Dissociable Effects of Antagonism of NMDA and AMPA/KA Receptors in the Nucleus Accumbens Core and Shell on Cocaine-seeking Behavior

Activation of Group II Metabotropic Glutamate Receptors in the Nucleus Accumbens Shell Attenuates Context-Induced Relapse to Heroin Seeking

“…In studies on the neuronal circuits underlying cueinduced cocaine seeking it was found that blockade of AMPA receptors in the NAc core, but not the shell, attenuates lever responding maintained by discrete cues in a second-order schedule procedure (Di Ciano and Everitt, 2001); in this procedure, the conditioned reinforcing properties of the contingent discrete cues control drug seeking (Goldberg, 1976;Everitt and Robbins, 2000;Schindler et al, 2002). The finding of Di Ciano and Everitt are in agreement with those demonstrating that permanent NAc core lesions had a more pronounced effect than NAc shell lesions on responding reinforced by heroin or cocaine cues in this procedure (Hutcheson et al, 2001;Ito et al, 2004).…”

“…This anatomical distinction is important because there are reports that NAc core and shell differentially modulate the conditioned and unconditioned behavioral effects of opiate and psychostimulant drugs (Everitt and Wolf, 2002;Di Chiara et al, 2004;Ikemoto and Wise, 2004). For example, reversible or permanent lesions of the NAc core, but not the shell, attenuate cue-controlled cocaine seeking, as measured by the second-order schedule and the cue-induced reinstatement procedures (Fuchs et al, 2004;Ito et al, 2004); see also Di Ciano and Everitt (2001) and Hyytia and Backstrom (2005) for similar findings with ionotropic glutamate receptor antagonists. On the other hand, 6-OHDA lesions of the NAc shell, but not the core, attenuate the reinforcing effects of amphetamine, as measured in the conditioned place preference procedure (Sellings and Clarke, 2003).…”

Homers regulate drug-induced neuroplasticity: Implications for addiction

“…The integrity of the corticoaccumbens glutamate pathway is required for expressing many drug-induced changes in behavior, including the sensitization To whom correspondence should be addressed: Karen K. Szumlinski, Ph.D., Department of Psychology, University of California Santa Barbara, Santa Barbara, CA, USA 93106-9660.of a drug's psychomotor-activating effects [e.g., 28-37], the development of tolerance to a drug's psychomotor-inhibiting effects [e.g., 38,39], drug-conditioned place-preference [e.g., 36,38,40-43], the maintenance of drug self-administration [e.g., [44][45][46] and the reinstatement of drug-seeking [47][48][49][50][51][52][53][54][55][56]. Further, in vivo microdialysis studies have revealed pronounced effects of either acute or repeated drug-induced changes in NAC or PFC extracellular levels of glutamate by a number of drugs of abuse, including: cocaine [e.g., 31,35,37, 47,53,57,58], amphetamines [e.g., 20,59,60-62, but see 63], alcohol [38,39,64], nicotine [65][66][67][68] and opiates [69,70], implicating drug-induced changes in presynaptic aspects of corticoaccumbens glutamate transmission in mediating the changes in behavior produced by drugs of abuse.…”

“…Acamprosate, a mixed antagonist at the NMDA ionotropic glutamate receptor (iGluR) and the mGluR5 subtype of the Group1 metabotropic glutamate receptor (mGluR) [71,72], is clinically effective at treating alcoholism [73,74] and may prove to be effective for treating psychomotor stimulant and opiate addiction [75,76]. Moreover, direct pharmacological manipulation of glutamate receptors within the PFC or the NAC result in reduced behavioral responsiveness to various drugs of abuse, including cocaine [48,50,53,[77][78][79]; but see 80], alcohol [e.g., 44, 81,82], amphetamines [e.g., [83][84][85][86][87][88][89] and opiates [90-92, but see 79], and systemic administration of antagonists of glutamate receptors blocks several aspects of nicotine reward in laboratory animals [e.g., 93-100, but see 101]. Taken together, these data pose cellular factors regulating pre-and postsynaptic aspects of corticoaccumbens glutamatergic transmission as likely molecular candidates contributing to an addicted phenotype.…”

Previous Exposure to Psychostimulants Enhances the Reinstatement of Cocaine Seeking by Nucleus Accumbens AMPA

“…Thus, cocaine-induced reinstatement is associated with an increase in extracellular glutamate levels in the NAcc (McFarland et al, 2003). AMPA receptors appear to be specifically implicated because infusing AMPA into the NAcc reinstates drug seeking (Cornish et al, 1999;Cornish and Kalivas, 2000) while infusion of AMPA receptor antagonists into this site blocks the reinstatement produced by systemic cocaine, NAcc DA, or cocaine in the prefrontal cortex (Cornish and Kalivas, 2000;Park et al, 2002) as well as responding for cocaine-associated cues under a second-order schedule of reinforcement (Di Ciano and Everitt, 2001). NMDA receptor agonists and antagonists have been reported to produce mixed effects (Cornish et al, 1999;Cornish and Kalivas, 2000;Park et al, 2002).…”