Rapid nongenomic estrogen signaling controls alcohol drinking behavior in mice.

Ovarian-derived estrogen can signal non-canonically at membrane-associated receptors in the brain to rapidly regulate neuronal function. Early alcohol drinking confers greater risk for alcohol use disorder in women than men, and binge alcohol drinking is correlated with high estrogen levels, but a causal role for estrogen in driving alcohol drinking has not been established. We found that female mice displayed greater binge alcohol drinking and reduced avoidance when estrogen was high during the estrous cycle than when it was low.

Rapid nongenomic estrogen signaling controls alcohol drinking behavior.

Ovarian-derived estrogen is a key modulator of numerous physiological processes via genomic and nongenomic mechanisms, including signaling non-canonically at membrane-associated estrogen receptors in the brain to rapidly regulate neuronal function. However, the mechanisms mediating estrogen regulation of behaviors such as alcohol consumption remain unclear. Early alcohol drinking confers greater risk for alcohol use disorder in women than men, and binge alcohol drinking is correlated with high circulating estrogen levels, but a causal role for estrogen signaling in driving alcohol drinking in gonadally-intact animals has not been established.

Sex differences in binge alcohol drinking and the behavioral consequences of protracted abstinence in C57BL/6J mice.

Background: Binge alcohol drinking is a risk factor linked to numerous disease states including alcohol use disorder (AUD). While men binge drink more alcohol than women, this demographic gap is quickly shrinking, and preclinical studies demonstrate that females consistently consume more alcohol than males. Further, women are at increased risk for the co-expression of AUD with neuropsychiatric diseases such as anxiety and mood disorders.

Sex differences in binge alcohol drinking and the behavioral consequences of protracted abstinence in C57BL/6J mice.

Background: Binge alcohol drinking is a risk factor linked to numerous disease states including alcohol use disorder (AUD). While men binge drink more alcohol than women, this demographic gap is quickly shrinking, and preclinical studies demonstrate that females consistently consume more alcohol than males. Further, women are at increased risk for the co-expression of AUD with neuropsychiatric diseases such as anxiety and mood disorders.

Valence and salience encoding by parallel circuits from the paraventricular thalamus to the nucleus accumbens.

The anterior and posterior subregions of the paraventricular thalamus (aPVT and pPVT, respectively) play unique roles in learned behaviors, from fear conditioning to alcohol/drug intake, potentially through differentially organized projections to limbic brain regions including the nucleus accumbens medial shell (mNAcSh). Here, we found that the aPVT projects broadly to the mNAcSh and that the aPVT-mNAcSh circuit encodes positive valence, such that manipulations of the circuit modulated both innately programmed and learned behavioral responses to positively and negatively valenced stimuli, particularly in females. Further, the endogenous activity of aPVT presynaptic terminals in the mNAcSh was greater in response to positively than negatively valenced stimuli, and the probability of synaptic glutamate release from aPVT neurons in the mNAcSh was higher in females than males.

Sex differences in the medial prefrontal cortical glutamate system.

Background: Dysregulation in the prefrontal cortex underlies a variety of psychiatric illnesses, including substance use disorder, depression, and anxiety. Despite the established sex differences in prevalence and presentation of these illnesses, the neural mechanisms driving these differences are largely unexplored. Here, we investigate potential sex differences in glutamatergic transmission within the medial prefrontal cortex (mPFC).

A closer look at alcohol-induced changes in the ghrelin system: novel insights from preclinical and clinical data.

Ghrelin is a gastric-derived peptide hormone with demonstrated impact on alcohol intake and craving, but the reverse side of this bidirectional link, that is, the effects of alcohol on the ghrelin system, remains to be fully established. To further characterize this relationship, we examined (1) ghrelin levels via secondary analysis of human laboratory alcohol administration experiments with heavy-drinking participants; (2) expression of ghrelin, ghrelin receptor, and ghrelin-O-acyltransferase (GOAT) genes (GHRL, GHSR, and MBOAT4, respectively) in post-mortem brain tissue from individuals with alcohol use disorder (AUD) versus controls; (3) ghrelin levels in Ghsr knockout and wild-type rats following intraperitoneal (i.p.

