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mGluR's and decreases synaptic glutamate release. Therefore, downregulation of xc- will lead to less extrasynaptic glutamate, a reduction in inhibitory tone and ultimately in enhanced synaptic glutamate release probability upon cocaine administration (Fig. 3). These presynaptic effects lead to long-term postsynaptic adaptations. Changes in dendritic spine density and morphology have been well established, which could be a result of an underlying increase in actin cycling. A reduction in Lim kinase which regulates F-actin depolymerization and spine maturation may contribute to the cocaine-induced increase in actin cycling. In addition, there is a decrease in Homer 1b/c and 2a/b scaffold proteins in the NA, which colocalizes with F-actin/Shank/PSD-95/GKAP/NMDA complexes. Additional postsynaptic effects include the membrane insertion of AMPA glutamate receptors and an inability to induce long-term depression (LTD). Controversy remains, since the inability to induce LTD is normally associated with a decrease in AMPA receptors.

As mentioned earlier the emerging view that cocaine dependence is a learning and memory disorder could lead to pharmacotherapy development related to reverting compulsive relapse to regulated relapse. These include normalizing glutamatergic neurotransmission either by altering glutamate levels in the PFC or glutamate receptor activity in the striatum. For example, ► N-acetylcysteine which is a cysteine pro-drug used in treating acetaminophen overdose, has been examined for its potential in affecting relapse, as it appears to increase cystine-glutamate exchange activity and thereby restore inhibitory tone on presynaptic metabotropic glutamate receptors. In fact, recent clinical trials have supported a role for N-acetylcysteine in the treatment of drug addiction. In 23 treatment-seeking cocaine-dependent patients, doses of 1,200, 2,400, or 3,600 mg/day were well tolerated. The majority of subjects either stopped using cocaine or significantly reduced their use of cocaine during treatment. Furthermore, in a crossover, double-blind, placebo-controlled inpatient trial, 15 cocaine-dependent participants received four doses of 600 mg N-acetylcysteine or placebo. After the final dose, participants completed a cue-reactivity procedure that involved presentations of four categories of slides (cocaine, neutral, pleasant, and unpleasant). Each participant rated how

Cocaine Dependence. Fig. 3. Molecular changes associated with glutamate synapses after chronic cocaine use. In a drug-naïve state, extrasynaptic glutamate provides inhibitory tone via the mGluR's on the presynaptic inputs from the PFC, thus preventing an increase in glutamate levels when cocaine is administered. Chronic cocaine use leads to the downregulation of system xc- and therefore less extrasynaptic glutamate. This decrease in glutamate results in a reduction in inhibitory tone (from the presynaptic mGluR's) and ultimately in enhanced synaptic glutamate release probability upon cocaine administration. In addition, there is a reduction in Lim kinase, Homer 1b/c and 2a/b scaffold proteins in the NA, which colocalizes with F-actin/Shank/PSD-95/GKAP/NMDA complexes and AMPA receptors are inserted into the membrane.

much craving, desire to use cocaine, and interest was evoked by each slide on a 21-point Likert scale. N-acetylcysteine significantly reduced the desire to use cocaine, interest in cocaine, and cue viewing time in these patients. Other potential new treatment strategies based on regulating glutamate transmission include the modulation of mGluR's. These include the mGluR2/3 agonist LY379268 ((—)-2-oxa-4-aminobicyclo[3.1.0]hex-ane-4,6-dicarboxylic acid), which is effective in inhibiting cocaine seeking in preclinical animal models and could decrease stress-induced relapse due to its anxiolytic effects. Similarly, the mGluR1/5 antagonists, 2-methyl-6-(pheny-lethynyl) pyridine (MPEP) and its analog 3-[(2-methyl-4-thiazolyl)ethynyl]pyridine (MTEP) have shown to be effective in preclinical models of cocaine addiction.

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