Functional role for cortical-striatal circuitry in modulating alcohol self-administration

Abstract

The cortical-striatal brain circuitry is heavily implicated in drug-use. As such, the present study investigated the functional role of cortical-striatal circuitry in modulating alcohol self-administration. Given that a functional role for the nucleus accumbens core (AcbC) in modulating alcohol-reinforced responding has been established, we sought to test the role of cortical brain regions with afferent projections to the AcbC: the medial prefrontal cortex (mPFC) and the insular cortex (IC). Long-Evans rats were trained to self-administer alcohol (15% alcohol (v/v)+2% sucrose (w/v)) during 30 min sessions. To test the functional role of the mPFC or IC, we utilized a chemogenetic technique (hM4D-Designer Receptors Activation by Designer Drugs) to silence neuronal activity prior to an alcohol self-administration session. Additionally, we chemogenetically silenced mPFC→AcbC or IC→AcbC projections, to investigate the role of cortical-striatal circuitry in modulating alcohol self-administration. Chemogenetically silencing the mPFC decreased alcohol self-administration, while silencing the IC increased alcohol self-administration, an effect absent in mCherry-Controls. Interestingly, silencing mPFC→AcbC projections had no effect on alcohol self-administration. In contrast, silencing IC→AcbC projections decreased alcohol self-administration, in a reinforcer-specific manner as there was no effect in rats trained to self-administer sucrose (0.8%, w/v). Additionally, no change in self-administration was observed in the mCherry-Controls. Together these data demonstrate the complex role of the cortical-striatal circuitry while implicating a role for the insula-striatal circuit in modulating ongoing alcohol self-administration.

Perineuronal Nets in the Insula Regulate Aversion-Resistant Alcohol Drinking

“…The deficits in insula volume could be caused by chronic alcohol exposure, or could be a predisposing factor for AUD. In rats, chemogenetic silencing of the anterior insula increases alcohol self-administration (11). Together, these studies indicate that individuals with AUD are unable to appropriately engage the insula during risky decisionmaking because of structural deficits in the insula.…”

“…Similarly, chemogenetic silencing of insula projections to the nucleus accumbens decreased alcohol self-administration and potentiated the subjective, or interoceptive, effects of alcohol in rats (10)(11)(12). Analogous behavioral studies in humans showed that heavy drinkers attempted to earn more alcohol drinks than light drinkers under threat of shock and exhibited greater connectivity between the insula and nucleus accumbens, a brain region involved in motivation and reward, when viewing shock-predictive alcohol cues (3).…”

Alterations in White Matter Microstructure and Connectivity in Young Adults with Alcohol Use Disorder

“…The insula is an important neural substrate for reward and addiction (Droutman et al., ; Naqvi et al., ) and is critical for mediating cue‐induced craving that can drive drug use (Droutman et al., ; Naqvi et al., ). This is supported by rodent models of alcohol addiction, which have shown that disrupting excitatory insular‐striatal circuitry decreases alcohol self‐administration and increases sensitivity to alcohol (Jaramillo et al., ,). Decrements in FA in the vicinity of the insula in our young adult AUD sample may lead to impaired ability to detect changes in internal states such as alcohol intoxication (Berk et al., ; Migliorini et al., ).…”

Insular Cortex Projections to Nucleus Accumbens Core Mediate Social Approach to Stressed Juvenile Rats

“…Recent reports in drug administration models show excitaiton of IC projections to central amygdala promote relapse of methamphetmaine use (Venniro et al, 2017) and IC projections to the bed nucleus of the stria terminalis mediate negative affect during alcohol abstinence (Centanni et al, 2019). Similarily, silencing of the IC projection to NAc decreased alcohol self-administration (Jaramillo et al, 2018b) and increased sensitivity to alcohol (Jaramillo et al, 2018a), and IC projections to cthe entral amydala drive avoidance of an avertisve tastant (Schiff et al, 2018). While more work will add clarification, an emergent theme is that IC mediates both appetitive and aversive behavioral responses to external stimuli via different projections.…”

“…has been used to investigate IC projections to NAc and central amygdala in different paradigms (Jaramillo et al, 2018a;Venniro et al, 2017). Therefore, we first sought to replicate our prior finding and establish feasibility of chemogenetic control of IC neurons by using the inhibitory chemogenetic hM4Di receptor expressed in neurons under control of the synapsin promoter.…”