- Email: [email protected]
Oxytocin blocks compulsive-like alcohol drinking in rats
218
Abstracts / Alcohol 60 (2017) 203e243
personalized guided imageries (stress, cue, relaxing) on consecutive days. Craving, mood, Stroop performance and plasma cortisol were assessed. Participants were grouped by high or low ALLO. Results: STUDY 1: Healthy females were better at managing emotions than healthy males. Moreover, high endogenous progesterone improved emotion management in all women. STUDY 2: Exogenous progesterone improved ability to facilitate thought. STUDY 3: Exogenous progesterone also increased ALLO in both men and women. The high ALLO group showed decreased tonic and increased phasic cortisol and improved Stroop performance and craving following stress. Conclusions: Addicted women may be particularly vulnerable to stress. Both endogenous and exogenous progesterone, possibly via its neurosteroid-metabolite ALLO, may normalize stress dysfunction, emotion regulation and craving in addiction. Support: NIH Grants: P50-DA016556; R01 AA020504; R01 AA020095; 5T32DA007238.
Symposium XVI Feeding- and stress-related neuroendocrine pathways in alcohol use disorder: recent findings. Co-Chairs: Lorenzo Leggio, M.D., Ph.D., M.Sc. & Falk Kiefer, M.D. Discussant: Leandro Vendruscolo, Ph.D.
S64 RECENT RESULTS ON GHRELIN IN ALCOHOL USE DISORDERS Falk Kiefer, Anne Koopmann. Central Institute of Mental Health, Mannheim, Germany Recent preclinical and clinical studies suggested ghrelin to have an orexigenic role in the regulation of appetite and energy balance. Thereby, food consumption in humans is not only a response to an intrinsic sensation of hunger which ensures energy homeostasis but also a result of neuronal processes influenced by the rewarding and positively reinforcing features of food. Preclinical studies also provided support for an important role of ghrelin in the neurobiology of addiction-related reward pathways, affecting the self-administration of alcohol and drugs as well as conditioned place preference. In the past years there was an increasing interest in the role of ghrelin in Alcohol Use Disorders in humans. We want to present two studies concerning the dynamics of craving and plasma ghrelin and their interaction in alcohol dependent patients during early abstinence. The first longitudinal study assessed associations between plasma levels of ghrelin and craving in a group of 61 alcohol-dependent male inpatients twice: once at the onset of withdrawal and then again after 14 days of controlled abstinence. In the second randomized human laboratory study 23 alcohol-dependent male inpatient subjects underwent an alcohol exposure session combined with the oral consumption of 1000 ml of mineral water in 10 minutes, while participants of control group were not allowed to drink anything. Changes in craving and plasma ghrelin as well as their associations were followed-up for 120 minutes. S65 GHRELIN AS POTENTIAL NEW PATHWAY TOWARD MEDICATION DEVELOPMENT FOR ALCOHOL USE DISORDER: RECENT CLINICAL DATA Lorenzo Leggio M.D., Ph.D., M.Sc. CPN, NIAAA & NIDA, NIH, Bethesda, MD, USA The rewarding properties of natural and chemical reinforcers are mediated via multiple and complex pathways in the brain. There is an underlying disruption in reward processing in animal models of and individuals with addictions. This raises the possibility that endocrine signals from the gut traditionally known to regulate food intake may play an important role in reward regulation as well as in development of drug dependence. Dr. Leggio will present recent clinical data suggesting that GLP-1 and ghrelin represent potential new pathways toward medication development for alcohol use disorder. In particular, preliminary clinical studies indicate that there is a relationship between endogenous blood ghrelin levels and drinking status and craving for alcohol. Additionally, a recent human laboratory study demonstrated, for the first time, that intravenous administration of exogenous ghrelin resulted in acute increase of cueinduced alcohol craving. Finally, a recent clinical study suggests that a genetic functional variation in the GLP-1 receptor gene is associated with
