Role of glutamate on dopamine neurochemistry and the behavioral pharmacology of cocaine in squirrel monkeys

Basal glutamate originating primarily from the cystine-glutamate transporter provides glutamatergic tone on extrasynaptic glutamate receptors such as the metabotropic glutamate 2/3 receptors (mGluR2/3). Glutamate has been shown to regulate dopamine function in the mesocorticolimbic pathway in rodents, which plays an important role in the behavioral pharmacology of psychostimulants. Hence, glutamate systems may be effective targets for cocaine pharmacotherapeutics. To investigate whether cystine-glutamate transporter or mGluR2/3 modulation would alter the neurochemical and behavioral effects of cocaine, NAC, a cystine prodrug, and LY379268, an mGluR2/3 agonist, were administered prior to cocaine during in vivo microdialysis and operant behavioral tasks. It was hypothesized that augmenting extrasynaptic glutamate release or mGluR2/3 activation would attenuate cocaine- or amphetamine-induced increases in extracellular dopamine and their corresponding behavioral-stimulant, reinforcing and reinstatement effects. NAC significantly attenuated cocaine-induced increases in dopamine but had inconsistent effects on amphetamine-induced increases in dopamine. However, NAC did not alter the behavioral effects of either cocaine or amphetamine. Similarly, LY379268 significantly attenuated cocaine-induced increases in dopamine. LY379268 also significantly attenuated cocaine-induced behavioral-stimulant effects but drug interactions on cocaine self-administration and reinstatement were less robust and inconsistent across pretreatment doses. Hence, drug interactions on neurochemistry were only partially reflected in behavioral measures, likely due to the incomplete blockade of cocaine-induced increase in extracellular dopamine by NAC and LY379268.