Stress and Addiction Neuroscience Unit

National Institute On Drug Abuse

Investigators

Linked publications, trials & patents

Abstract

The Stress and Addiction Neuroscience Unit (SANU) advanced understanding of molecular and circuit mechanisms underlying alcohol and substance use disorders through integrated preclinical studies. We demonstrated that alcohol differentially regulates the cyclic AMP cascade depending on exposure pattern. Using a PDE4B-preferring PET radioligand, we showed that acute alcohol increases, whereas chronic alcohol dependence reduces, radioligand binding in the rat brain. These findings highlight PDE4B as both a biomarker and potential therapeutic target, complementing ongoing clinical evaluation of PDE4 inhibitors for alcohol use disorder (AUD). Building on prior evidence that ghrelin receptor (GHSR) antagonism reduces binge-like drinking, we found that blockade of β1-adrenergic receptors, which regulate peripheral ghrelin release, does not prevent the effects of central GHSR antagonists. These results suggest that central GHSR activity, rather than circulating ghrelin, drives binge-like alcohol drinking, supporting both GHSRs and β1ARs as therapeutic targets. In parallel, work with GHSR knockout rats showed protection against diet-induced obesity, with sex-specific effects on thermogenesis, brain glucose metabolism, and fat oxidation. These findings emphasize the role of GHSR in energy balance and reward-related behaviors. We investigated interactions between the oxytocin and opioid systems in emotion regulation. μ-Opioid receptor blockade potentiated, while κ-opioid receptor blockade inhibited, oxytocin’s anxiolytic-like effects, indicating that endogenous opioids critically shape oxytocin signaling in stress-related behaviors. Separately, we validated the elevated zero maze as a model of anxiety-like behavior and discovered that the commonly used vehicle Kolliphor (a castor oil derivative) exerts its own anxiolytic-like effects. These results underscore the importance of vehicle choice in behavioral pharmacology and suggest novel bioactive properties of castor oil and ricinoleic acid. In models of cocaine use disorder (CUD), we found that negative allosteric modulation of metabotropic glutamate receptor subtype 5 (mGlu5) reduces escalated cocaine self-administration under long-access conditions without locomotor effects. These results support mGlu5 as a promising target for clinical evaluation in CUD. Together, these studies identify novel molecular targets (PDE4B, GHSR, β1AR, mGlu5), clarify receptor interactions (oxytocin–opioid crosstalk), and refine behavioral models (zero maze, vehicle effects) relevant to stress and addiction. SANU’s work integrates molecular imaging, receptor pharmacology, and behavioral neuroscience to inform translational strategies for the prevention and treatment of alcohol and substance use disorders.