Compounds in the first category are likely to be the most specific for psychostimulant addiction, and perhaps carry the least number of unwanted side effects, while the latter category may be less selective not only regarding effects on other

addictive drugs, but also in terms of unwanted side effects. Table I lists some potential pharmacotherapeutic targets according to these two categories. Table I. List of compounds that affect glutamate neurotransmission Inhibitors,research,lifescience,medical with potential pharmacotherapeutic value in treating addiction to amphetamine-like psychostimulants. mGluR2/3, metabotropic glutamate receptors; GABA, γ-aminobutyric acid; AMPA, α-amino-3-hydroxy-5-methylisoxazole-4-propionic

… Neuroplasticity produced by chronic cocaine Inhibitors,research,lifescience,medical administration that could potentially contribute to pathological glutamate release includes downregulation of cystine-glutamate exchange, downregulation of glial glutamate transporters, and downregulation of release-regulating presynaptic metabotropic glutamate receptors (mGluR2/3). Importantly, these three changes are interrelated due to the cystine-glutamate exchanger and glutamate transporter regulating extrasynaptic glutamate tone on release regulating mGluR2/3.70,71 Inhibitors,research,lifescience,medical Drugs have been examined in animal models of psychostimulant addiction, and to a lesser extent in clinical trials with cocaine addicts that regulate one or more of these processes. For example, N-acetylcysteine upregulates ABT-199 molecular weight cystine glutamate exchange, and has been shown in animal models to prevent synaptic glutamate release associated with drug-seeking, restore inhibitory Inhibitors,research,lifescience,medical tone on synaptic release through activation of mGluR2/3, and to inhibit the desire for cocaine in a double-blind cue-reactivity trial in non-treatment-seeking cocaine addicts.71-73 Also, mGluR2/3 Inhibitors,research,lifescience,medical agonists have proven effective at inhibiting cocaine seeking in animal models; however, unlike Nacetylcysteine, food-seeking was inhibited at only a 3- to 10-fold increase

in dose relative to inhibiting cocaineseeking.74,75 Although no studies have yet evaluated regulating glutamate transport in drug-seeking models of psychostimulant addiction, recent reports of the use of β-lactam antibiotics to increase glutamate transporter membrane Montelukast Sodium insertion poses an interesting possibility for pharmacologically overcoming the cocaine-induced downregulation of glutamate transporters. Finally, while the mechanism is not clear, modafinil has been reported to increase extracellular glutamate levels, which would restore tone on release inhibiting mGluR2/3.76 Notably, modafinil has been found to successfully decrease cocaine relapse in a number of clinical trials.