RESUMO
BACKGROUND: Alcohol use disorder (AUD) is a complex psychiatric disease characterized by high alcohol intake as well as hyperkatifeia and hyperalgesia during withdrawal. A role for Sigma-1 receptors (Sig-1Rs) in the rewarding and reinforcing effects of alcohol has started to emerge in recent years, as rat studies have indicated that Sig-1R hyperactivity may result in excessive alcohol drinking. Sig-1R studies in mice are very scarce, and its potential role in alcohol-induced hyperalgesia is also unknown. METHODS: In this study, we investigated the role of Sig-1R in alcohol drinking and associated hyperalgesia in male mice, using an intermittent access 2-bottle choice model of heavy drinking. RESULTS: The Sig-1R antagonist BD-1063 was found dose dependently to reduce both alcohol intake and preference, without affecting either water or sucrose intake, suggesting that the effects are specific for alcohol. Notably, the ability of BD-1063 to suppress ethanol intake correlated with the individual baseline levels of alcohol drinking, suggesting that the treatment was more efficacious in heavy drinking animals. In addition, BD-1063 reversed alcohol-induced hyperalgesia during withdrawal, assessed using an automatic Hargreaves test, without affecting thermal sensitivity in alcohol-naïve animals or locomotor activity in either group. CONCLUSIONS: These data show that Sig-1R antagonism dose-dependently reduced ethanol consumption in heavy drinking mice as well as its efficacy in reducing alcohol-induced hyperalgesia. These findings provide a foundation for the development of novel treatments for AUD and associated pain states.
Assuntos
Consumo de Bebidas Alcoólicas/prevenção & controle , Etanol/administração & dosagem , Hiperalgesia/prevenção & controle , Piperazinas/administração & dosagem , Receptores sigma/antagonistas & inibidores , Animais , Relação Dose-Resposta a Droga , Cabeça , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Atividade Motora/efeitos dos fármacos , Medição da Dor , Piperazinas/uso terapêutico , Receptores sigma/fisiologia , Síndrome de Abstinência a Substâncias/tratamento farmacológico , Sacarose/administração & dosagem , Receptor Sigma-1RESUMO
Binge eating disorder is an addiction-like disorder characterized by recurrent, excessive food consumption within discrete periods of time, and it has been linked to increased trait impulsivity. Within impulsivity components, while impulsive action was shown to predict binge-like and addictive-like eating, the role of impulsive choice is instead unknown. The goal of this study was to determine if impulsive choice predicted, or was altered by binge-like eating of a sugary, highly palatable diet. We utilized a modified adjusting delay task procedure in free-fed rats to assess impulsive choice behavior, that is. the tendency to respond for a larger, delayed reward over a lesser, immediate reward. We found that baseline impulsive choice was not a predictor of binge-like eating in 1-h sessions of palatable diet operant self-administration. Furthermore, binge-like eating of the same palatable diet had no effect on later impulsive choice behavior. Thus, our data suggest that, unlike impulsive action, impulsive choice behavior does not predict binge-like eating in rats.
Assuntos
Transtorno da Compulsão Alimentar/diagnóstico , Transtorno da Compulsão Alimentar/fisiopatologia , Comportamento de Escolha/fisiologia , Comportamento Impulsivo/fisiologia , Animais , Condicionamento Operante/fisiologia , Desvalorização pelo Atraso , Modelos Animais de Doenças , Comportamento Alimentar , Masculino , Valor Preditivo dos Testes , Ratos , Ratos Wistar , Recompensa , Resposta de SaciedadeRESUMO
Although extensive research has focused on understanding the neurobiological mechanisms underlying alcohol addiction, pharmacological treatments for alcohol use disorders are very limited and not always effective. This constraint has encouraged the search for novel pharmacological targets for alcoholism therapy. Sigma receptors were shown to mediate some of the properties of cocaine and amphetamine, which was attributed to the direct binding of psychostimulants to these receptors. More recently, the role of sigma receptors in the rewarding and reinforcing effects of alcohol was also proposed, and it was suggested that their hyperactivity may result in excessive alcohol drinking. This chapter reviews current knowledge on the topic, and suggests that the sigma receptor system may represent a new therapeutic target for the treatment of alcohol use disorders.
