Deficits in the extinction of ethanol-seeking behavior following chronic intermittent ethanol exposure are attenuated with positive allosteric modulation of mGlu5

Abstract

Alcoholism is a chronic relapsing disorder characterized by periods of heavy alcohol consumption and unsuccessful attempts at abstinence. Relapse is one of the most problematic aspects in the treatment of alcoholism and is triggered by ethanol-associated cues. Extinction-based cue exposure therapies have proven ineffective in the treatment of alcoholism. However, positive allosteric modulation of mGlu5 with CDPPB enhances the extinction learning of alcohol-seeking behavior. The current study investigated the impact of chronic alcohol exposure on the extinction of ethanol-seeking behavior. Adult Wistar rats were trained to self-administer alcohol with a light/tone stimulus serving as the alcohol cue. After training, one group of rats was exposed to chronic intermittent ethanol (CIE) daily for a period of 2 weeks to induce ethanol dependence. Control rats were exposed to air for the same period of time. Both groups were then retrained to self-administer ethanol and subsequently tested for changes in extinction learning. CIE exposed rats consumed more ethanol compared to their pre-CIE levels and to control rats. During extinction training, CIE rats responded significantly more on the previously active lever and required more sessions to reach extinction criteria compared to control rats. Treatment with CDPPB facilitated extinction in control rats and attenuated the increased resistance to extinction in CIE-exposed rats. These results demonstrate that chronic ethanol exposure not only alters ethanol intake, but also the extinction of ethanol-seeking behaviors. The ability to attenuate deficits through modulation of mGlu5 provides a potential target for pharmacological manipulation that could ultimately reduce relapse in alcoholics.

Metabotropic Glutamate Receptors in Alcohol Use Disorder: Physiology, Plasticity, and Promising Pharmacotherapies

“…21 These effects are dependent on the inhibition of SK channels and persist in a model of ethanol dependence. 162 On the other hand, systemic administration of an mGlu 5 NAM reduces ethanol-induced, 144 cue-induced, 148,163 and stress-induced 137 reinstatement, and receptors located in the BLA and NAC appear to be particularly important for these effects. An agonist of mGlu 2/3 receptors blocked both stress-and cue-induced reinstatement of ethanol seeking, and actions within the extended amygdala may be particularly relevant for these effects.…”

Allosteric Modulation of GPCRs: New Insights and Potential Utility for Treatment of Schizophrenia and Other CNS Disorders

“…However, these findings also raise the question of what signaling pathways and physiological responses are critical for specific in vivo actions of mGlu 5 PAMs. As new tools are further developed that selectively modulate specific signaling pathways by mGlu 5 , they will provide opportunities to develop a full understanding of the specific signaling pathways that are critical for mediating the efficacy of mGlu 5 PAMs in preclinical models of numerous CNS disorders including schizophrenia, fragile X syndrome, Rett syndrome, autistic spectrum disorders, obsessive compulsive disorder, Parkinson's disease, substance abuse (Ade et al, 2016; Gass et al, 2016; Gogliotti et al, 2016; Gould et al, 2016; Michalon et al, 2012; Rylander et al, 2010; Vicidomini et al, 2016), and others.…”

Compulsivity in Alcohol Use Disorder and Obsessive Compulsive Disorder: Implications for Neuromodulation

“…In other words, although alcohol seeking is initially a goal-directed behavior consolidated by operant conditioning, in which alcohol is sought for its rewarding effect, it becomes ultimately a maladaptive optimized response elicited by alcohol-associated stimuli, characterized by over-active striatal habit forming circuitries coupled with lack of sufficient inhibitory control (Chamberlain et al, 2005; Vanderschuren and Everitt, 2005; Menzies et al, 2008; Smith et al, 2014). As seen in OCD, there is a lack of extinction of obsessions (Lovibond et al, 2009), in AUD there is disruption in extinction learning of ethanol-seeking behavior with persistency of the behavior overtime despite adverse consequences (Gass et al, 2017; Grodin et al, 2018). Development of compulsivity may thus explain part of the treatment resistance and relapse in AUD (Sinha et al, 2011; Courtney et al, 2013; Lee et al, 2013).…”