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  • br Methods br Results br Discussion The lowest intra

    2019-09-11


    Methods
    Results
    Discussion The lowest intra-CeA dose of R278995/CRA0450 that prevented the elevations in cell division cycle reward thresholds associated with nicotine withdrawal was 0.05μg/side (0.1μg total bilateral dose). The total bilateral dose in the present study is 100 times lower than the lowest icv dose of R278995/CRA0450, 10μg, that prevents the elevations in brain reward thresholds associated with nicotine withdrawal (Bruijnzeel et al., 2009). Therefore, the amount of R278995/CRA0450 that was infused into the CeA would not have prevented the elevations in brain reward thresholds when administered into the lateral ventricles. This excludes the possibility that R278995/CRA0450 diffused into the lateral ventricles and attenuated nicotine withdrawal by acting upon distant brain sites. We also investigated the effect of the administration of R278995/CRA0450 into a brain site in close proximity to the CeA, namely the BLA. The administration of R278995/CRA0450 into the BLA did not affect the brain reward thresholds of nicotine withdrawing rats. This suggests that in the first experiment, R278995/CRA0450 mediated its effects on nicotine withdrawal by blocking CRF1 receptors in the CeA and not by blocking CRF1 receptors in brain sites in close proximity to the CeA such as the BLA. The administration of a nAChR antagonist to nicotine dependent animals leads to elevations in brain reward thresholds in the ICSS procedure and an increased release of CRF in the CeA (Epping-Jordan et al., 1998, George et al., 2007). The data presented here indicate that blockade of CRF1 receptors in the CeA prevents the elevation in brain reward thresholds associated with nicotine withdrawal. This study extends and corroborates a previous study that showed that the administration of the non-specific CRF1/CRF2 receptor antagonist d-Phe CRF(12-41) into the CeA prevents the elevations in brain reward thresholds associated with nicotine withdrawal (Marcinkiewcz et al., 2009). The icv administration of the CRF2 receptor antagonist astressin-2B does not affect the elevations in brain reward thresholds associated with precipitated nicotine withdrawal (Bruijnzeel et al., 2009). Therefore these studies strongly suggest that precipitated nicotine withdrawal leads to an increased release of CRF in the CeA which induces a negative mood state via the activation of CRF1, but not CRF2, receptors in this brain site. The negative emotional state associated with nicotine withdrawal may play a role in the development and maintenance of a tobacco addiction in humans. George et al. (2007) showed that the self-administration of nicotine in rats is increased after a period of abstinence (i.e., nicotine-deprivation effect). This deprivation effect is prevented by pretreatment with a specific CRF1 receptor antagonist (George et al., 2007). CRF1 receptor antagonists also prevent the dysphoria and anxiety-like behavior associated with nicotine withdrawal (Bruijnzeel et al., 2009, George et al., 2007). Therefore, these findings suggest that after a period of abstinence, rats may increase their nicotine intake to diminish the CRF-induced dysphoria and anxiety-like behavior. Pharmacological evidence suggests that the CRF1 receptor antagonist R278995/CRA0450 also blocks sigma-1 receptors (Chaki et al., 2004). Although sigma-1 receptors have been detected in the amygdala, it is unlikely that R278995/CRA0450 prevented the nicotine withdrawal-induced elevations in brain reward thresholds by blocking these receptors (Alonso et al., 2000). Animal studies suggest that stimulation of sigma-1 receptors has antidepressant and anxiolytic-like effects (Kamei et al., 1996, Ukai et al., 1998, Wang et al., 2007). In contrast, blockade of sigma-1 receptors does not affect the behavior of rats and mice in a wide variety of anxiety and depression tests (Chaki et al., 2004, Noda et al., 2000, Ukai et al., 1998). The present study showed that blockade of α1-adrenergic receptors and stimulation of α2-adrenergic receptors in the CeA does not affect the elevations in brain reward thresholds associated with precipitated nicotine withdrawal. It is unlikely that the lack of effect of prazosin or clonidine on nicotine withdrawal was due to the absence of α1 or α2-adrenergic receptors in the CeA. Previous studies have shown that α1 and α2-adrenergic receptors are expressed in this brain site (Rainbow and Biegon, 1983, Young and Kuhar, 1980). It is also unlikely that the doses of clonidine or prazosin were too low. Previous studies by our group and others have shown that lower doses than those used in the present studies affect the behavior of rats (Ferry et al., 1999, Yamada and Bruijnzeel, 2011). The highest dose of clonidine in the present study was 1μg/side. In a previous study, we reported that the bilateral administration of the same dose of clonidine into the CeA attenuates stress-induced reinstatement of nicotine-seeking behavior in rats (Yamada and Bruijnzeel, 2011). At this point, we are not aware of any studies that investigated the behavioral effects of the administration of prazosin in the CeA. However, one study investigated the effects of the administration of prazosin into the BLA in a learning and memory test. It was shown that the administration of 0.1–1μg/side of prazosin produces deficits in shock-induced avoidance learning (Ferry et al., 1999). These doses fall in the same dose-range as the prazosin doses, 0.3–1.5μg/side, which were used in the present nicotine withdrawal study.