Probenecid Reduces Alcohol Drinking in Rodents. Is Pannexin1 a Novel Therapeutic Target for Alcohol Use Disorder?

Aims: The development of novel and more effective medications for alcohol use disorder (AUD) is an important unmet medical need. Drug repositioning or repurposing is an appealing strategy to bring new therapies to the clinic because it greatly reduces the overall costs of drug development and expedites the availability of treatments to those who need them. Probenecid, p-(di-n-propylsulfamyl)-benzoic acid, is a drug used clinically to treat hyperuricemia and gout due to its activity as an inhibitor of the kidneys' organic anion transporter that reclaims uric acid from urine.

Oxytocin blocks enhanced motivation for alcohol in alcohol dependence and blocks alcohol effects on GABAergic transmission in the central amygdala.

Oxytocin administration has been reported to decrease consumption, withdrawal, and drug-seeking associated with several drugs of abuse and thus represents a promising pharmacological approach to treat drug addiction. We used an established rat model of alcohol dependence to investigate oxytocin's effects on dependence-induced alcohol drinking, enhanced motivation for alcohol, and altered GABAergic transmission in the central nucleus of the amygdala (CeA). Intraperitoneal oxytocin administration blocked escalated alcohol drinking and the enhanced motivation for alcohol in alcohol-dependent but not nondependent rats.

Glucagon-Like Peptide-1 (GLP-1) and 5-Hydroxytryptamine 2c (5-HT) Receptor Agonists in the Ventral Tegmental Area (VTA) Inhibit Ghrelin-Stimulated Appetitive Reward.

Current literature indicates that the orexigenic peptide ghrelin increases appetitive motivation via signaling in the mesolimbic reward system. Another gastric peptide, glucagon-like peptide-1 (GLP-1), and the neurotransmitter 5-hydroxytryptamine (5-HT), are both known to suppress operant responding for food by acting on key mesolimbic nuclei, including the ventral tegmental area (VTA). In order to investigate the interaction effects of ghrelin, GLP-1, and 5-HT within the VTA, we measured operant responding for sucrose pellets after the administration of ghrelin, the GLP-1 receptor agonist exendin-4 (Ex-4), and the 5-HT receptor agonist Ro60-0175 in male Sprague-Dawley rats.

Ghrelin receptor deletion reduces binge-like alcohol drinking in rats.

Ghrelin is a gastric hormone that has been implicated in the neurobiology of alcohol drinking. We have recently developed a ghrelin receptor (growth hormone secretagogue receptor; GHSR) knockout (KO) rat model, which exhibits reduced food consumption and body weight. In addition, recent preliminary work suggests that the gut-microbiome, which appears to interact with the ghrelin system, may modulate alcohol drinking.

Development and initial characterization of a novel ghrelin receptor CRISPR/Cas9 knockout wistar rat model.

Background/objectives: Ghrelin, a stomach-derived hormone implicated in numerous behaviors including feeding, reward, stress, and addictive behaviors, acts by binding to the growth hormone secretagogue receptor (GHSR). Here, we present the development, verification, and initial characterization of a novel GHSR knockout (KO) Wistar rat model created with CRISPR genome editing.

Methods: Using CRISPR/Cas9, we developed a GHSR KO in a Wistar background.

The Role of the Ghrelin System in Drug Addiction.

In the past years, a significant volume of research has implicated the appetitive hormone ghrelin in the mechanisms underlying drug use and addiction. From a neuroscientific standpoint, ghrelin modulates both reward and stress pathways, two key drivers of substance use behaviors. Previous investigations support a connection between the ghrelin system and alcohol, stimulants, and tobacco use in both animals and humans, while the research on opioids and cannabis is scarce.