Converging Effects of Chronic Pain and Binge Alcohol Consumption on Corticostriatal Neurons and the Effects of Acute Alcohol Exposure on the Medial Prefrontal Cortex

Chronic pain and alcohol use disorder (AUD) are highly comorbid, but whether the two conditions share common brain pathways is unclear. Prior work shows that the anterior insular cortex (AIC) is involved in both chronic pain and alcohol use disorder. However, circuit-specific changes elicited by the combination of pain and alcohol use remain understudied. The goal of this work was to elucidate the converging effects of binge alcohol consumption and chronic pain on AIC neurons that send projections to the dorsolateral striatum (DLS). Here, we used the Drinking-in-the-Dark paradigm to model binge-like alcohol drinking in mice that underwent spared nerve injury (SNI). We found that SNI male mice with no prior alcohol exposure consumed less alcohol compared to sham mice. Electrophysiological analyses showed that AIC-DLS neurons from SNI-alcohol male mice displayed increased neuronal excitability and increased frequency of miniature excitatory postsynaptic currents. However, mice exposed to alcohol prior to SNI consumed similar amounts of alcohol compared to sham mice following SNI. Together, our data suggest that the pain and alcohol interaction can sensitize the AIC-DLS circuit in mice, which may be critical in understanding how chronic pain alters motivated behaviors associated with alcohol. My second goal was to assess the acute pharmacological effects of alcohol on prodynorphin-expressing neurons in the prelimbic cortex (PLPdyn+), a subregion of the medial prefrontal cortex (mPFC). Kappa opioid receptor (KOR) system dysregulation contributes to alcohol addiction. Prodynorphin (Pdyn) is the precursor peptide to the endogenous opioid ligand for KORs. Early studies demonstrated that acute alcohol exposure elevates Pdyn mRNA expression in the mPFC. However, its functional effects on Pdyn-expressing neurons are not known. Here, we used whole-cell patch-clamp electrophysiology in acute brain slices and glutamate-uncaging via laser scanning photo to map local excitatory and inhibitory inputs onto PL neurons. We found that acute alcohol increases local inhibitory inputs to both layer 2/3 PLPdyn+ and PLPdyn- neurons but has no effect on excitatory inputs. Under untreated conditions, PLPdyn+ neurons show stronger local excitatory inputs compared to PLPdyn- neurons. Overall, these data suggest that acute alcohol intoxication inhibits intracortical circuit of PL neurons regardless of neuronal subtypes.