Upregulation of Ionotropic Glutamate Receptor Subunits within Specific Mesocorticolimbic Regions during Chronic Nicotine Self-Administration

Abstract

Nicotine, an addictive substance, is the major psychoactive component in cigarette smoke. Both a-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid and N-methyl-D-aspartate (NMDA) receptors are essential for the acute stimulative effects of nicotine on the mesocorticolimbic dopamine system, yet little is known about the effects of chronic nicotine treatment on glutamate receptors. Therefore, we used a model of chronic nicotine self-administration (SA), which emulates important aspects of nicotine intake by humans, to determine whether glutamate receptor subunits were affected. After 18 days of saline vs nicotine SA, ionotropic glutamate receptor subunit levels were determined in brain regions within the mesocorticolimbic system by Western blotting. In prefrontal cortex (PFC), the levels of NMDA receptor subunit 2A (NR2A) and NR2B were increased by 67% (p ¼ 0.04) and 83% (p ¼ 0.027), respectively. In the ventral tegmental area (VTA), glutamate receptor subunit 2/3 (GluR2/3) increased by 34% (p ¼ 0.011). Nicotine SA did not affect the expression of these subunits in dorsal striatum and nucleus accumbens. These findings suggest that chronic nicotine SA selectively increased the levels of ionotropic glutamate receptor subunits in a brain region-specific manner.

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

“…Thus, the altered NMDA receptor subunit expression levels that were observed may reflect, in part, altered levels of intracellular subunits not yet incorporated into mature receptors in the membrane. In contrast to the present data, a recent study reported that nicotine intake did not alter NMDA receptor subunit expression in the VTA, and increased expression in the PFC (Wang et al, 2007). The effects of nicotine self-administration on NMDA receptor subunit expression in the amygdala were not assessed in this previous study (Wang et al, 2007).…”

“…In contrast to the present data, a recent study reported that nicotine intake did not alter NMDA receptor subunit expression in the VTA, and increased expression in the PFC (Wang et al, 2007). The effects of nicotine self-administration on NMDA receptor subunit expression in the amygdala were not assessed in this previous study (Wang et al, 2007). There are a number of methodological differences that may account for these apparent discrepancies.…”

“…Further, in our studies rats were permitted 1-h daily access to nicotine self-administration, whereas the previous study employed a 23-h daily access schedule. Finally, in our study brain tissues were harvested approximately 23-h after the final nicotine self-administration session, whereas Wang et al collected brains approximately 30 min after the last nicotine infusion (Wang et al, 2007). Thus, it is possible that expression levels of NMDA receptor subunits may be temporally regulated in a highly dynamic manner, such that the time since last nicotine exposure may be important in determining the direction in which NMDA receptor subunit levels are altered.…”

Neurobiology of nicotine dependence

“…Nicotine-induced changes in these brain sites have started to be investigated, as well as how manipulations of these brain sites may impact on the effects of nicotine (e.g. Liechti et al 2007;Wang et al 2007;Kenny et al in press). Accordingly, compounds that decrease glutamate transmission either through presynaptic or postsynaptic action, or enhance GABA function through GABA B receptors, decrease the primary rewarding effects of nicotine, the motivation to self-administer nicotine and the reward-enhancing effects of nicotine, as well as the motivational impact of stimuli previously associated with nicotine administration.…”

Smoking Restores Impaired LTD-Like Plasticity in Schizophrenia: a Transcranial Direct Current Stimulation Study

“…Reduced inhibition in schizophrenia has been linked to a substantial decrease in GABAergic interneurons, the GABA-synthesizing enzyme glutamic acid decarboxylase (GAD67), and GABA-related gene expression in various parts of the schizophrenia brain (Benes, 2011;Hashimoto et al, 2008b). Adding to the complexity of neuroplasticity regulation, the transmitter release and receptor expression of NMDA and GABA have both been shown to be modulated through cholinergic presynaptic projections (Wang et al, 2007) that increase GABAergic input towards pyramidal cells (McGehee, 2007). Given the influence of nicotine and acetylcholine on the regulation of cortical excitability functions (Alkondon et al, 2000), one could assume that the associations between impaired glutamatergic, GABAergic, and cholinergic neurotransmission might result in an imbalance between facilitation and inhibition tilted toward disinhibition and excessive excitatory pruning, as discussed as one important pathophysiological feature of schizophrenia (Rapoport et al, 2012).…”