diagnosis of alcohol use disorder as well as will increased alcohol selfadministration and brain reward in humans. Altogether, these results are consistent with preclinical work suggesting that ghrelin and GLP-1 may represent novel potential targets for medications development for alcohol use disorder. S66 OXYTOCIN BLOCKS COMPULSIVE-LIKE ALCOHOL DRINKING IN RATS Brendan Tunstall Ph.D. NAS, NIDA/NIH, Baltimore, MD, USA We hypothesized that brain signaling by the neuropeptide oxytocin, known to be involved in both stress and reward function, contributes to compulsive alcohol drinking. To test our hypothesis, we used a preclinical model of alcohol dependence that reliably produces somatic and motivational signs of dependence. Wistar rats were trained to lever press for access to alcohol and then either made alcohol dependent (via repeated cycles of alcohol vapor exposure and withdrawal) or exposed to air to provide a nondependent control group. Oxytocin (0-1 mg/kg) was administered intraperitoneally and intranasally. The results indicate that alcohol-dependent rats developed escalated alcohol consumption and increased motivation to work to obtain alcohol (responding in a progressive ratio schedule of reinforcement) compared to nondependent controls. Both intraperitoneal and intranasal oxytocin administration blocked compulsive-like alcohol consumption in dependent rats, at doses that did not disrupt alcohol drinking in nondependent rats. Additional experiments indicated that intraperitoneal but not intranasal oxytocin administration reduced spontaneous locomotion (open field test) and the consumption of sweet (non-caloric saccharin) and caloric (non-sweet maltodextrin) fluids. Collectively, these findings suggest that oxytocin selectively blocks the compulsive-like alcohol motivated behaviors that emerge in alcohol dependence and that this effect is likely mediated by reducing motivation for alcohol’s pharmacological effect. Thus, intranasal oxytocin administration may represent a viable approach to treating humans with alcohol use disorders. S67 OXYTOCIN REDUCES ALCOHOL SELF-ADMINISTRATION AND STRESSINDUCED ALCOHOL RELAPSE BEHAVIOR IN MICE Howard C. Becker, Courtney E. King, William C. Griffin. Medical University of South Carolina & VAMC, Charleston, SC, USA Recent evidence implicates the neuropeptide oxytocin (OXT) as a potential therapeutic for alcoholism. The present studies examined the effects of systemic administration of OXT on alcohol self-administration and stressinduced relapse-like behavior. Adult male C57BL/6J mice were trained using standard operant procedures to lever respond on a fixed ratio (FR4) schedule for 12% (v/v) alcohol or 5% (w/v) sucrose reinforcement (20 ul) during daily 20-min sessions. In a second study, after establishing stable alcohol self-administration and then extinction testing, reinstatement of alcohol responding was provoked by yohimbine (0.3 or 0.625 mg/kg) injection. In another study, after stable FR4 responding was established, mice were exposed 15 min to a predator odor (TMT) or left undisturbed over 5 consecutive days. Baseline alcohol responding was re-established and after extinction testing, relapse behavior was tested in all mice after exposure to TMT. OXT (0.1e1 mg/kg; 30 min pretreatment) reduced operant oral alcohol self-administration in a dose-related manner at doses that did not alter sucrose responding. Additionally, OXT (1 mg/kg) blocked alcohol relapse-like behavior (reinstatement of alcohol seeking behavior) provoked by exposure to different stressors (yohimbine and TMT). OXT also reduced enhanced stress-induced reinstatement responding in mice with a history of prior trauma (TMT) exposure. Collectively, these results suggest that systemic administration of OXT effectively reduces alcohol selfadministration as well as attenuates stress-induced relapse-like behavior in mice. Studies are currently being conducted to examine these effects in female mice as well as explore mechanisms underlying this apparent therapeutic effect of oxytocin treatment. Supported by NIH (P50 AA1076, U01 AA014095, U01 AA020929, T32 AA007474), DOD/US Army (803-94), and VAMR (BX000813).