Assuntos
Consumo de Bebidas Alcoólicas/efeitos adversos , Transtornos Relacionados ao Uso de Álcool/metabolismo , Bebidas Alcoólicas/efeitos adversos , Depressores do Sistema Nervoso Central/efeitos adversos , Sistema Nervoso Central/efeitos dos fármacos , Etanol/efeitos adversos , Receptores sigma/efeitos dos fármacos , Consumo de Bebidas Alcoólicas/epidemiologia , Consumo de Bebidas Alcoólicas/metabolismo , Consumo de Bebidas Alcoólicas/psicologia , Transtornos Relacionados ao Uso de Álcool/epidemiologia , Transtornos Relacionados ao Uso de Álcool/psicologia , Animais , Comportamento Aditivo/metabolismo , Comportamento Aditivo/psicologia , Sistema Nervoso Central/metabolismo , Sistema Nervoso Central/fisiopatologia , Comportamento de Procura de Droga , Humanos , Locomoção/efeitos dos fármacos , Receptores sigma/metabolismo , Recompensa , Transdução de Sinais/efeitos dos fármacos , Síndrome de Abstinência a Substâncias/metabolismo , Síndrome de Abstinência a Substâncias/psicologiaRESUMO
Thanks to advances in neuroscience, addiction is now recognized as a chronic brain disease with genetic, developmental, and cultural components. Drugs of abuse, including alcohol, are able to produce significant neuroplastic changes responsible for the profound disturbances shown by drug addicted individuals. The current lack of efficacious pharmacological treatments for substance use disorders has encouraged the search for novel and more effective pharmacotherapies. Growing evidence strongly suggests that Sigma Receptors are involved in the addictive and neurotoxic properties of abused drugs, including cocaine , methamphetamine , and alcohol. The present chapter will review the current scientific knowledge on the role of the Sigma Receptor system in the effects of drugs and alcohol, and proposes that this receptor system may represent a novel therapeutic target for the treatment of substance use disorders and associated neurotoxicity.
Assuntos
Receptores sigma/metabolismo , Transtornos Relacionados ao Uso de Substâncias/tratamento farmacológico , Transtornos Relacionados ao Uso de Substâncias/metabolismo , Animais , Comportamento Aditivo/tratamento farmacológico , Comportamento Aditivo/metabolismo , Humanos , Síndromes Neurotóxicas/tratamento farmacológico , Síndromes Neurotóxicas/metabolismoRESUMO
The prevalence of eating disorders and obesity in western societies is epidemic and increasing in severity. Preclinical research has focused on the development of animal models that can mimic the maladaptive patterns of food intake observed in certain forms of eating disorders and obesity. This study was aimed at characterizing a recently established model of palatable diet alternation in female rats. For this purpose, females rats were fed either continuously with a regular chow diet (Chow/Chow) or intermittently with a regular chow diet for 2 days and a palatable, high-sucrose diet for 1 day (Chow/Palatable). Following diet cycling, rats were administered rimonabant (0, 0.3, 1, 3 mg/kg intraperitoneally) during access to either palatable diet or chow diet and were assessed for food intake and body weight. Finally, rats were pretreated with rimonabant (0, 3 mg/kg, intraperitoneally) and tested in the elevated plus maze during withdrawal from the palatable diet. Female rats with alternating access to palatable food cycled their intake, overeating during access to the palatable diet and undereating upon returning to the regular chow diet. Rimonabant treatment resulted in increased chow hypophagia and anxiety-like behavior in Chow/Palatable rats. No effect of drug treatment was observed on the compulsive eating of palatable food in the diet-cycled rats. The results of this study suggest that withdrawal from alternating access to the palatable diet makes individuals vulnerable to the anxiogenic effects of rimonabant and provides etiological factors potentially responsible for the emergence of severe psychiatric side-effects following rimonabant treatment in obese patients.
Assuntos
Ansiedade/induzido quimicamente , Antagonistas de Receptores de Canabinoides/farmacologia , Ingestão de Alimentos/efeitos dos fármacos , Piperidinas/farmacologia , Pirazóis/farmacologia , Animais , Comportamento Animal/efeitos dos fármacos , Antagonistas de Receptores de Canabinoides/administração & dosagem , Sacarose Alimentar/administração & dosagem , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Transtornos da Alimentação e da Ingestão de Alimentos/induzido quimicamente , Feminino , Aprendizagem em Labirinto/efeitos dos fármacos , Piperidinas/administração & dosagem , Pirazóis/administração & dosagem , Ratos , Ratos Wistar , Receptor CB1 de Canabinoide/antagonistas & inibidores , RimonabantoRESUMO
Binge eating disorder is an addiction-like disorder characterized by excessive food consumption within discrete periods of time. This study was aimed at understanding the role of the opioid system within the medial prefrontal cortex (mPFC) in the consummatory and motivational aspects of binge-like eating. For this purpose, we trained male rats to obtain either a sugary, highly palatable diet (Palatable rats) or a chow diet (Chow rats) for 1 hour/day. We then evaluated the effects of the opioid receptor antagonist, naltrexone, given either systemically or site-specifically into the nucleus accumbens (NAcc) or the mPFC on a fixed ratio 1 (FR1) and a progressive ratio schedule of reinforcement for food. Finally, we assessed the expression of the genes proopiomelanocortin (POMC), pro-dynorphin (PDyn) and pro-enkephalin (PEnk), coding for the opioids peptides in the NAcc and the mPFC in both groups. Palatable rats rapidly escalated their intake by four times. Naltrexone, when administered systemically and into the NAcc, reduced FR1 responding for food and motivation to eat under a progressive ratio in both Chow and Palatable rats; conversely, when administered into the mPFC, the effects were highly selective for binge eating rats. Furthermore, we found a twofold increase in POMC and a â¼50% reduction in PDyn gene expression in the mPFC of Palatable rats, when compared to control rats; however, no changes were observed in the NAcc. Our data suggest that neuroadaptations of the opioid system in the mPFC occur following intermittent access to highly palatable food, which may be responsible for the development of binge-like eating.
