Glutamatergic modulation of subcortical motor and limbic circuits.

The ventral striatum is a critical component of parallel circuits associated with motor and limbic functions, termed the corticostriatopallidothalamic circuit (CSPT).1 The interconnectivity of the regions comprising these circuits is believed to mediate the processing of sensory information that leads to the modulation of both motor and limbic behaviors. This well-defined circuitry allows for the neurochemical anatomical examination of functionally integrated regions. The striatum is one of the critical integrative areas in the CSPT because of the convergence of its glutamatergic and dopaminergic afferents, and the modulatory effects of its efferents.1 Corticostriatal glutamate projections synapse on mesostriatal dopaminergic projections, and modulate dopamine release in the dorsal and ventral striatum.2 Modulators of all four glutamate receptor subtypes—NMDA, AMPA, kainate, and metabotropic—affect dopamine release in dorsal and ventral striatum. We previously reported that systemic treatment with the NMDA receptor antagonist MK-801 alters D2 receptor mRNA in the ventral tegmental area (VTA) but not the substantia nigra, pars compacta (SNc), or in the dorsal or ventral striatum.2 These data suggest that NMDA receptors exert a tonic effect on dopamine autoreceptor expression preferentially in limbic regions. We now present data from a follow-up experiment to determine the effects of other glutamate receptor modulators on dopamine receptor expression in caudate-putamen (CPu), nucleus accumbens, core (core), and nucleus accumbens, shell (shell). Sprague-Dawley male rates (225–275 g) were treated with seven daily injections of CNQX (an antagonist of both AMPA and kainate receptors), GYKI52466 (an AMPA receptor desensitization facilitator), riluzole (a glutamate release inhibitor), or DMSO (vehicle), and rats were sacrificed 24 hours after the last injection.3 Ten animals were treated per group. In situ histochemistry for preprodynorphin and preproenkephalin transcripts, and D1 and D2 receptor mRNAs was performed as previously described.2 Results are shown in FIGURE 1. D1 and opioid peptide precursor mRNA were not affected by any of the treatments, while D2 mRNA was significantly decreased by riluzole and GYKI52466 treatments. Riluzole and GYKI52466 equally decreased the expression of D2 receptors in both dorsal and ventral striatal regions. This is in contrast to the effects of MK-801,2 and suggests that our previously reported results after NMDA receptor antagonist