Glutamate: The New Frontier in Pharmacotherapy for Cocaine Addiction

Abstract

Considerable research into the neurobiology of cocaine addiction has shed light on the role of glutamate. Findings from models of relapse to cocaine-seeking indicate that the glutamatergic system is critically involved, as glutamate levels in the nucleus accumbens increase during reinstatement and glutamate receptor activation is necessary for reinstatement to drug-seeking. Thus, it would seem beneficial to block the increased glutamate release, but full antagonists of ionotropic glutamate receptors produce undesirable side effects. Therefore, modulation of glutamatergic transmission would be advantageous and provide novel pharmacotherapeutic avenues. Pharmacotherapies have been developed that have the potential to modulate excessive glutamatergic transmission through ionotropic and metabotropic (mGluR) glutamate receptors. Compounds that modulate glutamatergic transmission through ionotropic glutamate receptors include the non-competitive N-methyl-D-aspartic acid antagonists, amantadine and memantine, and the partial N-methyl-D-aspartic acid agonist d-cycloserine. They have shown promise in preclinical models of cocaine addiction. The mGluR2/3 agonist LY379268 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-(phenylethynyl)pyridine and 3-[2-methyl-4-thiazolyl)ethynyl]pyridine, have shown to be effective in preclinical models of cocaine addiction. The cysteine pro-drug, N-acetylcysteine, restores the inhibitory tone on presynaptic glutamate receptors and has been effective in reducing cue-induced craving and cocaine use in humans. Furthermore, anticonvulsants, such as topiramate or lamotrigine, have shown efficacy in treating cocaine dependence or reducing relapse in humans. Future pharmacotherapy may focus on manipulating signal transduction proteins and pathways, which include Homer/N-methyl-D-aspartic acid complexes, to provide effective treatment for cocaine addiction.

Thinking Outside the Cleft to Understand Synaptic Activity: Contribution of the Cystine-Glutamate Antiporter (System xc−) to Normal and Pathological Glutamatergic Signaling

“…Drug addiction is a chronic relapsing disorder hypothesized to be produced by druginduced neuroplasticity that renders users vulnerable to craving-inducing stimuli. Drug-induced plasticity that may result in the addiction phenotype includes longterm changes in the activity of corticostriatal pathways, which originate in the prefrontal cortex and project to the nucleus accumbens Uys and LaLumiere, 2008;Kalivas, 2009;Wolf, 2010). Activation of this circuit or related structures correlates with craving in humans and is necessary for reinstatement in rodents (Volkow et al, 1991(Volkow et al, , 1999Breiter et al, 1997;McFarland and Kalivas, 2001;Park et al, 2002).…”

Viral-Mediated Knockdown of mGluR7 in the Nucleus Accumbens Mediates Excessive Alcohol Drinking and Increased Ethanol-Elicited Conditioned Place Preference in Rats

“…There are two types of glutamate receptors: metabotropic and ionotropic receptors (for review, see (Bird and Lawrence, 2009;Olive, 2009;Uys and LaLumiere, 2008)). More evidence regarding the involvement of the glutamatergic system in ethanol addiction focuses on the metabotropic receptors (mGluR).…”

Efectos del estrés sobre los procesos de plasticidad y neurogénesis: una revisión

“…La D-cicloserina ha sido utilizada en el tratamiento de diferentes trastornos neuropsiquiá-tricos tales como esquizofrenia (Farber, Newcomer & Olney, 1999), adicciones (Uys & LaLumiere, 2008), trastorno de ansiedad social (Westenberg, 2009), trastorno obsesivo compulsivo (McGuire et al, 2012;Wilhelm et al, 2008), fobias específicas (Guastella, Dadds, Lovibond, Mitchell & Richardson, 2007;Guastella et al, 2008) y trastorno por estrés postraumático (Difede et al, 2013), entre otros.…”