Assuntos
Transtorno da Compulsão Alimentar/prevenção & controle , Comportamento Alimentar/efeitos dos fármacos , Naltrexona/farmacologia , Peptídeos Opioides/fisiologia , Córtex Pré-Frontal/efeitos dos fármacos , Análise de Variância , Animais , Condicionamento Operante , Modelos Animais de Doenças , Masculino , Motivação/efeitos dos fármacos , Antagonistas de Entorpecentes/farmacologia , Ratos , Ratos Wistar , Reforço PsicológicoRESUMO
Dieting and the increased availability of highly palatable food are considered major contributing factors to the large incidence of eating disorders and obesity. This study was aimed at investigating the role of the cannabinoid (CB) system in a novel animal model of compulsive eating, based on a rapid palatable diet cycling protocol. Male Wistar rats were fed either continuously a regular chow diet (Chow/Chow, control group) or intermittently a regular chow diet for 2 days and a palatable, high-sucrose diet for 1 day (Chow/Palatable). Chow/Palatable rats showed spontaneous and progressively increasing hypophagia and body weight loss when fed the regular chow diet, and excessive food intake and body weight gain when fed the palatable diet. Diet-cycled rats dramatically escalated the intake of the palatable diet during the first hour of renewed access (7.5-fold compared to controls), and after withdrawal, they showed compulsive eating and heightened risk-taking behavior. The inverse agonist of the CB1 receptor, SR141716 reduced the excessive intake of palatable food with higher potency and the body weight with greater efficacy in Chow/Palatable rats, compared to controls. Moreover, SR141716 reduced compulsive eating and risk-taking behavior in Chow/Palatable rats. Finally, consistent with the behavioral and pharmacological observations, withdrawal from the palatable diet decreased the gene expression of the enzyme fatty acid amide hydrolase in the ventromedial hypothalamus while increasing that of CB1 receptors in the dorsal striatum in Chow/Palatable rats, compared to controls. These findings will help understand the role of the CB system in compulsive eating.
Assuntos
Antagonistas de Receptores de Canabinoides/farmacologia , Comportamento Compulsivo/prevenção & controle , Comportamento Alimentar/efeitos dos fármacos , Piperidinas/farmacologia , Pirazóis/farmacologia , Análise de Variância , Animais , Comportamento Animal/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Corpo Estriado/metabolismo , Preferências Alimentares/efeitos dos fármacos , Região Hipotalâmica Lateral/metabolismo , Masculino , Núcleo Accumbens/metabolismo , Ratos Wistar , Receptor CB1 de Canabinoide/metabolismo , Rimonabanto , Assunção de Riscos , Núcleo Hipotalâmico Ventromedial/metabolismoRESUMO
BACKGROUND: Binge drinking is defined as a pattern of alcohol drinking that brings blood alcohol levels to 80 mg/dl or above. In this study, we pharmacologically characterized the intermittent access to 20% ethanol (EtOH) model (Wise, Psychopharmacologia 1973;29:203) in Sardinian alcohol-preferring (sP) rats to determine to which of the compounds known to reduce drinking in specific animal models this binge-like drinking was sensitive to. METHODS: Adult male sP rats were divided into 2 groups and allowed to drink either 20% v/v alcohol or water for 24 hours on alternate days (Monday, Wednesday, and Friday) or 10% v/v alcohol and water for 24 hours every day. After stabilization of their intake, both groups were administered 3 pharmacological agents with different mechanisms of action, naltrexone-an opioid receptor antagonist, SCH 39166-a dopamine D1 receptor antagonist, and R121919-a Corticotropin-Releasing Factor 1 (CRF1 ) receptor antagonist, and their effects on alcohol and water intake were determined. RESULTS: Intermittent 20% alcohol ("Wise") procedure in sP rats led to binge-like drinking. Alcohol drinking was suppressed by naltrexone and by SCH 39166, but not by R121919. Finally, naltrexone was more potent in reducing alcohol drinking in the intermittent 20% binge-drinking group than in the 10% continuous access drinking group. CONCLUSIONS: The Wise procedure in sP rats induces binge-like drinking, which appears opioid- and dopamine-receptor mediated; the CRF1 system, on the other hand, does not appear to be involved. In addition, our results suggest that naltrexone is particularly effective in reducing binge drinking. Such different pharmacological responses may apply to subtypes of alcoholic patients who differ in their motivation to drink, and may eventually contribute to treatment response.
