A single, acute stressor can produce long-lasting increases in KOR signaling within the VTA, which promotes drug seeking [23,35]

A single, acute stressor can produce long-lasting increases in KOR signaling within the VTA, which promotes drug seeking [23,35]. another aversive drug, lithium chloride (LiCl). These data suggest U50 elicits its long-term anti-relapse effects through a KOR-p38 MAPK-specific aversive counterconditioning of the operant cocaine-seeking response. A single, albeit aversive treatment that is able to reduce relapse long-term warrants further consideration of the therapeutic potential of KOR agonists in the treatment of addiction. Introduction Cocaine relapse can be brought on by multiple factors, including conditioned cues that act as reminders of the drug experience, and stress [1]. The kappa opioid receptor (KOR) system may influence drug seeking by virtue of its prominent role in stress [2]. However, the complexity of this system is usually underscored by reports that both KOR agonists and antagonists reduce drug seeking in models of cocaine relapse [3C5]. KOR agonists elicit effects similar to stress in rodents, such as dysphoria and/or aversion [6,7], depressive symptoms such as elevated reward threshold [8], and antinociception [9,10]. Indeed, the clinical use of KOR agonists in humans has been limited by these known aversive properties [11,12]. KOR activation can trigger various signaling cascades, including those mediated directly through G-proteins, and indirectly through the recruitment of beta arrestins. Beta-arrestin signaling activates p38 mitogen-activated protein kinases (MAPK), which has been specifically implicated in the aversive and dysphoric effects of KOR agonists [6,7,13C15]. Thus, current treatment strategies are focused on the development of functionally selective or biased agonists that avoid the beta-arrestin/p38 MAPK signaling pathway, to improve tolerability [16C19]. By extension of this same logic, p38 MAPK inhibitors co-administered with KOR agonists, a strategy we employed in the present study, should prevent KOR-mediated aversion, and indeed prevent U50-induced conditioned place aversion (CPA) [7]. Stress causes release of corticotropin-releasing factor, which in turn induces dynorphin release and subsequent KOR activation [19,20]. Consistent with the notion that KOR activation emulates a stressor, KOR agonists can induce reinstatement of drug seeking [21,22]. KOR antagonists reduce depressive symptoms and stress-induced cocaine seeking in preclinical models [3,23]. Despite these promising therapeutic advantages, KOR antagonists may not be effective in reducing other forms of relapse, such as cocaine-primed reinstatement [3]. By contrast, KOR agonists reduce both cocaine taking and cocaine-primed reinstatement acutely, during KOR agonist exposure [4,5,24C26]. Thus, KOR agonists may be particularly therapeutic when combined with cocaine, perhaps through their known ability to oppose cocaine reward [8]. Repeated KOR agonist exposure, on the other hand, can result in opposing effects around the dopamine system [27], and desensitization of the KOR [28], Few studies have examined the long-lasting effects on drug seeking after a single administration of KOR agonist [26], or effects of KOR agonists on extinction and cue-induced reinstatement. The present study examined the ability of a single acute dose of the KOR agonist U50,488 (U50) to enhance extinction and reduce cue-induced reinstatement of cocaine seeking in the long term. Materials and methods Subjects Male Sprague-Dawley rats (72 total; Charles River Laboratories) weighing 250C275?g on arrival were individually housed in a heat and humidity controlled environment with a 12?h light/dark cycle (6:00?a.m. lights off). Experiments were conducted during the rats dark cycle. Rats were food-restricted to 20C22?g of food per day (80C95% of free-feeding body weight) to promote behavioral performance. Water was available ad libitum in the home cage. Seven.That the long-term therapeutic effect of U50 was not mimicked by another aversive compound, namely LiCl, suggests KOR agonists have unique properties for reducing long-term relapse rates after exposure therapy. not its acute reduction in drug seeking on extinction day 1. The long-term therapeutic effect of U50 required operant extinction during U50 exposure, extended to cocaine-primed reinstatement, and was not mimicked by another aversive drug, lithium chloride (LiCl). These data suggest U50 elicits its long-term anti-relapse effects through a KOR-p38 MAPK-specific aversive counterconditioning of the operant cocaine-seeking response. A single, albeit aversive treatment that is able to reduce relapse long-term warrants further consideration of the therapeutic potential of KOR agonists in the treatment of addiction. Introduction Cocaine relapse can be triggered by multiple factors, including conditioned cues that act as reminders of the drug experience, and stress [1]. The kappa opioid receptor (KOR) system may influence drug seeking by virtue of its prominent role in stress [2]. However, the complexity of this system is underscored by reports that both KOR agonists and antagonists reduce drug seeking in models of cocaine relapse [3C5]. KOR agonists elicit effects similar to stress in rodents, such as dysphoria and/or aversion [6,7], depressive symptoms such as elevated reward threshold [8], and antinociception [9,10]. Indeed, the clinical use of KOR agonists in humans has been limited by these known aversive properties [11,12]. KOR activation can trigger various signaling cascades, including those mediated directly through G-proteins, and indirectly through the recruitment of beta arrestins. Beta-arrestin signaling activates p38 mitogen-activated protein kinases (MAPK), which has been specifically implicated in the aversive and dysphoric effects of KOR agonists [6,7,13C15]. Thus, current treatment strategies are focused on the development of functionally selective or biased agonists that avoid the beta-arrestin/p38 MAPK