NMDA Receptors Regulate Nicotine-Enhanced Brain Reward Function and Intravenous Nicotine Self-Administration: Role of the Ventral Tegmental Area and Central Nucleus of the Amygdala

Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, FL 33458, USA.
Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology (Impact Factor: 7.05). 05/2008; 34(2):266-81. DOI: 10.1038/npp.2008.58
Source: PubMed


Nicotine is considered an important component of tobacco responsible for the smoking habit in humans. Nicotine increases glutamate-mediated transmission throughout brain reward circuitries. This action of nicotine could potentially contribute to its intrinsic rewarding and reward-enhancing properties, which motivate consumption of the drug. Here we show that the competitive N-methyl-D-aspartate (NMDA) receptor antagonist LY235959 (0.5-2.5 mg per kg) abolished nicotine-enhanced brain reward function, reflected in blockade of the lowering of intracranial self-stimulation (ICSS) thresholds usually observed after experimenter-administered (0.25 mg per kg) or intravenously self-administered (0.03 mg per kg per infusion) nicotine injections. The highest LY235959 dose (5 mg per kg) tested reversed the hedonic valence of nicotine from positive to negative, reflected in nicotine-induced elevations of ICSS thresholds. LY235959 doses that reversed nicotine-induced lowering of ICSS thresholds also markedly decreased nicotine self-administration without altering responding for food reinforcement, whereas the alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor antagonist NBQX had no effects on nicotine intake. In addition, nicotine self-administration upregulated NMDA receptor subunit expression in the central nucleus of the amygdala (CeA) and ventral tegmental area (VTA), suggesting important interactions between nicotine and the NMDA receptor. Furthermore, nicotine (1 microM) increased NMDA receptor-mediated excitatory postsynaptic currents in rat CeA slices, similar to its previously described effects in the VTA. Finally, infusion of LY235959 (0.1-10 ng per side) into the CeA or VTA decreased nicotine self-administration. Taken together, these data suggest that NMDA receptors, including those in the CeA and VTA, gate the magnitude and valence of the effects of nicotine on brain reward systems, thereby regulating motivation to consume the drug.

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    • "Furthermore, pharmacological treatments that attenuate drug-induced lowering of ICSS thresholds (e.g. glutamate receptor blockers) can also reduce drug consumption (Kenny et al., 2005; Paterson et al., 2008; Kenny et al., 2009; Jin et al., 2010). "
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    • "In addition, microdialysis studies on the striatum of rats have reported that the administration of nicotine increases the extracellular levels of glutamate as a result of the activation of a7 nAChR, which are also implicated in the modulation of DA release (Grilli et al., 2009) and locomotor activity (Del Arco et al., 2008; Kenny et al., 2009; Neff et al., 1998; O'Neill et al., 1991; Wooltorton et al., 2003). However, studies have not addressed the effect of chronic nicotine administration on NMDA currents. "
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    • "In fact, the functional impact of nicotine is dependent on ionotropic glutamatergic receptors (Liechti and Markou, 2008; Reissner and Kalivas, 2010; D'Souza and Markou, 2011; Timofeeva and Levin, 2011). Conversely, the acute nicotine administration alters the functional responses of ionotropic glutamate receptors in different brain areas (Risso et al., 2004a; Yamazaki et al., 2006; Vieyra-Reyes et al., 2008, Lin et al., 2010) and chronic nicotine administration affects NMDAR subunit composition (Delibas et al., 2005; Levin et al., 2005; Wang et al., 2007; Rezvani et al., 2008; Kenny et al., 2009). Importantly, previous studies have provided initial evidence that nAChR and NMDAR might also interact to control the release of DA in the NAc (Risso et al., 2004a), whereby the co-activation of nAChR with NMDAR provides a sufficient membrane depolarization to engage NMDAR (Desce et al., 1992; Raiteri et al., 1992; Pittaluga et al., 2005; Tebano et al., 2005). "
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