Systemic nicotine stimulates dopamine release in nucleus accumbens: re-evaluation of the role of N-methyl-D-aspartate receptors in the ventral tegmental area

Systemic nicotine stimulates dopamine (DA) release in the nucleus accumbens (NAcc), and N-methyl-D-aspartate (NMDA) receptors in the ventral tegmental area (VTA) appear to be involved. However, it is not known whether the sec retion of DA elicited by nicotine depends on the tonic and/or phasic activa tion of NMDA receptors by glutamate (Glu). To clarify this, in vivo microdi alysis was conducted in freely moving, alert rats to measure DA and Glu ove rflows in the NAcc and Glu in the VTA. Nicotine (0.065, 0.09, or 0.135 mg/k g delivered i.v. at 0.09 mg/kg/60 s via a jugular cannula) dose dependently stimulated NAcc DA secretion (P<.05). However, 0.065 mg/kg nicotine failed to stimulate Glu release in the VTA, whereas higher doses of nicotine (gre ater than or equal to 0.09 mg/kg) were effective (P<.05). Administering the competitive NMDA receptor antagonists, 2-amino-5-phosphonopentanoic acid ( AP-5; 1 mM) or 0.2 mM cis-4-phosphonomethyl-2-piperidine carboxylic acid (C GS 19755) through the VTA probe, abolished NAcc DA release after 0.065 mg/k g nicotine (P<.01) and reduced the response to 0.09 mg/kg nicotine. Therefo re, the NAcc DA response to a relatively low dose of nicotine depends on th e tonic activation of NMDA receptors in the VTA. In contrast, infusing 1 mM 2-amino-5-phosphonopentanoic acid or 1 mM 6-cyano-7-nitroquinoxaline-2,3- dione (CNQX), an alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA ) receptor antagonist, into the NAcc through the microdialysis probe had no effect on NAcc DA secretion in response to 0.09 mg/kg nicotine. These find ings, coupled with data showing that Glu secretion in the VTA was stimulate d only by higher doses of nicotine, indicate that the phasic release of VTA Glu is involved in the NAcc DA response to higher doses of nicotine (great er than or equal to 0.09 mg/kg).