Abstracts / Alcohol 60 (2017) 203e243
personalized guided imageries (stress, cue, relaxing) on consecutive days. Craving, mood, Stroop performance and plasma cortisol were assessed. Participants were grouped by high or low ALLO. Results: STUDY 1: Healthy females were better at managing emotions than healthy males. Moreover, high endogenous progesterone improved emotion management in all women. STUDY 2: Exogenous progesterone improved ability to facilitate thought. STUDY 3: Exogenous progesterone also increased ALLO in both men and women. The high ALLO group showed decreased tonic and increased phasic cortisol and improved Stroop performance and craving following stress. Conclusions: Addicted women may be particularly vulnerable to stress. Both endogenous and exogenous progesterone, possibly via its neurosteroid-metabolite ALLO, may normalize stress dysfunction, emotion regulation and craving in addiction. Support: NIH Grants: P50-DA016556; R01 AA020504; R01 AA020095; 5T32DA007238.
Symposium XVI Feeding- and stress-related neuroendocrine pathways in alcohol use disorder: recent findings. Co-Chairs: Lorenzo Leggio, M.D., Ph.D., M.Sc. & Falk Kiefer, M.D. Discussant: Leandro Vendruscolo, Ph.D.
S64 RECENT RESULTS ON GHRELIN IN ALCOHOL USE DISORDERS Falk Kiefer, Anne Koopmann. Central Institute of Mental Health, Mannheim, Germany Recent preclinical and clinical studies suggested ghrelin to have an orexigenic role in the regulation of appetite and energy balance. Thereby, food consumption in humans is not only a response to an intrinsic sensation of hunger which ensures energy homeostasis but also a result of neuronal processes influenced by the rewarding and positively reinforcing features of food. Preclinical studies also provided support for an important role of ghrelin in the neurobiology of addiction-related reward pathways, affecting the self-administration of alcohol and drugs as well as conditioned place preference. In the past years there was an increasing interest in the role of ghrelin in Alcohol Use Disorders in humans. We want to present two studies concerning the dynamics of craving and plasma ghrelin and their interaction in alcohol dependent patients during early abstinence. The first longitudinal study assessed associations between plasma levels of ghrelin and craving in a group of 61 alcohol-dependent male inpatients twice: once at the onset of withdrawal and then again after 14 days of controlled abstinence. In the second randomized human laboratory study 23 alcohol-dependent male inpatient subjects underwent an alcohol exposure session combined with the oral consumption of 1000 ml of mineral water in 10 minutes, while participants of control group were not allowed to drink anything. Changes in craving and plasma ghrelin as well as their associations were followed-up for 120 minutes. S65 GHRELIN AS POTENTIAL NEW PATHWAY TOWARD MEDICATION DEVELOPMENT FOR ALCOHOL USE DISORDER: RECENT CLINICAL DATA Lorenzo Leggio M.D., Ph.D., M.Sc. CPN, NIAAA & NIDA, NIH, Bethesda, MD, USA The rewarding properties of natural and chemical reinforcers are mediated via multiple and complex pathways in the brain. There is an underlying disruption in reward processing in animal models of and individuals with addictions. This raises the possibility that endocrine signals from the gut traditionally known to regulate food intake may play an important role in reward regulation as well as in development of drug dependence. Dr. Leggio will present recent clinical data suggesting that GLP-1 and ghrelin represent potential new pathways toward medication development for alcohol use disorder. In particular, preliminary clinical studies indicate that there is a relationship between endogenous blood ghrelin levels and drinking status and craving for alcohol. Additionally, a recent human laboratory study demonstrated, for the first time, that intravenous administration of exogenous ghrelin resulted in acute increase of cueinduced alcohol craving. Finally, a recent clinical study suggests that a genetic functional variation in the GLP-1 receptor gene is associated with