Assuntos
Consumo Excessivo de Bebidas Alcoólicas/tratamento farmacológico , Consumo Excessivo de Bebidas Alcoólicas/fisiopatologia , Modelos Animais de Doenças , Antagonistas de Dopamina/uso terapêutico , Etanol/administração & dosagem , Antagonistas de Entorpecentes/uso terapêutico , Consumo de Bebidas Alcoólicas/tratamento farmacológico , Consumo de Bebidas Alcoólicas/fisiopatologia , Consumo de Bebidas Alcoólicas/psicologia , Animais , Benzazepinas/farmacologia , Benzazepinas/uso terapêutico , Consumo Excessivo de Bebidas Alcoólicas/psicologia , Comportamento de Escolha/efeitos dos fármacos , Comportamento de Escolha/fisiologia , Antagonistas de Dopamina/farmacologia , Masculino , Naltrexona/farmacologia , Naltrexona/uso terapêutico , Antagonistas de Entorpecentes/farmacologia , Pirimidinas/farmacologia , Ratos , Receptores de Hormônio Liberador da Corticotropina/antagonistas & inibidores , AutoadministraçãoRESUMO
BACKGROUND: Anxiety disorders are the most prevalent psychiatric disorders, and they are highly comorbid with chronic pain conditions. The central nucleus of the amygdala (CeA) is known not only for its role in the regulation of anxiety but also as an important site for the negative affective dimension of pain. Pituitary adenylate cyclase activating polypeptide (PACAP), a neuropeptide whose terminals are abundant in the CeA, is strongly implicated in the stress response as well as in pain processing. Here, using Cre-dependent viral vectors, we explored in greater detail the role of the PACAP projection to the CeA that originates in the lateral parabrachial nucleus (LPB). METHODS: We first performed a circuit mapping experiment by injecting an anterograde Cre-dependent virus expressing a fluorescent reporter in the LPB of PACAP-Cre mice and observing their projections. Then, we used a chemogenetic approach (a Cre-dependent Designer Receptors Activated by Designer Drugs, DREADDs) to assess the effects of the direct stimulation of the PACAP LPB to CeA projection on general locomotor activity, anxiety-like behavior (using a defensive withdrawal test), and mechanical pain sensitivity (using the von Frey test). RESULTS: We found that the CeA, together with other areas, is one of the major downstream projection targets of PACAP neurons originating in the lateral parabrachial nucleus (LPB). In the DREADD experiment, we then found that the selective activation of this neuronal pathway is sufficient to increase both anxiety-like behavior and mechanical pain sensitivity in mice, without affecting general locomotor activity. CONCLUSION: In conclusion, our data suggest that the dysregulation of this circuit may contribute to a variety of anxiety disorders and chronic pain states, and that PACAP may represent an important therapeutic target for the treatment of these conditions.
Assuntos
Núcleo Central da Amígdala , Dor Crônica , Camundongos , Animais , Polipeptídeo Hipofisário Ativador de Adenilato Ciclase , Núcleo Central da Amígdala/metabolismo , Hiperalgesia/metabolismo , Dor Crônica/metabolismo , Ansiedade/metabolismo , Doença Crônica , Neurônios/metabolismoRESUMO
Alcohol use disorder (AUD) is a complex psychiatric disease characterized by periods of heavy drinking and periods of withdrawal. Chronic exposure to ethanol causes profound neuroadaptations in the extended amygdala, which cause allostatic changes promoting excessive drinking. The bed nucleus of the stria terminalis (BNST), a brain region involved in both excessive drinking and anxiety-like behavior, shows particularly high levels of pituitary adenylate cyclase-activating polypeptide (PACAP), a key mediator of the stress response. Recently, a role for PACAP in withdrawal-induced alcohol drinking and anxiety-like behavior in alcohol-dependent rats has been proposed; whether the PACAP system of the BNST is also recruited in other models of alcohol addiction and whether it is of local or nonlocal origin is currently unknown. Here, we show that PACAP immunoreactivity is increased selectively in the BNST of C57BL/6J mice exposed to a chronic, intermittent access to ethanol. While pituitary adenylate cyclase-activating polypeptide (PACAP) type 1 receptor-expressing cells were unchanged by chronic alcohol, the levels of a peptide closely related to PACAP, the calcitonin gene-related neuropeptide, were found to also be increased in the BNST. Finally, using a retrograde chemogenetic approach in PACAP-ires-Cre mice, we found that the inhibition of PACAP neuronal afferents to the BNST reduced heavy ethanol drinking. Our data suggest that the PACAP system of the BNST is recruited by chronic, voluntary alcohol drinking in mice and that nonlocally originating PACAP projections to the BNST regulate heavy alcohol intake, indicating that this system may represent a promising target for novel AUD therapies.
