Inhibiting CRF-projections from the Central Amygdala to Lateral Hypothalamus blunts Ethanol Binge-Drinking in Male Mice only with no such changes following inhibition of GABAergic Projections

Corticotrophin releasing factor (CRF) neuropeptides within the central amygdala (CeA) and lateral hypothalamus have been implicated in binge-like ethanol drinking in rodent models. The CeA is a particularly important region in relation to Alcohol Use Disorders, as it integrates neurobiological responses to stress and reward to form behavioral responses via the CRF system. CRF also plays a major role in the lateral hypothalamus (LH) to activate that area during anxiety and reward behavior in response to ethanol consumption. To investigate the role of CRF in these anxiety and reward pathways, chemogenetic approaches were used on male and female cre-mouse lines. Results (in collaboration with Drs. Jose Manuel Lerma-Cabrera and Francisca Carvajal) show interesting sex-differences regarding the CeA-LH pathway. Placing the Gi DREADD into the CeA, and activating it with CNO injections from the LH, a sex-specific reduction in ethanol drinking was found in males only, with no such effect during sucrose drinking. Furthermore, this sex-effect during ethanol consumption was not seen using a control DREADD, which suggests direct involvement of the CRF pathway between the CeA and LH during ethanol consumption. Via pharmacological blunting of CRF1 receptors (CRF1R) and activating CRF2 receptors (CRF2R) in the LH, we also saw male-specific reductions in binge-like ethanol consumption, which suggests a reciprocal receptor mechanism in the CeA to LH pathway that is sex-specific. On the other hand, general inhibition of GABAergic projections in the CeA to LH pathway failed to alter binge-like ethanol intake. The present results indicate that CRF+ neuron in LH-projecting CeA neurons modulate ethanol consumption in male mice only, suggesting that there might be differential functioning in CRF signaling between males and females.Master of Art