Putative role of presynaptic alpha 7*nicotinic receptors in nicotine stimulated increases of extracellular levels of glutamate and aspartate in the ventral tegmental area

We have previously provided evidence that the stimulatory action of systemi c nicotine on dopamine release in the rat nucleus accumbens is initiated in the ventral tegmental area (VTA), and that it appears to be mediated partl y through an indirect, presynaptic mechanism. Thus, it was found that block ade of N-methyl-D-aspartate (NMDA) receptors in the VTA attenuates the enha ncing effect of nicotine on extracellular levels of dopamine in the nucleus accumbens. Moreover, the nicotine-induced dopamine output in the nucleus a ccumbens was found to be blocked by pretreatment with methyllycaconitine (M LA) in the VTA, indicating a role for alpha7* nicotinic acetylcholine recep tors (nAChRs) in this mechanism. Thus, nicotine may exert its effects in th e VTA through stimulation of alpha7* nAChRs localized on excitatory amino a cid (EAA)ergic afferents. To test this hypothesis, we here measured extrace llular concentrations of glutamate and aspartate in the VTA in response to systemic nicotine, with or without concurrent infusion of MLA in the VTA, u sing microdialysis in anaesthetized rats. Since the medial prefrontal corte x is an important source of EAA input to the VTA, we also assessed the dens ity of oc-bungarotoxin binding sites in the VTA in rats lesioned bilaterall y in the prefrontal cortex with ibotenic acid and in sham-lesioned rats by means of quantitative autoradiography. Nicotine (0.5 mg/kg, s.c.) significa ntly increased extracellular levels of both aspartate and glutamate in the VTA. MLA (0.3 mM) infused locally in the VTA prevented the nicotine-induced increase in glutamate and aspartate levels. Ibotenic acid lesions of the p refrontal cortex decreased the density of alpha -bungarotoxin binding sites in the VTA by about 30%. These data indicate that nicotine increases the e xtracellular levels of excitatory amino acids in the VTA through stimulatio n of nAChRs in the VTA and that part of the alpha7* nAChR population in the VTA is localized on neurons originating in the prefrontal cortex. (C) 2000 Wiley-Liss, Inc.