Assuntos
Alcoolismo , Núcleos Septais , Animais , Camundongos , Ratos , Consumo de Bebidas Alcoólicas , Etanol , Camundongos Endogâmicos C57BL , Polipeptídeo Hipofisário Ativador de Adenilato Ciclase/metabolismo , Polipeptídeo Hipofisário Ativador de Adenilato Ciclase/farmacologia , Receptores de Polipeptídeo Hipofisário Ativador de Adenilato Ciclase/metabolismo , Núcleos Septais/metabolismo , Estresse PsicológicoRESUMO
The increased availability of highly palatable foods is a major contributing factor toward the development of compulsive eating in obesity and eating disorders. It has been proposed that compulsive eating may develop as a form of self-medication to alleviate the negative emotional state associated with withdrawal from highly palatable foods. This study was aimed at determining whether withdrawal from chronic, intermittent access to a highly palatable food was responsible for the emergence of depressive-like behavior. For this purpose, a group of male Wistar rats was provided a regular chow diet 7 days a week (Chow/Chow), whereas a second group of rats was provided chow for 5 days a week, followed by a 2-day access to a highly palatable sucrose diet (Chow/Palatable). Following 7 weeks of diet alternation, depressive-like behavior was assessed during withdrawal from the highly palatable diet and following renewed access to it, using the forced swim test, the sucrose consumption test, and the intracranial self-stimulation threshold procedure. It was found that Chow/Palatable rats withdrawn from the highly palatable diet showed increased immobility time in the forced swim test and decreased sucrose intake in the sucrose consumption test compared with the control Chow/Chow rats. Interestingly, the increased immobility in the forced swim test was abolished by renewing access to the highly palatable diet. No changes were observed in the intracranial self-stimulation threshold procedure. These results validate the hypothesis that withdrawal from highly palatable food is responsible for the emergence of depressive-like behavior, and they also show that compulsive eating relieves the withdrawal-induced negative emotional state.
Assuntos
Comportamento Compulsivo , Depressão/etiologia , Dieta , Comportamento Alimentar , Preferências Alimentares , Animais , Ansiedade/dietoterapia , Ansiedade/etiologia , Ansiedade/psicologia , Comportamento Animal , Comportamento Compulsivo/psicologia , Depressão/dietoterapia , Depressão/psicologia , Dieta/efeitos adversos , Dieta/psicologia , Sacarose Alimentar/administração & dosagem , Ingestão de Energia , Comportamento Alimentar/psicologia , Preferências Alimentares/psicologia , Masculino , Ratos , Ratos Wistar , Recompensa , Autoestimulação , Limiar Sensorial , Fatores de TempoRESUMO
Dieting to control body weight involves cycles of deprivation from palatable food that can promote compulsive eating. The present study shows that rats withdrawn from intermittent access to palatable food exhibit overeating of palatable food upon renewed access and an affective withdrawal-like state characterized by corticotropin-releasing factor-1 (CRF(1)) receptor antagonist-reversible behaviors, including hypophagia, motivational deficits to obtain less palatable food, and anxiogenic-like behavior. Withdrawal was accompanied by increased CRF expression and CRF(1) electrophysiological responsiveness in the central nucleus of the amygdala. We propose that recruitment of anti-reward extrahypothalamic CRF-CRF(1) systems during withdrawal from palatable food, analogous to abstinence from abused drugs, may promote compulsive selection of palatable food, undereating of healthier alternatives, and a negative emotional state when intake of palatable food is prevented.
Assuntos
Comportamento Compulsivo , Hormônio Liberador da Corticotropina/metabolismo , Dieta , Ingestão de Alimentos/fisiologia , Receptores de Hormônio Liberador da Corticotropina/metabolismo , Tonsila do Cerebelo/citologia , Tonsila do Cerebelo/metabolismo , Animais , Comportamento Aditivo/metabolismo , Comportamento Aditivo/psicologia , Comportamento Animal/fisiologia , Ingestão de Alimentos/psicologia , Eletrofisiologia , Masculino , Aprendizagem em Labirinto , Pirimidinas/metabolismo , Ratos , Ratos Wistar , Receptores de Hormônio Liberador da Corticotropina/antagonistas & inibidores , Recompensa , Estresse Psicológico/metabolismo , Estresse Psicológico/psicologia , Síndrome de Abstinência a Substâncias/metabolismo , Síndrome de Abstinência a Substâncias/psicologiaRESUMO
Many psychiatric diseases stem from an inability to cope with stressful events, as chronic stressors can precipitate or exacerbate psychopathologies. The neurobiological mechanisms underlying the response to chronic stress and the resulting anxiety states remain poorly understood. Stress neuropeptides in the extended amygdala circuitry mediate the behavioral response to stress, and hyperactivity of these systems has been hypothesized to be responsible for the emergence of persistent negative outcomes and for the pathogenesis of anxiety-related and trauma-related disorders. Pituitary adenylate cyclase-activating polypeptide (PACAP) and its receptor PAC1R are highly expressed within the central amygdala (CeA) and play a key role in stress regulation. Here, we used chronic social defeat stress (CSDS), a clinically relevant model of psychosocial stress that produces robust maladaptive behaviors in rodents. We found that 10 days of CSDS cause a significant increase in PACAP levels selectively in the CeA of rats, as well as an increase in PAC1R mRNA. Using a viral vector strategy, we found that PAC1R knock-down in the CeA attenuates the CSDS-induced body weight loss and prevents the CSDS-induced increase in anxiety-like behavior. Notably, CSDS animals display reduced basal corticosterone (CORT) levels and PAC1R knock-down in CeA further reduce them. Finally, the CeA PAC1R knock-down blocks the increase in corticotropin-releasing factor (CRF) immunoreactivity induced by CSDS in CeA. Our findings support the notion that the persistent activation of the PACAP-PAC1R system in the CeA mediates the behavioral outcomes of chronic psychosocial stress independently of the hypothalamic-pituitary-adrenal axis, perhaps via the recruitment of the CRF system.
