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.
Thank you for submitting a comment on this article. It will be reviewed by JAMA Psychiatry editors. You will be notified when your comment has been published. Comments should not exceed 500 words of text and 10 references.
Do not submit personal medical questions or information that could identify a specific patient, questions about a particular case, or general inquiries to an author. Only content that has not been published, posted, or submitted elsewhere should be submitted. By submitting this Comment, you and any coauthors transfer copyright to the journal if your Comment is posted.
* = Required Field
Disclosure of Any Conflicts of Interest*
Indicate all relevant conflicts of interest of each author below, including all relevant financial interests, activities, and relationships within the past 3 years including, but not limited to, employment, affiliation, grants or funding, consultancies, honoraria or payment, speakers’ bureaus, stock ownership or options, expert testimony, royalties, donation of medical equipment, or patents planned, pending, or issued. If all authors have none, check "No potential conflicts or relevant financial interests" in the box below. Please also indicate any funding received in support of this work. The information will be posted with your response.
Some tools below are only available to our subscribers or users with an online account.
Download citation file:
Web of Science® Times Cited: 1
Customize your page view by dragging & repositioning the boxes below.
More Listings atJAMACareerCenter.com >
All results at
Enter your username and email address. We'll send you a link to reset your password.
Enter your username and email address. We'll send instructions on how to reset your password to the email address we have on record.
Athens and Shibboleth are access management services that provide single sign-on to protected resources. They replace the multiple user names and passwords necessary to access subscription-based content with a single user name and password that can be entered once per session. It operates independently of a user's location or IP address. If your institution uses Athens or Shibboleth authentication, please contact your site administrator to receive your user name and password.