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

Abstract

Nicotine is considered an important component of tobacco responsible for the smoking habit in humans. Nicotine increases glutamatemediated 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 a-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 mM) 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.

The Metabotropic Glutamate 2/3 Receptor Agonist LY379268 Blocked Nicotine-Induced Increases in Nucleus Accumbens Shell Dopamine only in the Presence of a Nicotine-Associated Context in Rats

“…Therefore, blockade of nicotine-induced dopamine release in the NAcc shell may not be the only mechanism by which LY379268 increases the latency to self-administer nicotine and attenuates nicotine intake. As described in the Introduction, LY379268 decreases glutamate release by activating inhibitory presynaptic mGlu2/3 receptors (Cartmell and Schoepp, 2000;Xi et al, 2002a), and blockade of glutamatergic neurotransmission also attenuates the reinforcing effects of nicotine (Kenny et al, 2009(Kenny et al, , 2003Palmatier et al, 2008;Paterson and Markou, 2005;Paterson et al, 2003). Therefore, mGlu2/3-mediated attenuation of glutamatergic neurotransmission is likely to be another mechanism contributing to LY379268-induced increases in the latency to self-administer nicotine (this study) and attenuation of the reinforcing effects of nicotine .…”

“…Nicotine increases glutamatergic transmission by activating excitatory nicotinic receptors located on presynaptic glutamatergic terminals (Fu et al, 2000;Mansvelder and McGehee, 2002;Reid et al, 2000). Blockade of glutamatergic neurotransmission by systemic administration of receptor antagonists that act at postsynaptically located ionotropic or metabotropic glutamate (mGlu) receptors attenuated both nicotine selfadministration (Kenny et al, 2009(Kenny et al, , 2003Palmatier et al, 2008;Paterson and Markou, 2005;Paterson et al, 2003) and nicotine-induced increases in NAcc dopamine release (Fu et al, 2000;Kosowski et al, 2004;Schilstrom et al, 1998;Sziraki et al, 2002).…”

D-Amino Acid Aberrations in Cerebrospinal Fluid and Plasma of Smokers

“…In addition, nicotine self-administration in rats upregulates the expression of NMDAR subunits in the VTA and amygdala (Kenny et al, 2009). In vivo blockade of the NMDAR by NMDAR antagonists diminishes nicotineinduced dopamine release (Schilstrom et al, 1998) and nicotine self-administration (Kenny et al, 2009), but promotes tolerance to nicotine administration in rats (Shoaib et al, 1994;Shoaib and Stolerman, 1992). NMDAR antagonism could therefore constitute a target in the treatment of nicotine dependence, although to date this has not been successful in humans (Liechti and Markou, 2008).…”

“…Glutamate is the prime excitatory neurotransmitter in the central nervous system (CNS) and binds to several receptors, including the ionotropic N-methyl-D-aspartate receptor (NMDAR). Animal studies have reported that nicotine increases glutamate concentrations in the ventral tegmental area (VTA) (Fu et al, 2000;Schilstrom et al, 2000) and exerts an excitatory effect on the NMDAR in dopaminergic neurons in the VTA (Fu et al, 2000;Grillner and Svensson, 2000;Mansvelder and McGehee, 2000), the nucleus accumbens (Schilstrom et al, 1998), and the central nucleus of the amygdala (Kenny et al, 2009). In addition, nicotine self-administration in rats upregulates the expression of NMDAR subunits in the VTA and amygdala (Kenny et al, 2009).…”

“…Animal studies have reported that nicotine increases glutamate concentrations in the ventral tegmental area (VTA) (Fu et al, 2000;Schilstrom et al, 2000) and exerts an excitatory effect on the NMDAR in dopaminergic neurons in the VTA (Fu et al, 2000;Grillner and Svensson, 2000;Mansvelder and McGehee, 2000), the nucleus accumbens (Schilstrom et al, 1998), and the central nucleus of the amygdala (Kenny et al, 2009). In addition, nicotine self-administration in rats upregulates the expression of NMDAR subunits in the VTA and amygdala (Kenny et al, 2009). In vivo blockade of the NMDAR by NMDAR antagonists diminishes nicotineinduced dopamine release (Schilstrom et al, 1998) and nicotine self-administration (Kenny et al, 2009), but promotes tolerance to nicotine administration in rats (Shoaib et al, 1994;Shoaib and Stolerman, 1992).…”