Acute increases in monoamine release in the rat prefrontal cortex by the mGlu2/3 agonist LY379268 are similar in profile to risperidone, not locally mediated, and can be elicited in the presence of uptake blockade

Our recent work (Cartmell et al., Journal of Neurochemistry, 75 (2000) 1147 -1154) demonstrated that systemic injection of the potent, selective mGlu2/ 3 receptor agonist, LY379268, acutely increased extracellular levels of dop amine, its metabolites DOPAC and HVA, and the 5-HT metabolite, 5-HIAA, in r at medial prefrontal cortex (mPFC). Here, we compared the acute effects of LY379268 with those of clozapine and risperidone (atypical antipsychotics) on extracellular levels of both dopamine and 5-HT in the mPFC of freely-mov ing rats. Uptake blockers were included to minimize metabolism of monoamine s near the probe area. One hour after injection, LY379268 (10 mg/kg s.c.), clozapine (10 mg/kg s.c.) or risperidone (1 mg/kg s.c.) maximally increased dopamine by 224, 257 and 234% of basal levels. These effects were followed by maximal increases in DOPAC and HVA levels 2 to 3.5 hours after administ ration. LY379268, at 3 and 10 mg/kg s.c., and risperidone (1 mg/kg s.c.) al so increased dialysate 5-HT to 169, 179 and 140% of basal levels and 5-HIAA to 144, 154 and 121% of basal levels, respectively. These neurochemical ch anges in the mPFC could not be mimicked when LY379268 (3 or 30 muM) was adm inistered locally via the microdialysis probe. These data demonstrate that increases in extracellular monoamines in the rat prefrontal cortex evoked a cutely by the mGlu2/3 agonist, LY379268, are similar in profile to risperid one, not locally mediated, and can be elicited in the presence of uptake bl ockade. (C) 2001 Elsevier Science Ltd. All rights reserved.