Assuntos
Adaptação Psicológica , Núcleo Central da Amígdala , Polipeptídeo Hipofisário Ativador de Adenilato Ciclase , Derrota Social , Estresse Psicológico , Animais , Ratos , Núcleo Central da Amígdala/metabolismo , Hormônio Liberador da Corticotropina/metabolismo , Sistema Hipotálamo-Hipofisário/metabolismo , Polipeptídeo Hipofisário Ativador de Adenilato Ciclase/metabolismo , Sistema Hipófise-Suprarrenal/metabolismo , Estresse Psicológico/metabolismoRESUMO
Alcohol use disorders (AUD) have a strong component of heritability; however, the neurobiological mechanisms mediating the propensity to consume excessive amounts of alcohol are still not well understood. Pituitary adenylate cyclase-activating polypeptide (PACAP), a highly conserved neuropeptide which exerts its effects mainly through the PAC1 receptor (PAC1R), has been suggested to be one of the mediators of the effects of drugs of abuse and alcohol. Here, we investigated the role of the PACAP/PAC1R system in excessive alcohol drinking in alcohol-preferring rats, an established animal model of AUD. Intracerebroventricular (i.c.v.) administration of the PAC1R antagonist PACAP(6-38) blocked excessive alcohol drinking and motivation to drink in Sardinian alcohol-preferring (Scr:sP) rats, without affecting water, saccharin, or sucrose intake. Notably, PACAP(6-38) did not affect ethanol responding in outbred Wistar rats. PACAP(6-38) also significantly reduced alcohol-seeking behavior under a second-order schedule of reinforcement. Using immunohistochemistry, a significant increase in the number of PAC1R positive cells was observed selectively in the nucleus accumbens (NAcc) Core of Scr:sP rats, compared to Wistar rats, following alcohol drinking. Finally, excessive drinking in Scr:sP rats was suppressed by intra-NAcc Core, but not intra-NAcc Shell, PACAP(6-38), as well as by virally-mediated PAC1R knockdown in the NAcc Core. The present study shows that hyperactivity of the PACAP/PAC1R system specifically in the NAcc Core mediates excessive drinking of alcohol-preferring rats, and indicates that this system may represent a novel target for the treatment of AUD.
Assuntos
Consumo de Bebidas Alcoólicas , Alcoolismo , Polipeptídeo Hipofisário Ativador de Adenilato Ciclase , Receptores de Polipeptídeo Hipofisário Ativador de Adenilato Ciclase , Consumo de Bebidas Alcoólicas/tratamento farmacológico , Consumo de Bebidas Alcoólicas/metabolismo , Alcoolismo/tratamento farmacológico , Alcoolismo/metabolismo , Animais , Núcleo Accumbens/metabolismo , Polipeptídeo Hipofisário Ativador de Adenilato Ciclase/farmacologia , Ratos , Ratos Wistar , Receptores de Polipeptídeo Hipofisário Ativador de Adenilato Ciclase/antagonistas & inibidores , Receptores de Polipeptídeo Hipofisário Ativador de Adenilato Ciclase/metabolismoRESUMO
Alcohol use disorder (AUD) is a chronic, relapsing disorder whose genetic and environmental susceptibility components are not fully understood. Neuropeptidergic signaling has been repeatedly implicated in modulating excessive alcohol drinking, especially within sub-regions of the striatum. Here, we investigated the potential involvement of the selective receptor for pituitary adenylate cyclase-activating polypeptide (PACAP), PAC1R, in the nucleus accumbens shell (NAcc Shell) in excessive alcohol drinking in alcohol-preferring rats, an established animal model of the genetic propensity for alcoholism. Scr:sP alcohol-preferring rats were trained to operantly self-administer alcohol and then either an AAV virus short-hairpin RNA (shRNA) targeted to knockdown PAC1R, or an AAV control virus were microinfused into the NAcc Shell. NAcc Shell PAC1R shRNA knockdown virus was confirmed to significantly decrease PAC1R levels in the NAcc Shell. The effects of NAcc Shell PAC1R shRNA knockdown on ethanol self-administration were investigated using a Fixed Ratio (FR) 1 and a Progressive Ratio (PR) schedule of reinforcement. The effect of PAC1R knockdown on self-administration of an alternative reinforcer, saccharin, was also assessed. The results showed that the reduction in PAC1R in the NAcc Shell led to excessive ethanol drinking, increased preference for ethanol, and higher motivation to drink. NAcc Shell PAC1R shRNA knockdown did not comparably increase saccharin self-administration, suggesting selectivity of action. These data suggest that NAcc Shell PAC1R may serves as a "brake" on alcohol drinking, and thereby the loss of function of PAC1R leads to excessive alcohol consumption. Therefore, the PACAP/PAC1R system may represent a novel target for the treatment of AUD.