diagnosis of alcohol use disorder as well as will increased alcohol selfadministration and brain reward in humans. Altogether, these results are consistent with preclinical work suggesting that ghrelin and GLP-1 may represent novel potential targets for medications development for alcohol use disorder. S66 OXYTOCIN BLOCKS COMPULSIVE-LIKE ALCOHOL DRINKING IN RATS Brendan Tunstall Ph.D. NAS, NIDA/NIH, Baltimore, MD, USA We hypothesized that brain signaling by the neuropeptide oxytocin, known to be involved in both stress and reward function, contributes to compulsive alcohol drinking. To test our hypothesis, we used a preclinical model of alcohol dependence that reliably produces somatic and motivational signs of dependence. Wistar rats were trained to lever press for access to alcohol and then either made alcohol dependent (via repeated cycles of alcohol vapor exposure and withdrawal) or exposed to air to provide a nondependent control group. Oxytocin (0-1 mg/kg) was administered intraperitoneally and intranasally. The results indicate that alcohol-dependent rats developed escalated alcohol consumption and increased motivation to work to obtain alcohol (responding in a progressive ratio schedule of reinforcement) compared to nondependent controls. Both intraperitoneal and intranasal oxytocin administration blocked compulsive-like alcohol consumption in dependent rats, at doses that did not disrupt alcohol drinking in nondependent rats. Additional experiments indicated that intraperitoneal but not intranasal oxytocin administration reduced spontaneous locomotion (open field test) and the consumption of sweet (non-caloric saccharin) and caloric (non-sweet maltodextrin) fluids. Collectively, these findings suggest that oxytocin selectively blocks the compulsive-like alcohol motivated behaviors that emerge in alcohol dependence and that this effect is likely mediated by reducing motivation for alcohol’s pharmacological effect. Thus, intranasal oxytocin administration may represent a viable approach to treating humans with alcohol use disorders. S67 OXYTOCIN REDUCES ALCOHOL SELF-ADMINISTRATION AND STRESSINDUCED ALCOHOL RELAPSE BEHAVIOR IN MICE Howard C. Becker, Courtney E. King, William C. Griffin. Medical University of South Carolina & VAMC, Charleston, SC, USA Recent evidence implicates the neuropeptide oxytocin (OXT) as a potential therapeutic for alcoholism. The present studies examined the effects of systemic administration of OXT on alcohol self-administration and stressinduced relapse-like behavior. Adult male C57BL/6J mice were trained using standard operant procedures to lever respond on a fixed ratio (FR4) schedule for 12% (v/v) alcohol or 5% (w/v) sucrose reinforcement (20 ul) during daily 20-min sessions. In a second study, after establishing stable alcohol self-administration and then extinction testing, reinstatement of alcohol responding was provoked by yohimbine (0.3 or 0.625 mg/kg) injection. In another study, after stable FR4 responding was established, mice were exposed 15 min to a predator odor (TMT) or left undisturbed over 5 consecutive days. Baseline alcohol responding was re-established and after extinction testing, relapse behavior was tested in all mice after exposure to TMT. OXT (0.1e1 mg/kg; 30 min pretreatment) reduced operant oral alcohol self-administration in a dose-related manner at doses that did not alter sucrose responding. Additionally, OXT (1 mg/kg) blocked alcohol relapse-like behavior (reinstatement of alcohol seeking behavior) provoked by exposure to different stressors (yohimbine and TMT). OXT also reduced enhanced stress-induced reinstatement responding in mice with a history of prior trauma (TMT) exposure. Collectively, these results suggest that systemic administration of OXT effectively reduces alcohol selfadministration as well as attenuates stress-induced relapse-like behavior in mice. Studies are currently being conducted to examine these effects in female mice as well as explore mechanisms underlying this apparent therapeutic effect of oxytocin treatment. Supported by NIH (P50 AA1076, U01 AA014095, U01 AA020929, T32 AA007474), DOD/US Army (803-94), and VAMR (BX000813).