Effect of nitric oxide synthase inhibitor and NMDA receptor antagonist on the development of nicotine sensitization of nucleus accumbens dopamine release: an in vivo microdialysis study.

We have previously found that the neuronal nitric oxide synthase inhibitor N-nitro-L-arginine (L-NNA) and the noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 prevent behavioral sensitization to nicotine. This study aimed to investigate the effect of L-NNA and MK-801 on a neurochemical component of nicotine sensitization by evaluating the effect of the drugs on nicotine sensitization of nucleus accumbens dopamine (DA) release. Sprague-Dawley rats were pretreated with L-NNA (15 mg/kg, i.p.), MK-801 (0.3mg/kg, i.p.), or saline 30 min before injection of nicotine (0.4 mg/kg, s.c., once daily) for seven consecutive days. Twenty-four hours after the last drug injection, animals were challenged with local perfusion of 5 mM nicotine into the shell of nucleus accumbens for 60 min and DA release was monitored using in vivo microdialysis. In rats treated with repeated nicotine, acute nicotine challenge induced a greater increase of accumbal DA release than in saline-treated animals (maximal DA response=969+/-235% (mean+/-S.E.M.) of basal level versus 520+/-93%, p=0.042). Co-administration of L-NNA or MK-801 with nicotine attenuated an increase of DA release elicited by acute nicotine challenge, compared with nicotine alone (maximal DA response=293+/-58% and 445+/-90% of basal level, respectively versus 969+/-235%, p=0.004 and p=0.013, respectively). These data demonstrate that L-NNA and MK-801 block the development of nicotine sensitization of nucleus accumbens DA release, further supporting the involvement of nitric oxide and NMDA receptors in the development of behavioral sensitization to nicotine.