RESUMO
Alcohol use disorder (AUD) is a devastating illness defined by periods of heavy drinking and withdrawal, often leading to a chronic relapsing course. Initially, alcohol is consumed for its positive reinforcing effects, but later stages of AUD are characterized by drinking to alleviate withdrawal-induced negative emotional states. Brain stress response systems in the extended amygdala are recruited by excessive alcohol intake, sensitized by repeated withdrawal, and contribute to the development of addiction. In this study, we investigated one such brain stress response system, pituitary adenylate cyclase-activating polypeptide (PACAP), and its cognate receptor, PAC1R, in alcohol withdrawal-induced behaviors. During acute withdrawal, rats exposed to chronic intermittent ethanol vapor (ethanol-dependent) displayed a significant increase in PACAP levels in the bed nucleus of the stria terminalis (BNST), a brain area within the extended amygdala critically involved in both stress and withdrawal. No changes in PACAP levels were observed in the central nucleus of the amygdala. Site-specific microinfusion of the PAC1R antagonist PACAP(6-38) into the BNST dose-dependently blocked excessive alcohol intake in ethanol-dependent rats without affecting water intake overall or basal ethanol intake in control, nondependent rats. Intra-BNST PACAP(6-38) also reversed ethanol withdrawal-induced anxiety-like behavior in ethanol-dependent rats, but did not affect this measure in control rats. Our findings show that chronic intermittent exposure to ethanol recruits the PACAP/PAC1R system of the BNST and that these neuroadaptations mediate the heightened alcohol drinking and anxiety-like behavior observed during withdrawal, suggesting that this system represents a major brain stress element responsible for the negative reinforcement associated with the "dark side" of alcohol addiction.
Assuntos
Polipeptídeo Hipofisário Ativador de Adenilato Ciclase/metabolismo , Núcleos Septais , Consumo de Bebidas Alcoólicas , Animais , Ansiedade/tratamento farmacológico , Emoções , Masculino , Ratos , Receptores de Polipeptídeo Hipofisário Ativador de Adenilato Ciclase , Núcleos Septais/metabolismoRESUMO
Alcohol Use Disorder (AUD) is a chronic relapsing disorder characterized by compulsive alcohol intake, loss of control over alcohol intake, and a negative emotional state when access to alcohol is prevented. AUD is also closely tied to pain, as repeated alcohol drinking leads to increased pain sensitivity during withdrawal. The sigma-2 receptor, recently identified as transmembrane protein 97 (σ2R/TMEM97), is an integral membrane protein involved in cholesterol homeostasis and lipid metabolism. Selective σ2R/Tmem97 modulators have been recently shown to relieve mechanical hypersensitivity in animal models of neuropathic pain as well as to attenuate alcohol withdrawal signs in C. elegans and to reduce alcohol drinking in rats, suggesting a potential key role for this protein in alcohol-related behaviors. In this study, we tested the effects of a potent and selective σ2R/TMEM97 ligand, JVW-1034, on heavy alcohol drinking and alcohol-induced heightened pain states in mice using an intermittent access model. Administration of JVW-1034 decreased both ethanol intake and preference for ethanol, without affecting water intake, total fluid intake, or food intake. Notably, this effect was specific for alcohol, as JVW-1034 had no effect on sucrose intake. Furthermore, JVW-1034 reduced both thermal hyperalgesia and mechanical hypersensitivity in ethanol withdrawn mice. Our data provide important evidence that modulation of σ2R/TMEM97 with small molecules can mediate heavy alcohol drinking as well as chronic alcohol-induced heightened pain sensitivity, thereby identifying a promising novel pharmacological target for AUD and associated pain states.
