Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) of the Bed Nucleus of the Stria Terminalis Mediates Heavy Alcohol Drinking in Mice.

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.

Stimulation of lateral parabrachial (LPB) to central amygdala (CeA) pituitary adenylate cyclase-activating polypeptide (PACAP) neurons induces anxiety-like behavior and mechanical allodynia.

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.

The Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) System of the Central Amygdala Mediates the Detrimental Effects of Chronic Social Defeat Stress in Rats.

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.

Pituitary adenylate cyclase-activating polypeptide type 1 receptor within the nucleus accumbens core mediates excessive alcohol drinking in alcohol-preferring rats.

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.

Viral-Mediated Knockdown of Nucleus Accumbens Shell PAC1 Receptor Promotes Excessive Alcohol Drinking in Alcohol-Preferring Rats.

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.

Characterization of a differential reinforcement of low rates of responding task in non-deprived male and female rats: Role of Sigma-1 receptors.

Impulsive action can be defined as the inability to withhold a response and represents one of the dimensions of the broad construct impulsivity. Here, we characterized a modified differential reinforcement of low rates of responding (DRL) task developed in our laboratory, in which impulsive action is measured in ad libitum fed/watered subjects. Specifically, we first determined the effects of both sex and estrous cycle on impulsive action by systematically comparing male and estrous-synchronized female subjects. In addition, we evaluated the convergent validity of this modified DRL task by testing the effects of the D2R/5HT2AR antagonist, aripiprazole, and the noncompetitive NMDAR antagonist, MK-801. Finally, we tested the effects of the selective antagonist BD-1063 and agonist PRE-084 of Sigma-1 receptor (Sig-1R) on impulsive action using this modified DRL task. We found that female rats showed and increased inability to withhold a response when compared to males, and this effect was driven by the metestrus/diestrus phase of the estrous cycle. In addition, aripiprazole and MK-801 fully retained their capability to reduce and increase impulsive action, respectively. Finally, the selective Sig-1R antagonist, BD-1063 dose-dependently reduced the inability to withhold a response in both sexes, though more potently in female rats. In summary, we show that impulsive action, as measured in a modified DRL task which minimizes energy-homeostatic influences, is a function of both sex and estrous cycle. Furthermore, we validate the convergent validity of the task and provide evidence that Sig-1R antagonism may represent a novel pharmacological strategy to reduce impulsive action.

Antagonism of Sigma-1 receptor blocks heavy alcohol drinking and associated hyperalgesia in male mice.

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.

The Sigma-2 receptor / transmembrane protein 97 (σ2R/TMEM97) modulator JVW-1034 reduces heavy alcohol drinking and associated pain states in male mice.

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.

Pituitary adenylate cyclase-activating polypeptide (PACAP) modulates dependence-induced alcohol drinking and anxiety-like behavior in male rats.

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.

The Alpha-1 Adrenergic Receptor Antagonist Prazosin Reduces Binge-Like Eating in Rats.

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.

Consummatory, Feeding Microstructural, and Metabolic Effects Induced by Limiting Access to Either a High-Sucrose or a High-Fat Diet.

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.

Withdrawal from Extended, Intermittent Access to A Highly Palatable Diet Impairs Hippocampal Memory Function and Neurogenesis: Effects of Memantine.

BACKGROUND: Compulsive eating can be promoted by intermittent access to palatable food and is often accompanied by cognitive deficits and reduction in hippocampal plasticity. Here, we investigated the effects of intermittent access to palatable food on hippocampal function and neurogenesis. METHODS: Male Wistar rats were either fed chow for 7 days/week (Chow/Chow group), or fed chow intermittently for 5 days/week followed by a palatable diet for 2 days/week (Chow/Palatable group). Hippocampal function and neurogenesis were assessed either during withdrawal or following renewed access to palatable food. Furthermore, the ability of the uncompetitive N-methyl-d-aspartate receptor (NMDAR) antagonist memantine to prevent the diet-induced memory deficits and block the maladaptive feeding was tested. RESULTS: Palatable food withdrawn Chow/Palatable rats showed both a weakened ability for contextual spatial processing and a bias in their preference for a "novel cue" over a "novel place," compared to controls. They also showed reduced expression of immature neurons in the dentate gyrus of the hippocampus as well as a withdrawal-dependent decrease of proliferating cells. Memantine treatment was able both to reverse the memory deficits and to reduce the excessive intake of palatable diet and the withdrawal-induced hypophagia in food cycling rats. CONCLUSIONS: In summary, our results provide evidence that withdrawal from highly palatable food produces NMDAR-dependent deficits in hippocampal function and a reduction in hippocampal neurogenesis.

