Alcohol-dependent patients commonly show problems in executive functions that facilitate craving and can lead to relapse. However, the molecular mechanisms leading to executive dysfunction in alcoholism are poorly understood. A team from the Central Institute of Mental Health (Mannheim, Germany) identified molecular alterations in alcoholism that are responsible for both impaired executive control and alcohol craving. In preclinical research psychedelics were able to restore the molecular deficits and reduce relapse behaviour.
Alcohol consumption is widespread, but it is also an important cause of morbidity and mortality worldwide. Most people can control their alcohol drinking behaviour, but some become excessive drinkers and may eventually develop a problematic alcohol use disorder (AUD). The clinical presentation of the disorder is very heterogeneous, but it is often accompanied by deficits in executive functions, i.e., impairments in higher cognitive abilities involved in self-control, emotion regulation, motivation, working memory, decision-making, attention, and cognitive flexibility.
Clinically, excessive alcohol use in humans causes damage in the prefrontal cortex, leading to strong cravings for alcohol, as well as impaired cognitive functioning. Metabotropic group II glutamate receptors have recently attracted much interest in addiction research because of their abundance in the pathway from the medial prefrontal cortex (mPFC) to the nucleus accumbens (NAc), which mediates substance craving and relapse, as well as cognitive flexibility.
During Insight 2021 Marcus Meinhardt, from the Central Institute of Mental Health Mannheim, presented preclinical data from his group's research into the hypothesis of using psychedelics as a treatment for problematic alcohol use. Dr. Meinhardt's presentation focused on the role of the mGluR2 (metabotropic glutamate receptor 2) receptor, which is thought to be a particularly important target of drug-induced neuroadaptations, since it has been reported that long-term exposure to drugs of abuse causes its downregulation and impaired function.
Data show that alcohol dependence, both in humans (brain sections from cadavers of subjects with AUD were analysed) and in rats, leads to a long-lasting downregulation of mGluR2 expression, particularly in the infralimbic subregion of the mPFC, which is associated with a loss of control over alcohol-seeking behaviour in rats. Furthermore, that mGluR2 can modulate cognitive flexibility and that its stimulation improves cognitive flexibility in rats.
To test the hypothesis that mGluR2 dysfunction in the mPFC may comprise a common molecular mechanism for deficits in different behavioural domains, Meinhardt's team assessed cognitive flexibility in alcohol-dependent rats. Their results identify a deficit of mGluR2 in the mPFC as a common pathological mechanism that is necessary and sufficient for both increased craving and reduced cognitive flexibility in rats, identifying mGluR2 activation as a potential therapeutic mechanism in alcohol dependence.
The role of mGluR2 could open the door to a therapeutic use of psychedelics in AUD patients. Indeed, classic psychedelics, such as LSD or psilocybin, act by stimulating serotonin 2A receptors (5-HT2AR) in the brain. These receptors are expressed in large quantities in the cortex, especially in the high-level regions of the brain's functional hierarchy.
Previous research has shown that 5-HT2AR and mGluR2 can assemble and form a single functional complex, modulating each other's functions. This heteromeric complex has been implicated in the mechanism of action of psychedelics (altered head contraction response in the presence of mGluR2/3 agonists, antagonists and mGluR-selective positive allosteric modulators). The necessity of mGluR2 in evoking the head contraction response has already been demonstrated in mGluR2 knockout mice in two independent studies.
Preclinical studies by Dr. Meinhardt's group suggest that psilocybin is able to increase mGluR2 levels, leading to a decrease in craving and relapse. According to Meinhardt, these preclinical results already provide support for considering mGluR2 the molecular target for the treatment of reduced cognitive flexibility, craving and relapse responses in alcohol-dependent patients, and suggest the possibility of clinical translation, for example by running an experimental medicine trial in alcohol-dependent patients to demonstrate improved cognitive flexibility in response to a single administration of an allosteric modulator.
Meinhardt M, Psychedelics as a Treatment for Alcohol use Disorder: Insights from Preclinical Models, Insight 2021