No abstract

Nicotine abuse and addiction is a major health liability. Nicotine, an active alkaloid in tobacco, is self-administered by animals and produces cellular adaptations in brain regions associated with drug reward, such as the nucleus accumbens. However, it is unknown whether, akin to illicit drugs of abuse such as cocaine or heroin, the adaptations endure and contribute to the propensity to relapse after discontinuing nicotine use. Using a rat model of cue-induced relapse, we made morphological and electrophysiological measures of synaptic plasticity, as well as quantified glutamate overflow, in the accumbens after 2 wk of withdrawal with extinction training. We found an enduring basal increase in dendritic spine head diameter and in the ratio of AMPA to NMDA currents in accumbens spiny neurons compared with yoked saline animals at 2 wk after the last nicotine self-administration session. This synaptic potentiation was associated with an increase in both AMPA (GluA1) and NMDA (GluN2A and GluN2B) receptor subunits, and a reduction in the glutamate transporter-1 (GLT-1). When nicotine seeking was reinstated by presentation of conditioned cues, there were parallel increases in behavioral responding, extracellular glutamate, and further increases in dendritic spine head diameter and ratio of AMPA to NMDA currents within 15 min. These findings suggest that targeting glutamate transmission might inhibit cue-induced nicotine seeking. In support of this hypothesis, we found that pharmacological inhibition of GluN2A with 3-Chloro-4-fluoro-N-[4-[[2-(phenylcarbonyl)hydrazino]carbonyl]benzyl]benzenesulfonamide (TCN-201) or GluN2B with ifenprodil abolished reinstated nicotine seeking. These results indicate that up-regulated GluN2A, GluN2B, and rapid synaptic potentiation in the accumbens contribute to cue-induced relapse to nicotine use. T obacco smoking is the leading preventable cause of mortality, and relapse rates remain high (1, 2). Nicotine is a primary active alkaloid in tobacco and is generally recognized as being responsible for maintaining smoking behavior in humans (3). Accordingly, current smoking pharmacotherapy relies largely on replacing nicotinic receptor stimulation with compounds having pharmacokinetic and/or receptor efficacy characteristics that decrease nicotine craving without producing significant reward (4). Given the high rates of failure by replacement therapies, there is a pressing need to develop effective new medications targeting the neurological changes produced by cigarette use that underpin persistent relapse vulnerability.Nicotine self-administration results from activating α 4 β 2 subunitcontaining nicotinic cholinergic receptors localized on dopamine cell bodies in the ventral tegmental area and by stimulating presynaptic α 7 -containing nicotinic acetylcholine receptors on glutamatergic afferents to dopamine neurons (5-7); the net consequence being increased dopamine release in the nucleus accumbens, a brain nucleus central to reward circuitry (8). In contrast to the wellunderstood synaptic...