Effect of different standard rodent diets on ethanol intake and associated allodynia in male mice.

Alcohol is the most ubiquitously consumed and misused mind-altering substance in the world. Various animal models exist to aid in our neurobiological understanding of alcohol addiction. One variable too often taken for granted and not consistently controlled is the "standard" chow diet rodents are maintained on. In this set of experiments, we sought to determine the effect of different commonly used diets on ethanol intake, ethanol preference, and mechanical pain sensitivity in a widely used mouse model of heavy alcohol drinking, the intermittent access to 20% alcohol model. We found that male mice kept on LabDiet 5001 (Diet 2 [LD5001]) and on Teklad Diet 7012 (Diet 3 [H7012]) consistently drank more ethanol than mice kept on Teklad Diet 2918 (Diet 1 [H2918]) as well as compared to mice on LabDiet 5V75 (Diet 4 [LD5V75]). In addition, water intake was consistently lower in mice kept on LabDiet 5001 (Diet 2 [LD5001]), and occasionally in mice kept on Teklad Diet 7012 (Diet 3 [H7012]), compared to the Teklad Diet 2918 (Diet 1 [H2918]) group. We found that male mice showed a strong mechanical allodynia following 8 weeks of intermittent ethanol drinking at 72 h of withdrawal, compared to water Control mice, regardless of the diet and hence of the different amount of ethanol consumed. Our data provide evidence that the type of rodent diet subjects are exposed to is an important variable to report and control, in all ethanol drinking studies.

Sigma receptor-induced heavy drinking in rats: Modulation by the opioid receptor system.

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.

Reward sensitivity deficits in a rat model of compulsive eating behavior.

Compulsive eating behavior is hypothesized to be driven in part by reward deficits likely due to neuroadaptations to the mesolimbic dopamine (DA) system. Therefore, the aim of this study was to assess deficits in reward system functioning and mesolimbic DA after alternating a standard chow with palatable diet, a model of compulsive eating. In this model, rats in the control group (Chow/Chow) are provided a standard chow diet 7 days a week, while the experimental group (Chow/Palatable) is provided chow for 5 days a week ("C Phase"), followed by 2 days of access to a highly palatable sucrose diet ("P Phase"). We first tested the sensitivity to d-Amphetamine's stimulatory, reward-enhancing, and primary rewarding effects using a locomotor activity assay, an intracranial self-stimulation (ICSS) procedure, and a conditioned place preference test, respectively. We then quantified DA release in the nucleus accumbens (NAc) shell after treatment with d-Amphetamine using in vivo microdialysis, quantified levels of tyrosine hydroxylase (TH) and dopamine transporter (DAT) mRNA using quantitative polymerase chain reaction (qPCR), and lastly, quantified baseline extracellular DA and function of DAT in vivo using quantitative "no-net-flux" microdialysis. Chow/Palatable rats displayed blunted d-Amphetamine-induced locomotor activity, insensitivity to d-Amphetamine potentiation of ICSS threshold, and decreased place preference for d-Amphetamine during the P Phase. We found that Chow/Palatable rats had blunted DA efflux following d-Amphetamine treatment. Furthermore, DAT mRNA was increased in Chow/Palatable rats during the P Phase. Finally, quantitative "no-net-flux" microdialysis revealed reduced extracellular baseline DA and DAT function in Chow/Palatable rats. Altogether, these results provide evidence of reduced reward system functioning and related neuroadaptations in the DA and DAT systems in this model of compulsive eating. Reward deficits, resulting from repeated overeating, may in turn contribute to the perpetuation of compulsive eating behavior.

Role of the PACAP system of the extended amygdala in the acoustic startle response in rats.

