Prefrontal sigma-1 receptors in alcohol use disorder and cognitive functioning
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INTRODUCTION: Alcohol Use Disorder (AUD) is a chronic relapsing condition characterized by compulsive, uncontrolled consumption of alcohol. AUD is also characterized by impairments in decision making, driven by dysregulation of prefronto-cortical regions, including the anterior cingulate cortex (ACC) and medial prefrontal cortex (mPFC). Little is known about the neurotransmitter systems involved in both the excessive, compulsive drinking and the cognitive deficits observed in alcohol addiction. The Sigma 1 Receptor (Sig-1R) system has been suggested as a novel target for the treatment of addictive disorders, due to its ability to modulate the rewarding and reinforcing effects of multiple drugs of abuse, including alcohol. OBJECTIVE: The goal of the present study was to examine the role of Sig-1Rs in prefronto-cortical regions in alcohol addiction-relevant behaviors, including alcohol self-administration, motivation to work to obtain alcohol, compulsive alcohol seeking, and cognitive flexibility. METHODS: Male Wistar rats were microinfused with a viral vector containing either a Sig-1R knockdown shRNA (Sig-1R-knockdown) or GFP-Control in prefrontal regions, which encompassed the mPFC and the ACC. Rats were trained to self-administer alcohol under increasing fixed-ratio (FR) schedules of reinforcement, as well as a progressive-ratio (PR) schedule of reinforcement, a measure of motivation to work to obtain alcohol. Animals were then trained to seek and take alcohol on a chained-schedule of reinforcement; in addition, to test compulsive alcohol seeking in the face of aversive consequences, a footshock punishment was introduced following the completion of a seeking response cycle. To test whether prefrontal Sig-1R-knockdown affected anxiety-like behavior, rats were subject to a light/dark box test, which involves allowing rats to move freely between a light and a dark compartment. The latency to leave the dark compartment and the amount of time spent in the light compartment were used as measures of anxiety-like behavior. A secondary aim of the study was to start investigating the effects of prefrontal Sig-1R-knockdown on cognitive flexibility. Alcohol naïve rats were tested in an operant attentional set-shifting paradigm, where rats were initially trained to lever press for a reward using a visual-cue strategy. Rats were then subsequently trained to lever press for a reward using a spatial response strategy. Thus, during this “set-shift,” rats were required to extinguish the use of the visual-cue and return to using the spatial response strategy for obtaining a reward. Finally, the spatial strategy rule was inverted in a reversal task. In both the attentional set-shifting and reversal tasks, a greater number of previously reinforced errors (e.g. perseverative responding) was considered to reflect lower cognitive flexibility. RESULTS: Prefrontal Sig-1R-knockdown resulted in significantly higher responding for alcohol under high-effort conditions (FR3 and FR5) and higher motivation for alcohol (PR). In the compulsive alcohol seeking task, while GFP-Control animals decreased seeking lever responses after the addition of the aversive footshock consequence, Sig-1R-knockdown animals showed no significant changes in lever responses. In the light/dark test, Sig-1R-knockdown animals displayed decreased latencies to enter the light compartment, possibly indicating lower anxiety-like behavior as compared to the GFP-Controls. In an attentional set-shifting task, Sig-1R-knockdown animals committed a greater number of perseverative errors during the shift to response discrimination strategy than GFP-Controls, indicating some deficits in cognitive flexibility. CONCLUSION: Prefrontal Sig-1R-knockdown resulted in greater alcohol responding, motivation, and compulsive seeking behavior. Additionally, prefrontal Sig-1R-knockdown reduced cognitive flexibility in an operant attentional set-shifting task in alcohol-naïve rats. Results from these experiments support a key role for prefrontal Sig-1Rs in alcohol addiction and cognitive flexibility.