Reinstatement of nicotine seeking is mediated by glutamatergic plasticity

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...

Reduction in Ventral Midbrain NMDA Receptors Reveals Two Opposite Modulatory Roles for Glutamate on Reward

“…It was shown for instance that repeated treatments with drugs of abuse known to enhance brain stimulation reward alter the expression of GluN2A and GluN2B, and their respective mRNA, in different limbic brain regions (Barr et al, 2014;Gipson and Reissner, 2013;Kindlundh-Högberg et al, 2008). Carlezon et al, (2001) compared the expression of GluN1 in the ventral tegmental area between rats that self-stimulated for one hour consecutively and rats that received no stimulation and found no difference between the two groups.…”

The Nucleus Accumbens: Mechanisms of Addiction across Drug Classes Reflect the Importance of Glutamate Homeostasis

“…This glial function is required for the fidelity of glutamatergic synaptic communication and protection from excitotoxicity, since GLT-1 is responsible for more than 90% of uptake in the brain (Danbolt, 2001). Chronic exposure to several classes of addictive substances, including cocaine, nicotine, ethanol, and heroin, reduces expression of GLT-1 (Knackstedt et al, 2010a;Sari and Sreemantula, 2012;Gipson et al, 2013b;Shen et al, 2014b;Reissner et al, 2015). As such, GLT-1 downregulation may serve as a common drug-induced neuroadaptation contributing to relapse vulnerability.…”

“…Selective depotentiation of PLC-to-NAcore projection using optogenetics reduced the incubation of cocaine seeking . Glutamate originating from the PLC was also shown to be necessary for cue-induced reinstatement of nicotine seeking and heroin seeking (LaLumiere and Gipson et al, 2013b). In addition, although direct projections have not yet been tested, both the PLC and NAcore are necessary for the cue-induced reinstatement of heroin, methamphetamine, ethanol, and 3,4-methylenedioxymethamphetamine seeking (Rogers et al, 2008;Chaudhri et al, 2010;Rocha and Kalivas, 2010;Ball and Slane, 2012;Willcocks and McNally, 2013).…”

“…For example, withdrawal from nicotine self-administration shows a similar potentiation (Gipson et al, 2013b), whereas the results are mixed for studies examining the NAc after withdrawal from heroin exposure Shen et al, 2011;Wu et al, 2012). Chronic ethanol induces an increase in mEPSC frequency with no change in amplitude; however, mEPSC frequency is decreased and mEPSC amplitude is increased after withdrawal, indicating that two opposing mechanisms are activated (Spiga et al, 2014).…”

Proteomic Approaches and Identification of Novel Therapeutic Targets for Alcoholism

“…Although previous studies have mostly reported changes engendered by alcohol consumption and exposure, low-cost access to an improved proteomics will lead to detailed studies where proteomes from discrete brain subregions will be profiled with an increased sample number and during different time points after withdrawal. Indeed, recent evidences in rodent models have suggested that, at least for cocaine or nicotine, a longer withdrawal corresponds to a greater drug-seeking, which may imply greater potential for relapse vulnerability (Gipson et al, 2013;Ben-Shahar et al, 2013). Long-lasting changes in the proteome that persist after protracted withdrawal and likely relate to relapse liability would be of high interest to translational scientist.…”