Anxiety-related disorders are the most prevalent mental disorders in the world and they are characterized by abnormal responses to stressors. Pituitary adenylate cyclase-activating polypeptide (PACAP) is a neuropeptide highly expressed in the extended amygdala, a brain macrostructure involved in the response to threat that includes the central nucleus of the amygdala (CeA) and the bed nucleus of the stria terminalis (BNST). The aim of this series of experiments was to systematically elucidate the role of the PACAP system of the CeA and BNST under both control, unstressed conditions and after the presentation of a stressor in rats. For this purpose, we used the acoustic startle response (ASR), an unconscious response to sudden acoustic stimuli sensitive to changes in stress which can be used as an operationalization of the hypervigilance present in anxiety- and trauma-related disorders. We found that infusion of PACAP, but not the related peptide vasoactive intestinal peptide (VIP), into either the CeA or the BNST causes a dose-dependent increase in ASR. In addition, while infusion of the antagonist PACAP(6-38) into either the CeA or the BNST does not affect ASR in non-stressed conditions, it prevents the sensitization of ASR induced by an acute footshock stress. Finally, we found that footshock stress induces a significant increase in PACAP, but not VIP, levels in both of these brain areas. Altogether, these data show that the PACAP system of the extended amygdala contributes to stress-induced hyperarousal and suggest it as a potential novel target for the treatment of stress-related disorders.

Role of Sigma Receptors in Alcohol Addiction.

Pharmacological treatments for alcohol use disorder (AUD) are few in number and often ineffective, despite the significant research carried out so far to better comprehend the neurochemical underpinnings of the disease. Hence, research has been directed towards the discovery of novel therapeutic targets for the treatment of AUD. In the last decade, the sigma receptor system has been proposed as a potential mediator of alcohol reward and reinforcement. Preclinical studies have shown that the motivational effects of alcohol and excessive ethanol consumption involve the recruitment of the sigma receptor system. Furthermore, sigma receptor antagonism has been shown to be sufficient to inhibit many behaviors related to AUDs. This paper will review the most current evidence in support of this receptor system as a potential target for the development of pharmacological agents for the treatment of alcohol addiction.

Impulsive choice does not predict binge-like eating in rats.

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.

Trace Amine Associated Receptor 1 (TAAR1) Modulation of Food Reward.

Eating disorders and some forms of obesity are characterized by addictive-like, compulsive eating behavior which contains numerous similarities with compulsive drug use. Food intake is in part mediated by reward and reinforcement processes that can become dysregulated in these disorders. Additionally, impairments in inhibitory control regulation of reward-related responding can cause or further exacerbate binge and compulsive eating. Dysfunctions in two neurotransmitter systems in the mesocorticolimbic pathway, dopamine and glutamate, are thought to contribute to maladaptive eating behaviors. The trace amine associated receptor 1 (TAAR1) system is a promising therapeutic target for compulsive eating behavior due to the role of TAAR1 in synaptic transmission and in the modulation of dopaminergic and glutamatergic signaling. In support of this notion, the TAAR1 agonist RO5256390 was found to decrease the reinforcing effects of palatable food-cues and to reduce binge-like and compulsive-like eating of palatable food. Additionally, prolonged, intermittent access to palatable food was shown to downregulate TAAR1 in the prefrontal cortex, suggesting a potential role for TAAR1 signaling in inhibitory control processes. Research into the role of TAAR1 in addiction, including TAAR1's ability to modulate psychostimulant reward and reinforcement, bolsters support for TAAR1 agonism as a pharmacological treatment for compulsive eating and other addictive behaviors. This review summarizes the evidence for TAAR1 agonism as a promising therapeutic for compulsive eating behavior as well as the hypothesized mechanism responsible for these effects.

Neuropharmacology of compulsive eating.

Compulsive eating behaviour is a transdiagnostic construct observed in certain forms of obesity and eating disorders, as well as in the proposed construct of 'food addiction'. Compulsive eating can be conceptualized as comprising three elements: (i) habitual overeating, (ii) overeating to relieve a negative emotional state, and (iii) overeating despite adverse consequences. Neurobiological processes that include maladaptive habit formation, the emergence of a negative affect, and dysfunctions in inhibitory control are thought to drive the development and persistence of compulsive eating behaviour. These complex psychobehavioural processes are under the control of various neuropharmacological systems. Here, we describe the current evidence implicating these systems in compulsive eating behaviour, and contextualize them within the three elements. A better understanding of the neuropharmacological substrates of compulsive eating behaviour has the potential to significantly advance the pharmacotherapy for feeding-related pathologies.This article is part of a discussion meeting issue 'Of mice and mental health: facilitating dialogue between basic and clinical neuroscientists'.