Acute Nicotine Changes Dynorphin and Prodynorphin mRNA in Striatum

ISOLA, RAFFAELLA;ZHANG H;TEJWANI G. A;NEFF N. H;HADJICONSTANTINOU M.

2009-01-01

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Abstract

Rationale. Nicotine displays rewarding and aversive effects, and while dopamine has been linked with nicotine’s reward, the neurotransmitter(s) involved with aversion remains speculative. The κ-dynorphinergic system has been associated with negative motivational and affective states, and whether dynorphin (Dyn) contributes to the behavioral pharmacology of nicotine is a pertinent question. Objective. We determined whether administration of a single dose of nicotine alters the biosynthesis of Dyn in the striatum of mice. Results. Nicotine free base, 1 mg/kg, sc, induced a biphasic, protracted increase of striatal Dyn, an initial rise by 1 h, which declined to control levels by 2 h, and a subsequent increase, between 6 and 12 h, lasting over 24 h. At 1 h, the nicotine effect was dose dependent, with doses ≥0.5 mg/kg inducing a response. Prodynorphin mRNA increased by 30 min for over 24 h, and in situ hybridization demonstrated elevated signal in caudate/putamen and nucleus accumbens. The nicotinic antagonist mecamylamine prevented the Dynresponse, and a similar effect was observed with D1- and D2-like dopamine receptor antagonists, SCH 23390, sulpiride, and haloperidol. The glutamate NMDA receptor antagonist MK-801 reversed the nicotine-induced increase of Dyn, while the AMPA antagonist NBQX had a marginal effect. Conclusions. We interpret our findings to indicate that acute nicotine enhances the synthesis and release of striatal Dyn. We propose that nicotine influences Dyn primarily through dopamine release and that glutamate plays a modulatory role. A heightened dynorphinergic tone may contribute to the aversive effects of nicotine in naive animals and first-time tobacco smokers.