signaling pathway, to improve tolerability [16C19]. By extension of this same logic, p38 MAPK inhibitors co-administered with KOR agonists, a strategy we employed in the present study, should prevent KOR-mediated aversion, and indeed prevent U50-induced conditioned place aversion (CPA) [7]. Stress causes release of corticotropin-releasing factor, which in turn induces dynorphin release and subsequent KOR activation [19,20]. Consistent with the notion that KOR activation emulates a stressor, KOR agonists can induce reinstatement of drug seeking [21,22]. KOR antagonists reduce depressive symptoms and stress-induced cocaine seeking in preclinical models [3,23]. Despite these promising therapeutic advantages, KOR antagonists may not be effective in reducing other forms of relapse, such as cocaine-primed reinstatement [3]. By contrast, KOR agonists reduce both cocaine taking and cocaine-primed reinstatement acutely, during KOR agonist exposure [4,5,24C26]. Thus, KOR agonists may be particularly therapeutic when combined with cocaine, perhaps through their known ability to oppose cocaine reward [8]. Repeated KOR agonist exposure, on the other hand, can result in opposing effects ML 7 hydrochloride on the dopamine system [27], and desensitization of the KOR [28], Few studies have examined the long-lasting effects on drug seeking after a single administration of KOR agonist [26], or effects of KOR agonists on extinction and cue-induced reinstatement. The present study examined the ability of a single acute dose of the KOR agonist U50,488 (U50) to enhance extinction and reduce cue-induced reinstatement of cocaine looking for in the long term. Materials and methods Subjects Male Sprague-Dawley rats (72 total; Charles River Laboratories) weighing 250C275?g about introduction were individually housed inside a temp and moisture controlled environment having a 12?h light/dark cycle (6:00?a.m. lamps off). Experiments were conducted during the rats dark cycle. Rats were food-restricted to 20C22?g of food per day (80C95% of free-feeding body weight) to promote behavioral performance. Water was available ad libitum in the home cage. Seven rats were eliminated from the final analysis due to misinjection of ML 7 hydrochloride drug ((9,?117)?=?9.46, (9,?117)?=?4.95, (18,162)?=?2.27, (9,?108)?=?6.62, (9,?108)?=?2.71, (23,276)?=?1.77, (10,130)?=?2.01, p?p?p?p?Dnm2 to reduce relapse long-term warrants further consideration of the therapeutic potential of KOR agonists in the treatment of addiction. Introduction Cocaine relapse can be brought on by multiple factors, including conditioned cues that act as reminders of the drug experience, and stress [1]. The kappa opioid receptor (KOR) system may influence drug seeking by virtue of its prominent role in stress [2]. However, the complexity of this system is usually underscored by reports that both KOR agonists and antagonists reduce drug seeking in models of cocaine relapse [3C5]. KOR agonists elicit effects similar to stress in rodents, such as dysphoria and/or aversion [6,7], depressive symptoms such as elevated reward threshold [8], and antinociception [9,10]. Indeed, the clinical use of KOR agonists in humans has been limited by these known aversive properties [11,12]. KOR activation can trigger various signaling cascades, including those mediated directly through G-proteins, and indirectly through the recruitment of beta arrestins. Beta-arrestin signaling activates p38 mitogen-activated protein kinases (MAPK), which has been specifically implicated in the aversive and dysphoric effects of KOR agonists [6,7,13C15]. Thus, current treatment strategies are focused on the development of functionally selective or biased agonists that avoid the beta-arrestin/p38 MAPK signaling pathway, to improve tolerability [16C19]. By extension of this same logic, p38 MAPK inhibitors co-administered with KOR agonists, a strategy we employed in the present study, should prevent KOR-mediated aversion, and indeed prevent U50-induced conditioned place aversion (CPA) [7]. Stress causes release of corticotropin-releasing factor, which in turn induces dynorphin release and subsequent KOR activation [19,20]. Consistent with the notion that KOR activation emulates a stressor, KOR agonists can induce reinstatement of drug seeking [21,22]. KOR antagonists reduce depressive symptoms and stress-induced cocaine seeking in preclinical models [3,23]. Despite these promising therapeutic advantages, KOR antagonists may not be effective in reducing other forms of relapse, such as cocaine-primed reinstatement [3]. By contrast, KOR agonists reduce both cocaine taking and cocaine-primed reinstatement acutely, during KOR agonist exposure [4,5,24C26]. Thus, KOR agonists may be particularly therapeutic when combined with cocaine, perhaps through their known ability to oppose cocaine reward [8]. Repeated KOR agonist exposure, on the other hand, can result in opposing effects around the dopamine system [27], and desensitization of the KOR [28], Few studies have examined the long-lasting effects on drug seeking after a single administration of KOR agonist [26], or effects of KOR agonists on extinction and cue-induced reinstatement. The present study examined the ability of a single acute dose of the KOR agonist U50,488 (U50) to enhance extinction and reduce cue-induced reinstatement of cocaine seeking in the long term. Materials and methods Subjects Male Sprague-Dawley rats (72 total; Charles River Laboratories) weighing 250C275?g on arrival were individually housed in a temperature and humidity controlled environment with a 12?h light/dark cycle (6:00?a.m. lights off). Experiments were conducted during the rats dark cycle. Rats were food-restricted to 20C22?g of food per day (80C95% of free-feeding body weight) to promote behavioral performance. Water was available ad libitum in the home cage. Seven rats were eliminated from the final analysis due to misinjection of drug ((9,?117)?=?9.46, (9,?117)?=?4.95, (18,162)?=?2.27, (9,?108)?=?6.62, (9,?108)?=?2.71, (23,276)?=?1.77, (10,130)?=?2.01, p?p?