Prefrontal Electrophysiological Biomarkers and Mechanism-Based Drug Effects in a Rat Model of Alcohol Addiction

Current treatments for alcohol use disorder (AUD) are often ineffective due to large variability in individual responses and high relapse rates. A precision medicine approach using biomarkers of prefrontal control mechanisms—which are severely disrupted in AUD, reducing inhibitory control and promoting compulsive behavior and relapse—may improve outcomes. In a rat model of alcohol addiction and relapse, a biocompatible neuroprosthesis measured prefrontal neural function during abstinence. Alcohol-dependent rats showed reduced amplitudes of P1N1 and N1P2 event-related potential components and attenuated event-related oscillatory activity. Treatment with psilocybin (a 5-HT2AR agonist) or LY379268 (an mGluR2 agonist) restored these impairments. Psilocybin also counteracted a dominance in higher beta frequencies indicative of hyperarousal prone to relapse. These findings identify prefrontal markers of relapse and treatment response, particularly for psychedelic drugs.

Study at a glance

Abstract

Abstract Current treatments for alcohol use disorder (AUD) show large heterogeneity in response and thus limited effectiveness and high relapse rates. A precision medicine approach with biomarkers responsive to new treatments is warranted to overcome this limitation. Promising biomarkers relate to prefrontal control mechanisms that are severely disturbed in AUD. This results in reduced inhibitory control of compulsive behavior and, eventually, relapse. We reasoned here that prefrontal dysfunction, which underlies vulnerability to relapse, is evidenced by altered neuroelectric signatures and should be restored by pharmacological interventions that specifically target prefrontal dysfunction. To test this, we applied our recently developed biocompatible neuroprosthesis to measure prefrontal neural function in a well-established rat model of alcohol addiction and relapse. We monitored neural oscillations and event-related potentials in awake alcohol-dependent rats during abstinence and following treatment with psilocybin or LY379268, agonists of the serotonin 2A receptor (5-HT2AR) and the metabotropic glutamate receptor 2 (mGluR2), that are known to reduce prefrontal dysfunction and relapse. Electrophysiological impairments in alcohol-dependent rats are reduced amplitudes of P1N1 and N1P2 components and attenuated event-related oscillatory activity. Psilocybin and LY379268 were able to restore these impairments. Furthermore, alcohol-dependent animals displayed a dominance in higher beta frequencies indicative of a state of hyperarousal that is prone to relapse, which particularly psilocybin was able to counteract. In summary, we provide prefrontal markers indicative of relapse and treatment response, especially for psychedelic drugs.