Assuntos
Consumo de Bebidas Alcoólicas/metabolismo , Analgésicos/metabolismo , Proteínas de Membrana/metabolismo , Medição da Dor/efeitos dos fármacos , Dor/metabolismo , Receptores sigma/metabolismo , Consumo de Bebidas Alcoólicas/tratamento farmacológico , Analgésicos/administração & dosagem , Analgésicos/química , Animais , Locomoção/efeitos dos fármacos , Locomoção/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Dor/tratamento farmacológico , Medição da Dor/métodosRESUMO
BACKGROUND: Binge-eating disorder is a pervasive addiction-like disorder that is defined by excessive and uncontrollable consumption of food within brief periods of time. The aim of the current study was to examine the role of the brain noradrenergic system in binge-like eating through the use of the alpha-1 adrenergic receptor antagonist prazosin. METHODS: For this purpose, we employed a limited access model whereby male Wistar rats were allowed to nosepoke for either chow (Chow rats) or a sugary, highly palatable food (Palatable rats) for 1 h/day. The effects of prazosin (0, 0.5, 1 and 2 mg/kg, i.p.) were tested in a fixed ratio 1 (FR1) and progressive ratio (PR) schedule of reinforcement. RESULTS: The results show that prazosin preferentially reduced the responses for palatable food in a FR1 reinforcement schedule; when tested in a PR schedule of reinforcement, prazosin increased breakpoint in both Chow and Palatable rats, but more potently and more efficaciously in the latter. Our results suggest that prazosin treatment preferentially increased the motivational properties of the palatable diet. CONCLUSIONS: The current findings provide the characterization of the effects of prazosin on binge-like eating and offer support to the existing literature showing the important role of the noradrenergic system in addiction-like behavior.
Assuntos
Antagonistas de Receptores Adrenérgicos alfa 1/administração & dosagem , Transtornos da Alimentação e da Ingestão de Alimentos/tratamento farmacológico , Dependência de Alimentos/tratamento farmacológico , Prazosina/administração & dosagem , Animais , Modelos Animais de Doenças , Transtornos da Alimentação e da Ingestão de Alimentos/etiologia , Dependência de Alimentos/etiologia , Masculino , Norepinefrina/metabolismo , Norepinefrina/fisiologia , Ratos Wistar , Resultado do TratamentoRESUMO
Alcohol use disorder (AUD) is a major cause of morbidity and mortality worldwide, for which new efficacious treatments are necessary. The opioid receptor system is a mediator of the rewarding effects of alcohol; in particular, while activation of µ opioid receptors enhances ethanol intake in rodents, opioid-receptor antagonists, such as naloxone and naltrexone, reduce its pleasurable and reinforcing effects, thereby decreasing alcohol. Sigma receptors (Sig-Rs) have been proposed as modulators of the effects of alcohol and, therefore, as a potential new pharmacological target for AUD. Somewhat analogously to µ opioid ligands, SigR agonists increase, while SigR antagonists decrease alcohol intake in animal models of excessive alcohol drinking. However, a potential cross-talk between these two receptor systems in relation to alcohol consumption has so far not been investigated. Here, we addressed this question pharmacologically, by testing the effects of either activating or inhibiting opioid receptors on the heavy alcohol drinking induced by chronic stimulation of SigR in alcohol-preferring rats. We found that the opioid receptor agonist morphine, which per se increases ethanol intake, at a sub-threshold dose reduces the binge-like drinking induced by the repeated treatment with the SigR agonist 1,3-di-o-tolylguanidine (DTG); conversely, the opioid receptor antagonist naltrexone, which per se reduces ethanol intake, at a sub-threshold dose potentiates the DTG-induced binge-like drinking. Our data show a cross-talk between the opioid and SigR systems relevant to the modulation of alcohol drinking, which provides important insights into the neurobiology of AUD and may lead to the development of novel therapies, either standalone or in combination.
Assuntos
Consumo Excessivo de Bebidas Alcoólicas/tratamento farmacológico , Consumo Excessivo de Bebidas Alcoólicas/etiologia , Depressores do Sistema Nervoso Central/administração & dosagem , Etanol/administração & dosagem , Guanidinas/efeitos adversos , Guanidinas/farmacologia , Morfina/administração & dosagem , Naltrexona/administração & dosagem , Antagonistas de Entorpecentes/administração & dosagem , Receptores sigma/agonistas , Receptores sigma/antagonistas & inibidores , Animais , Relação Dose-Resposta a Droga , Masculino , Morfina/farmacologia , Naltrexona/farmacologia , Antagonistas de Entorpecentes/farmacologia , Ratos , AutoadministraçãoRESUMO
BACKGROUND: Binge eating disorder (BED) is characterized by recurrent binge eating episodes consisting of rapid consumption of excessive amounts of highly palatable, energy-dense food within discrete periods of time. The aim of this study was to test the consummatory, food microstructural, and metabolic effects of a one hour limited access to either a high-sucrose diet (HSD) or a high-fat diet (HFD) in an operant rat model of binge-like eating. METHODS: Female rats were subject to a binge-like eating procedure in which a HSD, a HFD, or a standard chow diet were provided in a fixed ratio 1 (FR1) operant schedule of reinforcement. RESULTS: Limiting access to either a HSD or a HFD promoted binge-like eating as compared to the control chow diet. However, binge-like eating of HSD, but not HFD, was based on a true increase in the amount of food consumed, an increased eating rate, and a decrease in the intake of the home-cage standard chow, altogether suggesting an increase in palatability. Moreover, while HSD rats consumed overall less energy than HFD rats, the former were more energy efficient and gained more body weight than the latter. CONCLUSIONS: These results provide information on how the quality of food can deeply influence the behavioral and metabolic outcomes of binge-like eating.