The prevalence and impact of drug addiction on society are staggering. The abuse of alcohol, tobacco, and illicit drugs accounts for approximately 10% of the global burden of disease, and for the United States, it is estimated that substance use disorders affect 20.4 million individuals.1 Despite the deleterious economic and social consequences of drug use, approved medications to treat substance use disorders are few or absent depending on the drug. We and others have explored the possibility that dysregulation in prefrontal and allocortical (amygdala and hippocampus) glutamatergic inputs to the basal ganglia may be a mechanism responsible for relapse that is shared between classes of addictive drugs, as well as other disorders characterized by maladaptive compulsive behavior. Herein, we describe the bench-to-bedside chronology of preclinical discovery and clinical trials that led to the cysteine prodrug N-acetylcysteine being evaluated for the treatment of substance abuse and compulsive disorders.
The upper drawing is the control situation where glial glutamate uptake via glial glutamate transporter 1 (GLT1) is normal, thereby limiting access of synaptically released glutamate to extrasynaptic glutamate receptors, including metabotropic glutamate receptors (mGluRs) and N-methyl-d-aspartate (NMDA) receptors expressing the GluN2B subunit. After long-term drug use, glutamate uptake via GLT1 is downregulated. Thus, when an addict experiences drug-associated stimuli that can precipitate relapse, the corresponding release of glutamate more readily overflows the synaptic cleft to stimulate postsynaptic mGluR5 and NMDA receptors, which in turn increases AMPA signaling (elevated number of AMPA receptors) and synapse size, thereby potentiating synaptic activity. Supporting excessive presynaptic glutamate release, signaling via inhibitory presynaptic mGluR2 autoreceptors is reduced after long-term drug use. N-acetylcysteine restores GLT1, thereby normalizing synaptic potentiation by drug-associated stimuli and inhibiting relapse. Increases and decreases in signaling and glutamate uptake are indicated by larger or smaller arrowheads, respectively.
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