Alcohol use disorder (AUD) is a chronic relapsing condition characterized by compulsive alcohol-seeking behaviors, with serious detrimental health consequences. Despite high prevalence and societal burden, available approved medications to treat AUD are limited in number and efficacy, highlighting a critical need for more and novel pharmacotherapies. Glucagon-like peptide-1 (GLP-1) is a gut hormone and neuropeptide involved in the regulation of food intake and glucose metabolism via GLP-1 receptors (GLP-1Rs). GLP-1 analogs are approved for clinical use for diabetes and obesity. Recently, the GLP-1 system has been shown to play a role in the neurobiology of addictive behaviors, including alcohol seeking and consumption. Here we investigated the effects of different pharmacological manipulations of the GLP-1 system on escalated alcohol intake and preference in male Wistar rats exposed to intermittent access 2-bottle choice of 10% ethanol or water. Administration of AR231453 and APD668, two different agonists of G-protein receptor 119, whose activation increases GLP-1 release from intestinal L-cells, did not affect voluntary ethanol intake. By contrast, injections of either liraglutide or semaglutide, two long-acting GLP-1 analogs, potently decreased ethanol intake. These effects, however, were transient, lasting no longer than 48 h. Semaglutide, but not liraglutide, also reduced ethanol preference on the day of injection. As expected, both analogs induced a reduction in body weight. Co-administration of exendin 9-39, a GLP-1R antagonist, did not prevent liraglutide- or semaglutide-induced effects in this study. Injection of exendin 9-39 alone, or blockade of dipeptidyl peptidase-4, an enzyme responsible for GLP-1 degradation, via injection of sitagliptin, did not affect ethanol intake or preference. Our findings suggest that among medications targeting the GLP-1 system, GLP-1 analogs may represent novel and promising pharmacological tools for AUD treatment.

Chemotherapy-induced peripheral neuropathy (CIPN) is a severe and dose-limiting side effect of cancer treatment that affects millions of cancer survivors throughout the world and current treatment options are extremely limited by their side effects. Cannabinoids are highly effective in suppressing pain symptoms of chemotherapy-induced and other peripheral neuropathies but their widespread use is limited by central nervous system (CNS)-mediated side effects. Here, we tested one compound from a series of recently developed synthetic peripherally restricted cannabinoids (PRCBs) in a rat model of cisplatin-induced peripheral neuropathy. Results show that local or systemic administration of 4-{2-[-(1E)-1[(4-propylnaphthalen-1-yl)methylidene]-1H-inden-3-yl]ethyl}morpholine (PrNMI) dose-dependently suppressed CIPN mechanical and cold allodynia. Orally administered PrNMI also dose-dependently suppressed CIPN allodynia symptoms in both male and female rats without any CNS side effects. Co-administration with selective cannabinoid receptor subtype blockers revealed that PrNMI's anti-allodynic effects are mediated by CB1 receptor (CB1R) activation. Expression of CB2Rs was reduced in dorsal root ganglia from CIPN rats, whereas expression of CB1Rs and various endocannabinoid synthesizing and metabolizing enzymes was unaffected. Daily PrNMI treatment of CIPN rats for two weeks showed a lack of appreciable tolerance to PrNMI's anti-allodynic effects. In an operant task which reflects cerebral processing of pain, PrNMI also dose-dependently suppressed CIPN pain behaviors. Our results demonstrate that PRCBs exemplified by PrNMI may represent a viable option for the treatment of CIPN pain symptoms.

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Background: Individuals with alcohol use disorder (AUD) exhibit maladaptive responses of the hypothalamic-pituitary-adrenal (HPA) axis to stress, which has been linked to high rates of relapse to drinking among abstinent individuals. Corticotropinreleasing factor (CRF) parvocellular neuroendocrine cells (PNCs) within the paraventricular nucleus of the hypothalamus (PVN) are critical to stress-induced HPA axis activation. Here, we investigate sex differences in synaptic transmission and plasticity in PNCs following the application of the stress-associated neurotransmitter norepinephrine (NE) in a rat model of AUD.Methods: Adult Sprague-Dawley rats were exposed to 40 days of chronic intermittent ethanol (CIE) vapor and 30 to 108 days of protracted withdrawal. We measured changes in holding current, evoked synaptic currents, and short-term glutamatergic plasticity (STP) in putative PNCs following the application of NE (10 μM) with and without the selective α1 adrenergic receptor (AR) antagonist prazosin (10 μM) or the α2AR antagonist atipamezole (10 μM). The experiments were performed using wholecell patch clamp recordings in slices from CIE rats and air-exposed controls.Results: NE application caused two distinct effects: a depolarizing, inward, postsynaptic current and a reduction in amplitude of an evoked glutamatergic excitatory postsynaptic current (eEPSC). Both effects were sex-and CIE-specific. Prazosin blocked the postsynaptic inward current, while atipamezole blocked the NE-mediated suppression of eEPSCs. Additionally, STP formation was facilitated following NE application only in stress-naïve males and this response was lost in stressed animals exposed to a 30-min restraint stress following CIE exposure. Furthermore, NE + prazosin restored STP formation in stressed CIE males.Conclusions: NE exerts excitatory and inhibitory effects on CRF PVN PNCs, and both effects are influenced by sex and CIE. Behavioral and hormonal responses to stress are influenced by STP formation within the PVN, which is lost following CIE and restored with the preapplication of prazosin. The selective blockade of α1AR may, therefore, ameliorate CIE-induced deficits in HPA responses to stress in a sex-specific manner.

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