Brain region activation across acute and protracted alcohol withdrawal in male mice

Abstract

Alcohol use disorder (AUD) remains a significant public health issue, with high relapse rates complicated by its poorly understood neurochemical mechanisms. Both acute and protracted withdrawal symptoms contribute to relapse vulnerability, yet the brain regions involved in the development of these symptoms have not been extensively studied in this context. This study aims to bridge this gap of knowledge by investigating changes in the Ventral Tegmental Area (VTA), Habenula (Hb), and Mesopontine Tegmentum (MPT), areas that literature suggests may have plausible involvement, during acute and protracted alcohol withdrawal in male mice. Mice underwent 9 days of passive alcohol administration (2.5 g/kg, i.p. with 4-Methylpyrazole) and brain tissue was collected at either 24 hours (acute), or 7 days (protracted) after cessation. Brain region activity was assessed using immunohistological labeling of cFos as a proxy for neuron activation. During acute withdrawal, we observed a significant decrease in the activity of cholinergic neurons in the Pedunculopontine Tegmental Nucleus (PTg) but found no substantial changes in the other regions listed above. Activity in the Lateral Habenula (LHb), and specifically, cholinergic activity in the MPT, increased during protracted withdrawal. No changes were observed in the VTA or Medial Habenula at 7-day withdrawal. These findings suggest that the LHb and MPT may play a role in modulating neurochemical changes resulting from alcohol withdrawal. Further investigation into these regions may provide insight on the neural basis of relapse vulnerability and lead to more efficacious treatments for AUD.