N-METHYL-D-ASPARTATE RECEPTOR ANTAGONISM IN THE VENTRAL TEGMENTAL AREA DIMINISHES THE SYSTEMIC NICOTINE-INDUCED DOPAMINE RELEASE IN THE NUCLEUS-ACCUMBENS

Systemic nicotine enhances burst firing of dopamine neurons in the ven tral tegmental area and dopamine release in the nucleus accumbens, mai nly via stimulation of nicotinic acetylcholine receptors in the ventra l tegmental area. Given that both the neuronal activity of mesolimbic dopamine neurons and terminal dopamine release are regulated by excita tory amino acid inputs to the ventral tegmental area and that nicotine facilitates glutamatergic transmission in brain, we investigated the putative role of ionotropic glutamate receptors within the ventral teg mental area for the effects of nicotine on dopamine release in the nuc leus accumbens using microdialysis, with one probe implanted in the ve ntral tegmental area for drug application and another in the ipsilater al nucleus accumbens for measuring dopamine, in awake rats. Systemic n icotine (0.5 mg/kg, s.c.) and infusion of nicotine (1.0 mM) into the v entral tegmental area increased dopamine output in the nucleus accumbe ns. Intrategmental infusion of pha-amino-3-hydroxy-5-methylisoxazole-4 -propionate (0.1 mM) or N-methyl-D-aspartate (0.3 mM) increased accumb al dopamine release; these effects were antagonized by concomitant inf usion of a selective antagonist at N-methyl-D-aspartate receptors, 2-a mino-5-phosphonopentanoic acid (0.3 mM), and non-N-methyl-D-aspartate receptors, 6-cyano-7-nitroquinoxaline-2,3-dione (0.3 mM), respectively . Infusion of either antagonist (0.3 or 1.0 mM) into the ventral tegme ntal area did not affect basal dopamine levels, whereas infusion of 2- amino-5-phosphonopentanoic acid, but not 6-cyano-7-nitroquinoxaline-2, 3-dione, starting 40 min before nicotine injection dose-dependently at tenuated the nicotine-induced increase in accumbal dopamine release. C oncurrent intrategmental infusion of 2-amino-5-phosphonopentanoic acid and nicotine decreased nicotine-induced dopamine release in the nucle us accumbens. These results indicate that the stimulatory action of ni cotine on the mesolimbic dopamine system is to a considerable extent m ediated via stimulation of N-methyl-D-aspartate receptors within the v entral tegmental area. (C) 1997 IBRO. Published by Elsevier Science Lt d.