The Neurobiology of Addiction Research Center (NARC)
N-acetylcysteine reduces adolescent marijuana use. (10/31/12)
Dr. Kevin Gray in the Department of Psychiatry at MUSC and his colleagues demonstrated that N-acetylcysteine given over the course of 8 weeks to adolescent marijuana users reduced their use of marijuana. This was a double-blind randomized clinical trial with 116 participants ages 15-21 years. Adolescents receiving N-acetylcysteine had more that twice the odds, compared to those receiving placebo, of having negative urine cannabinoid (an active ingredient in marijuana) test results during treatment. This is the first randomized trial ever to show positive primary cessation outcome data for a pharmacotherapy in marijuana dependence.
This research was recently published in the American Journal of Psychiatry.
Gray, KM et al., A double-blind randomized controlled trial of N-actylcysteine in cannabis-dependent adolescents. American Journal of Psychiatry, 169: 805-12, 2012.
Dr. Kevin Gray is an Associate Professor of Psychiatry at MUSC, and is the recipient of a NARC pilot award to support his studies on the use of N-acetylcysteine to treat cocaine relapse. His work is based on 8 years of basic and clinical research by NARC faculty showing that N-acetylcysteine treatment reduces relapse and/or use of cocaine, marijuana, nicotine and heroin.
The figure above shows that there were more marijuana negative urines in adolescents while they were taking N-acetylcysteine, thank those taking placebo control.
Cocaine relapse causes rapid changes the structure and strength of neuronal connections. (01/15/13)
Drs. Cassandra Gipson, Yonatan Kupchik and Hao-wei Shen shared first authorship on a recent publication in Neuron using a rat model of cocaine relapse to show that when cocaine-addicted rats relapse there is a rapid increase in the size and strength of neuronal connections (synapses) in a brain region called the nucleus accumbens. These changes were correlated with the intensity of relapse, supported a causal link. Rats were trained to self-administer cocaine, then after two weeks of withdrawal relapse was induced by showing the rats a light/tone cue that had previously been shown only when cocaine was self-administered. This reminded the rats of cocaine and caused them to relapse (i.e. press the lever previously used to deliver cocaine). 15 min after inducing relapse synaptic connections were increased in size and strength, and went back to pre-relapse levels by 45 min, at the same time the relapse-induced lever pressing ended.
Gipson, CD, KUpchik, YM, Shen HW, et al. Relapse induced by cues predicting cocaine depends on rapid, transient synaptic potentiation. Neuron, in press, 2013.
Drs. Gipson and Kupchik are postdoctoral fellows in the lab of Dr. Kalivas, and Dr. Shen is an Assistant Professor at Peking University in Beijing. This work was completed as part of Project 1 in the NARC.
The figure above shows the increase in the size of dendritic spines (where synaptic connections are made) during cocaine relapse. Yoked saline in a control animal that never had cocaine, T=0 is from an animal trained to self-administer cocaine but before inducing relapse with conditioned cues, and T=15 shows the dendritic spines at 15 minutes after inducing relapse. Notice how much bigger the spines are in the animal that has relapses for 15 min.
Cocaine relapse after abstinence is regulated by protein phosphorylation in the prefrontal cortex
Using the same cocaine self-administration procedure used in Project 1 above, Wei-Lun Sun, Ph.D., a postdoctoral fellow in Dr. Jacqueline McGinty’s laboratory, found that the activity of learning and memory proteins in the prefrontal cortex and nucleus accumbens that are regulated by cyclic AMP-dependent protein kinase, is increased during abstinence from cocaine. When a light/tone cue that had previously been shown only when cocaine was self-administered caused the rats to relapse, the activation of these proteins was reduced. Further, when the cAMP kinase was inhibited by infusion of a drug into the prefrontal cortex, relapse to cue-induced cocaine seeking was decreased. Thus, by inhibiting cAMP kinase, relapse reverses abstinence-induced neuroadaptations in the addiction circuitry that are responsible, in part, for the ability of environmental cues to induce cocaine seeking.
Figure 1. Top. The average number of active and inactive lever responses during the last 3 sessions of yoked-saline or cocaine SA (left) and lever responses during a 30 min cue-induced relapse after 7 days of abstinence (right) (***p<0.001, cocaine self administration versus yoked-saline; #p<0.0001 active lever responses during cue test versus during cocaine self administration. Bottom. The average lever responses during the last 3 sessions of cocaine self administration (left) and the lever responses during a cue-induced relapse test 30 min after intra-dmPFC infusion (right). (*p<0.05 compared with vehicle-infused group; #p<0.01 when compared with active lever pressing during cocaine.
Figure 2. Protein levels of p-CREB (A), and p-GluA1 (B) in the dmPFC after abstinence or relapse (*p<0.05 and **p<0.01 compared to saline controls. (C) Protein level of p-synapsin I Ser9 in the NAc after abstinence or relapse (*p<0.05 compared with saline controls). S=saline; C=cocaine.