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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Available from: Marisa Roberto, Oct 09, 2015
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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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    ABSTRACT: Rats selectively bred for high (HiS) or low (LoS) saccharin intake are a well-established model of drug-abuse vulnerability, with HiS rats being more likely to consume sweets and cocaine than LoS rats. Still, the nature of these differences is poorly understood. This study examined whether the motivational consequences of cocaine exposure are differentially expressed in HiS and LoS rats by measuring intracranial self-stimulation (ICSS) thresholds following acute injections of cocaine (10 mg/kg). Reductions in ICSS thresholds following cocaine injection were greater in HiS rats than in LoS rats, suggesting that the reward-enhancing effects of cocaine are greater in the drug-vulnerable HiS than LoS rats. Higher cocaine-induced reward, indicated by lower ICSS thresholds, may explain the higher rates of drug consumption in sweet-preferring animal models, providing a clue to the etiology of cocaine addiction in vulnerable populations.
    Behavioural pharmacology 08/2015; DOI:10.1097/FBP.0000000000000182 · 2.15 Impact Factor
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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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    ABSTRACT: The presynaptic control of dopamine release in the nucleus accumbens (NAc) by glutamate and acetylcholine has a profound impact on reward signaling. Here we provide immunocytochemical and neurochemical evidence supporting the co-localization and functional interaction between nicotinic acetylcholine receptors (nAChRs) and N-methyl-D-aspartic acid (NMDA) receptors in dopaminergic terminals of the NAc. Most NAc dopaminergic terminals possessed the nAChR α4 subunit and the pre-exposure of synaptosomes to nicotine (30 μM) or to the α4β2-containing nAChR agonist 5IA85380 (10 nM) selectively inhibited the NMDA (100 μM)-evoked, but not the 4-aminopyridine (10 μM)-evoked, [(3)H] dopamine outflow; this inhibition was blunted by mecamylamine (10 μM). Nicotine and 5IA85380 pretreatment also inhibited the NMDA (100 μM)-evoked increase of calcium levels in single nerve terminals, an effect prevented by dihydro-β-erythroidine (1 μM). This supports a functional interaction between α4β2-containing nAChR and NMDA receptors within the same terminal, as supported by the immunocytochemical co-localization of α4 and GluN1 subunits in individual NAc dopaminergic terminals. The NMDA-evoked [(3)H]dopamine outflow was blocked by MK801 (1 μM) and inhibited by the selective GluN2B-selective antagonists ifenprodil (1 μM) and RO 25-6981 (1 μM), but not by the GluN2A-preferring antagonists CPP-19755 (1 μM) and ZnCl2 (1 nM). Notably, nicotine pretreatment significantly decreased the density of biotin-tagged GluN2B proteins in NAc synaptosomes. These results show that nAChRs dynamically and negatively regulate NMDA receptors in NAc dopaminergic terminals through the internalization of GluN2B receptors.
    Neuropharmacology 12/2013; 79. DOI:10.1016/j.neuropharm.2013.12.014 · 5.11 Impact Factor
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    • "Lesions of cholinergic innervation of the VTA arising from the pedunculopontine tegmental nucleus (PPTg) blocked the expression of reward-related behaviors in response to nicotine and rendered 'rewarding' doses of nicotine aversive, reflected in increased avoidance of the drug (Laviolette et al., 2002). Similarly, blockade of a7 nAChRs or NMDA receptors in the VTA switched the effects of nicotine from rewarding to aversive (Kenny et al., 2009b; Laviolette and van der Kooy, 2003b). Projections from the VTA into the striatum and NAc also appear to be influenced by nicotinic signaling. "
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    ABSTRACT: Nicotine stimulates brain reward circuitries, most prominently the mesocorticolimbic dopamine system, and this action is considered critical in establishing and maintaining the tobacco smoking habit. Compounds that attenuate nicotine reward are considered promising therapeutic candidates for tobacco dependence, but many of these agents have other actions that limit their potential utility. Nicotine is also highly noxious, particularly at higher doses, and aversive reactions to nicotine after initial exposure can decrease the likelihood of developing a tobacco habit in many first time smokers. Nevertheless, relatively little is known about the mechanisms of nicotine aversion. The purpose of this review is to present recent new insights into the neurobiological mechanisms that regulate avoidance of nicotine. First, the role of the mesocorticolimbic system, so often associated with nicotine reward, in regulating nicotine aversion is highlighted. Second, genetic variation that modifies noxious responses to nicotine and thereby influences vulnerability to tobacco dependence, in particular variation in the CHRNA5-CHRNA3-CHRNB4 nicotinic acetylcholine receptor (nAChR) subunit gene cluster, will be discussed. Third, the role of the habenular complex in nicotine aversion, primarily medial habenular projections to the interpeduncular nucleus (IPN) but also lateral habenular projections to rostromedial tegmental nucleus (RMTg) and ventral tegmental area (VTA) are reviewed. Forth, brain circuits that are enriched in nAChRs, but whose role in nicotine avoidance has not yet been assessed, will be proposed. Finally, the feasibility of developing novel therapeutic agents for tobacco dependence that act not by blocking nicotine reward but by enhancing nicotine avoidance will be considered.
    Neuropharmacology 09/2013; 76. DOI:10.1016/j.neuropharm.2013.09.008 · 5.11 Impact Factor
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