However, these studies have been conducted in rats in whom the frontal cortex is poorly evolved, and given the marked activation produced in the prefrontal cortex and amygdala by drug-associated stimuli in psychostimulant addicts, the conclusion that compulsive relapse is entirely derived from corticostriatal habit circuitry Inhibitors,research,lifescience,medical may be an oversimplification. Indeed, it has been argued that a primary role for therapy in treating addiction is to strengthen prefrontal regulation of drug-seeking behaviors, whether through psychosocial interventions or pharmacotherapy.27,58,59 Enduring psychostimulant-induced

neuroplasticity in the prefrontal to accumbens glutamate projection Given the apparent critical role played by Inhibitors,research,lifescience,medical glutamatergic afférents to the nucleus accumbens in initiating drugseeking or craving, recent studies have identified a number of enduring cellular changes in glutamate transmission that may be critical pathological neuroadaptations to psychostimulant use, and may serve as targets for pharmcotherapeutic intervention. In general the neuroplasticity can be categorized as postsynaptic, presynaptic and HCS assay nonsynaptic (ie, residing predominantly in glia). However, since these processes are intimately related to each other, it is perhaps best to consider all the adaptations Inhibitors,research,lifescience,medical as changes in glutamate homeostasis,

the end result of which is a psychostimulant-induced enduring change in the fidelity of communication between the prefrontal cortex and the nucleus accumbens, and the regulation by this projection of corticostriatal habit circuitry. It has been Inhibitors,research,lifescience,medical proposed that this loss of fidelity results

in a weakening or loss in the capacity of psychostimulant addicts to cognitively intervene in habitual behaviors, thereby making drug-seeking more difficult to control and increasing the vulnerability to relapse.27 As mentioned above, drug-seeking is associated with a large release Inhibitors,research,lifescience,medical of prefrontal glutamate into the nucleus accumbens. The large release of glutamate during drugseeking is all the more remarkable because it was discovered using microdialysis. which is not a very sensitive measure of glutamate NATURE REVIEWS DRUG DISCOVERY transmission.60 Indeed, when animals are trained to seek a biological reward, such as food, microdialysis cannot measure glutamate release.49 Thus, the large psychostimulant-induced release of glutamate has been hypothesized to be a pathological and perhaps critical mediator of relapse. This hypothesis is supported by the fact that treatments interrupting synaptic glutamate release also inhibit drug-seeking. This includes a variety of pharmacological treatments that have the potential to be developed into pharmacotherapeutic agents, as outlined below.