nicotine withdrawal syndrome has an affective component represented by anxiety- and depression-like symptoms (Kenny and Markou, 2001, Markou, 2008, Wonnacott et al., 2005), which are common in the withdrawal phase of all kinds of drug addiction.
Previous studies have already suggested that central administration of UCN 2 or UCN 3 could reverse the alcohol withdrawal-induced anxiety- and depression-like behavior (Valdez et al., 2004, Valdez, 2009). However, up to this date, there is no evidence that selective agonists of CRF2 receptors would ameliorate the affective component of nicotine withdrawal syndrome. Therefore, the aim of the present study was to investigate the effects of UCN 2 and UCN 3 on the anxiety- and depression-like signs induced by chronic nicotine treatment and consequent acute withdrawal in mice. In order to do so, male CFLP mice were exposed for 7 days to repeated intraperitoneal (IP) injection with nicotine or saline solution and 1 day of acute withdrawal and then a single intracerebroventricular (ICV) injection with UCN 2, UCN 3 or saline solution. After 30min the mice were observed in an elevated plus-maze test or a forced swim test, for anxiety- and depression-like behavior. States of anxiety and depression are usually associated with the hyperactivity of the HPA axis, reflected by increased 5-hme-CTP glucocorticoid concentration (Altemus et al., 1992, Chappell et al., 1996, Nemeroff, 1996a, Plotsky et al., 1998). Consequently, after 5min of testing, the plasma corticosterone concentration of the mice was also determined by a chemo-fluorescent method. Half of the animals were treated ICV and evaluated on the 8th day, the other half on the 9th day.
Discussion Our experiments from the 8th day seem to indicate that acute nicotine withdrawal after 12h (1/2day following 2mg/kg nicotine IP for 7 days, 4 times/day) may evoke anxiolysis, as mice treated with nicotine spent more time in the open arms of the elevated plus-maze than those treated with saline. This result is supported by a previous study that reported that subchronic administration of nicotine (.1mg/kg subcutaneously, SC, for 6 days) produces anxiolytic effect in mice (Biala et al., 2009) and it is opposed by other studies which referred that subchronic (.3mg/kg/day nicotine SC for 4 days) or chronic administration (25mg/kg/day nicotine via minipump for 14 days) of nicotine in higher doses than .1mg/kg induces anxiogenic behavior in mice (Bura et al., 2010, Hayase, 2007). Also, our experiments from the 8th day seem to indicate that acute nicotine withdrawal after 12h may provoke depression, as mice treated with nicotine spent less time with swimming and climbing in the water than those treated with saline. This result is underlined by previous studies according to which repeated SC nicotine treatment (.3mg/kg/day IP for 4 days) produces depression-like behavior (Hayase, 2008, Hayase, 2011). Although in our study despite of the remarkable decrease in the time spent with swimming and climbing, there was no significant difference in the time spent immobile - this being the typical sign of depression in the forced swim test - in nicotine-treated animals, when compared to the saline-treated animals. Therefore, our results could be rather interpreted as a consequence of the locomotor suppressive effect exerted by nicotine (Faraday et al., 1999, Faraday et al., 2003), than an apparently coexisting anxiolytic and depressive behavior. In accordance, the behavioral changes described on the 8th day were not accompanied by significant elevation of the plasma corticosterone concentration.