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  • UCM05 synthesis The aim of the present study was to investig

    2021-01-14

    The aim of the present study was to investigate the participation of CRF1 and CRF2 in the alterations of the dorsal and ventral striatal dopamine release and the vertical and horizontal locomotor activity observed in rats following chronic nicotine treatment and consequent acute withdrawal. In this purpose, male Wistar rats were exposed to repeated intraperitoneal (ip) injection with 1.4 mg/kg nicotine or saline solution for 7 days, two times/day (at 8:00 and at 20:00). Thus, 12 h passed between the nicotine treatments. This dose and schedule of administration should produce UCM05 synthesis nicotine levels in rats similar to plasma nicotine levels found in an individual who smokes 1–2 packs of cigarettes a day (Benowitz, 2008). In order to assess the behavioral and neurochemical changes induced by chronic nicotine treatment and acute nicotine withdrawal the rats were investigated on the morning of the 8th day (12 h after the last ip administration) and the 9th day (24 h after the last ip administration), respectively. Furthermore, the rats were injected intracerebroventricularly (icv) with selective CRF1 receptor antagonist antalarmin or selective CRF2 receptor antagonist astressin2B or saline solution on the 8th day or the 9th day. Thirty minutes after the icv injection the changes of the horizontal and vertical locomotor activity were recorded in an in vivo conducta system. Immediately after the behavioral recordings the changes of the dorsal and ventral striatal dopamine release were determined in an in vitro superfusion system.
    Results On the 8th day, the horizontal (Fig. 1) and vertical locomotor activity (Fig. 2) and the dorsal (Fig. 3) and ventral striatal dopamine release (Fig. 4) increased significantly in nicotine-treated rats, compared with the saline-treated rats. Tukey post-hoc test revealed the following p values: p < 0.0001 for horizontal locomotor activity, p = 0.0043 for vertical locomotor activity, p < 0.0001 for dorsal striatal dopamine release, and p < 0.0001 for ventral striatal dopamine release. All the changes observed on the 8th day were reduced significantly by icv treatment with antalarmin, but not astressin2B (Fig. 1, Fig. 2, Fig. 3, Fig. 4). Tukey post-hoc test indicated the following p values: p = 0.0304 for horizontal locomotor activity, p = 0.0002 for vertical locomotor activity, p < 0.0001 for dorsal striatal dopamine release, and p < 0.0001 for ventral striatal dopamine release. On the 9th day, the horizontal locomotor activity (Fig. 1) and the dorsal striatal dopamine release (Fig. 3) were increased significantly, while the vertical locomotor activity (Fig. 2) and the ventral striatal dopamine release (Fig. 4) were decreased significantly in the nicotine-treated rats, compared with the saline-treated rats. Tukey post-hoc test revealed the following p values: p < 0.0001 for horizontal locomotor activity, p = 0.0033 for vertical locomotor activity, p < 0.0009 for dorsal striatal dopamine release, and p < 0.0002 for ventral striatal dopamine release. All the changes assessed on the 9th day were reversed completely by icv treatment with antalarmin, but not astressin2B (Fig. 1, Fig. 2, Fig. 3, Fig. 4). Tukey post-hoc test indicated the following p values: p < 0.0001 for horizontal locomotor activity, p = 0.0321 for vertical locomotor activity, p = 0.0022 for dorsal striatal dopamine release, and p < 0.0001 for ventral striatal dopamine release. A summary of the effects of the antagonist treatment, the nicotine treatment and the interaction between them is presented in Table 1, Table 2, Table 3, Table 4.
    Discussion In rats exposed to 7 days of nicotine treatment (12 h after the last nicotine administration) we observed increases in horizontal and vertical locomotor activity along with increases in the dorsal and ventral striatal dopamine release. This finding is in line with previous studies which reported locomotor hyperactivity on the 4th and the 10th day of a chronic nicotine exposure (Fung and Lau, 1991, Fung and Lau, 1992). The authors of these studies suggested that nicotine-treated rats develop locomotor hyperactivity in response to nicotine initially due to increases of both the density of dopamine receptors (D1 and D2) and dopamine concentration, and lately due to dopamine receptor supersensitivity in the striatum (Fung and Lau, 1988). The interpretation of the behavioral changes observed following chronic nicotine treatment is somewhat complicated by the observation that the impact of chronic nicotine exposure on locomotion depend upon sex, age, and housing conditions (Faraday et al., 1999b, Faraday et al., 2001, Faraday et al., 2003a, Faraday et al., 2003b, Faraday et al., 2005). Female animals are less sensitive to the acute and chronic effects of nicotine, but more sensitive to the impact of acute nicotine withdrawal, including the neuroendocrine and behavioral stress responses, when compared to males (Bangasser and Wiersielis, 2018, Becker, 2016, Faraday et al., 1999a, Faraday et al., 2003b, Faraday et al., 2005). As regards the locomotor actions of nicotine in male and female Long-Evans and Sprague-Dawley rats, the horizontal activity was more enhanced in Long-Evans females, and the vertical activity was unaltered in Sprague-Dawley males (Faraday et al., 2003b). Also, younger animals exhibit increased sensitivity to the positive, rewarding effects of nicotine and reduced sensitivity to the negative, aversive effects of nicotine withdrawal which may contribute to the higher risk to develop nicotine addiction in adolescents, when compared to adults (Faraday et al., 2003a, Portugal et al., 2012). As regards the locomotor actions of nicotine, during chronic nicotine administration adolescent males exhibited a greater locomotor activity, when compared to adult males or adolescent females (Faraday et al., 2001). During nicotine cessation, nicotine-treated adolescent males continued to exhibit greater locomotor activity than saline-treated animals (Faraday et al., 2001). Another possible factor influencing the results is the housing condition (Faraday et al., 1999b). In saline-treated rats, group housing decreased the horizontal and vertical activity and the center time, a measure of anxiety with effects ocurring sooner in females (Faraday et al., 1999b). For males, nicotine altered both the horizontal and vertical activity, increasing these variables for group-housed males, but decreasing them for individually housed males (Faraday et al., 1999b). For females, nicotine altered only the center time, reducing this measure of anxiety for group-housed females (Faraday et al., 1999b). During nicotine cessation, housing effects appeared more robustly in males and continued in females (Faraday et al., 1999b). Therefore, investigation of additional factors, such as sex, age and housing conditions is desirable, but would require more complex experimental design and statistical analysis.