Do specific NMDA receptor subunits act as gateways for addictive behaviors?

Abstract

Addiction to alcohol and drugs is a major social and economic problem, and there is considerable interest in understanding the molecular mechanisms that promote addictive drives. A number of proteins have been identified that contribute to expression of addictive behaviors. NMDA receptors (NMDARs), a subclass of ionotropic glutamate receptors, have been of particular interest because their physiological properties make them an attractive candidate for gating induction of synaptic plasticity, a molecular change thought to mediate learning and memory. NMDARs are generally inactive at the hyperpolarized resting potentials of many neurons. However, given sufficient depolarization, NMDARs are activated and exhibit long-lasting currents with significant calcium permeability. Also, in addition to stimulating neurons by direct depolarization, NMDARs and their calcium signaling can allow strong and/or synchronized inputs to produce long-term changes in other molecules (such as AMPA-type glutamate receptors) which can last from days to years, binding internal and external stimuli in a long-term memory trace. Such memories could allow salient drug-related stimuli to exert strong control over future behaviors and thus promote addictive drives. Finally, NMDARs may themselves undergo plasticity, which can alter subsequent neuronal stimulation and/or the ability to induce plasticity. This review will address recent and past findings suggesting that NMDAR activity promotes drug- and alcohol-related behaviors, with a particular focus on GluN2B subunits as possible central regulators of many addictive behaviors, as well as newer studies examining the importance of non-canonical NMDAR subunits and endogenous NMDAR cofactors.

Sinomenine Protects Against Morphine Dependence through the NMDAR1/CAMKII/CREB Pathway: A Possible Role of Astrocyte-Derived Exosomes

“…In morphine-dependent mice and morphine-treated cells, the morphine-induced mental dependence effect was related to the upregulation of the NMDAR1/CAMKII/CREB memory formation pathway. Previous studies showed that addictive drugs stimulated the presynaptic membrane to release glutamate, which led to the rapid activation of α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid-type glutamate receptors (AMPARs) and depolarization in the postsynaptic membrane; as a consequence, NMDA receptors were activated after the sufficient depolarization mediated by AMPARs [ 26 ]. Extracellular calcium influx through activated NMDA receptors subsequently activates the downstream protein kinases of NMDA receptors and memory nuclear transcription factors, which regulate the expression of target genes and form new synapses, leading to the consolidation of addiction memory [ 27 ].…”

Obesity and Related Type 2 Diabetes: A Failure of the Autonomic Nervous System Controlling Gastrointestinal Function?

“…As with the abuse of drugs, appetizing foods are able to trigger the release of dopamine in the brain's nucleus accumbens. The nucleus accumbens (NAc or NAcc) (a region in the basal prosencephalon) that serves the cognitive processing of motivation, aversion, and gratification, and the ventral tegmental area (VTA), are central components [8,30,31]. The opioid system, in which the pleasure of eating originates, plays an important role (interacting with dopamine), with a wide secretion of opioid precursor proteins and the expression of their receptors [7,26].…”

“…In addition, the NMDAR is responsible for addictive behaviors [40], including food addiction (comprising the "binge" type), as a result of the plasticity of the two subunits, in particular the NR2B [30]. Therefore, selective antagonists of this subunit (including ifenprodil and Ro 04-5595) can be primary therapeutic tools [30,120].…”

Basic/Translational Development of Forthcoming Opioid- and Nonopioid-Targeted Pain Therapeutics

“…89 Channel blockers such as ketamine have identified abuse potential. This effect may be mediated by channels associated with specific subunit constituents.…”