Dorsomedial striatum calcium permeable AMPA receptors in the development of aversion-resistant alcohol drinking

Abstract Rationale Alcohol use disorder is defined by drinking alcohol despite knowledge of negative consequences, often referred to as aversion-resistant drinking (The dorsomedial (DMS) and dorsolateral striatum (DLS) are necessary for goal-directed and habitual action selection, respectively. Leading hypotheses posit that once drug use becomes compulsive, DMS dependence degrades while DLS dependence increases. This shift may be mediated by changes in synaptic weights from glutamatergic inputs. Objectives Using a combination of western-blot, micro-injections, and ex-vivo electrophysiology in male and female C57BL/6J mice, we investigated the role of α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors AMPAR, which drive glutamatergic transmission, during quinine-adulterated alcohol drinking in the DMS and DLS across the development of aversion-resistant drinking. Results We found that AMPAR subunit composition and function change in the DMS across the development of aversion-resistant drinking whereby, calcium permeable (CP) - AMPARs drive behavior. Western blots revealed a negative relationship between DMS GluA1 and quinine-adulterated alcohol drinking in alcohol naive mice and a positive relationship between DMS Glu A1/A2 ratios and quinine-adulterated alcohol drinking in aversion-resistant mice indicating that aversion-resistance positively predicts likelihood for CP-AMPAR expression in the DMS. Female aversion-resistant mice also had significant positive relationships with DMS or DLS Glu A1/A2 ratios and female aversion-resistant mice had a significant negative relationship with GluA2 and aversion-resistant alcohol drinking. DMS CP-AMPAR antagonism caused an increase in quinine-adulterated alcohol drinking in alcohol naïve mice suggesting that CP-AMPARs in the DMS prevent aversion-resistant drinking. Ex-vivo electrophysiology of DMS spiny projection neurons revealed that aversion-resistant drinking mice had greater inward rectification and CP-AMPAR antagonist sensitivity than alcohol naïve mice indicating that spiny projection neurons in the DMS express more CP-AMPARs following the development of aversion-resistant drinking. However, sensitivity to CP-AMPAR antagonism negatively predicted aversion-resistant drinking in alcohol history mice. Conclusions These data provide evidence that repeated alcohol binges alter DMS CP-AMPAR activity, where initial DMS activity acts to causally prevent aversion-resistant drinking but after repeated binges that result in aversion-resistant alcohol drinking, DMS spiny projection neurons recruit CP-AMPARs. CP-AMPAR antagonism was negatively association with aversion-resistant drinking within the alcohol history mice suggesting that plasticity of DMS CP-AMPARs is not related to quinine-sensitivity. These data provide evidence for a causal role of the DMS in aversion-resistant drinking and open questions as to the functional role of CP-AMPARs across the drinking history and striatal cell types.