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.