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  • Interestingly ASV infusion in the dRN of saline pre

    2019-07-16

    Interestingly, ASV-30 infusion in the dRN of saline pre-treated rats had no effect on anxiety-like behaviors. This result may be due to the saline pre-treated group exhibiting relatively low levels of anxiety-like behaviors (when compared to saline pre-treated rat of the first experiment that were not acclimated to handling prior to EPM testing). Our result is consistent with a number of studies showing that general CRF AMG-208 to antagonists administered intracranially or icv have little effect on the behavior of non-stressed animals (see ). However, in some studies, icv administration of ASV-30 decreases anxiety-like behavior of rats in the EPM without prior exposure to stress or drugs . The discrepancy in findings may be due to the site of infusion, with CRF receptor antagonism specific to the dRN only effective in rats that show heightened CRF receptor levels in this region. This implies that chronic exposure to amphetamine results in dRN CRF receptor regulation of behavior that is not typically mediated by the activity of these receptors in drug naive rats. In summary, the current data suggest that chronic amphetamine treatment of rats results in an increased anxiety state which persists following drug abstinence, and that CRF receptor antagonism within the dRN reverses this anxiety state. Future research should confirm these findings using different anxiety paradigms with more global antagonism of central CRF receptors. Such future studies may suggest CRF receptor antagonism as a possible direction for therapeutic treatment to reduce anxiety states during amphetamine withdrawal. Acknowledgements
    Introduction Addiction is a life-long condition in which individuals show an intense drug craving and a high risk of relapse even after years of drug abstinence [1], [2]. A major goal of successful treatment of addiction is being able to prevent craving, seeking and relapse [3], [4]. Persistent molecular changes, associated with chronic drug consumption and abstinence, are believed to mediate craving and relapse to drug use [5], [6]. In both human addicts and in animal models of addictive behaviour the relapse to drug seeking has been shown to be precipitated by the exposure to three distinct types of stimuli: (a) stress; (b) environmental cues associated with the drug experience and (c) the drug itself [7]. Over the last few years there have been promising advances in the understanding of addiction; however, the mechanisms by which stress enhances drug use and triggers relapse remain elusive [8], [9]. On one hand, drug addiction is related to the reward system which is centered in dopaminergic neurons located in the ventral tegmental area (VTA) that innervate several interconnected nuclei such as the nucleus accumbens (NAcc), lateral septum, bed nucleus of the stria terminalis (BNST), amygdala, lateral hypothalamus (LH) and prefrontal cortex (PFC). All drugs of abuse activate, directly or indirectly, the dopaminergic neurons and increase the release of dopamine in the NAcc [10]. On the other hand, the stress response is related to the brain corticotropin releasing factor (CRF) system. At present, the mammalian CRF system is composed of four peptides, CRF, urocortin-1, urocortin-2 and urocortin-3, originated from independent genes; a binding protein with high affinity for CRF (CRF-BP) and urocortin-1, and two receptors CRF1 and CRF2 [reviewed in 11]. CRF and urocortin-1 have high affinity for both CRF receptors. In contrast, urocortin-2 and urocortin-3 have high affinity only for CRF2 receptors. Anatomically, there is significant overlap between brain nuclei involved in stress response and in addiction [8], [12], [13]. Compelling evidence indicates that the CRF system is responsible for connecting stress and addiction [8], [14], [15]. Even though several studies have focussed on understanding the molecular and neurochemical mechanisms by which the CRF system determines stress-induced relapse to drug seeking, these phenomena are still only partially understood [9], [16], [17], [18].