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Effects of Repeated Ethanol Exposures on NMDA Receptor Expression and Locomotor Sensitization in Mice Expressing
Carolina R den Hartog1, Meghin Gilstrap1, Bethany Eaton1
1Department of Neuroscience, Medical University of South Carolina Charleston, SC, USA.
Abstract:
Evidence from a large number of preclinical studies suggests that chronic exposure to drugs of abuse, such as psychostimulants or ethanol induces changes in glutamatergic transmission in key brain areas associated with reward and control of behavior. These changes include alterations in the expression of ionotropic glutamate receptors including N-methyl-D-aspartate receptors (NMDAR) that are important for regulating neuronal activity and synaptic plasticity. NMDA receptors are inhibited by ethanol and reductions in NMDA-mediated signaling are thought to trigger homestatic responses that limit ethanol's effects on glutamatergic transmission. Following repeated exposures to ethanol, these homeostatic responses may become unstable leading to an altered glutamatergic state that contributes to the escalations in drinking and cognitive deficits observed in alcohol-dependent subjects. An important unanswered question is whether ethanol-induced changes in NMDAR expression are modulated by the intrinsic sensitivity of the receptor to ethanol. In this study, we examined the effects of ethanol on NMDAR subunit expression in cortical (orbitofrontal, medial prefrontal), striatal (dorsal and ventral striatum) and limbic (dorsal hippocampus, basolateral amygdala) areas in mice genetically modified to express ethanol-resistant receptors (F639A mice). These mice have been previously shown to drink more ethanol than their wild-type counterparts and have altered behavioral responses to certain actions of ethanol. Following long-term voluntary drinking, F639A mice showed elevations in GluN2A but not GluN1 or GluN2B expression as compared to wild-type mice. Mice treated with repeated injections with ethanol (2-3.5 g/kg; i.p.) showed changes in NMDAR expression that varied in a complex manner with genotype, brain region, subunit type and exposure protocol all contributing to the observed response. F639A mice, but not wild-type mice, showed enhanced motor activity following repeated ethanol injections and this was associated with differences in NMDAR subunit expression across brain regions thought to be involved in drug sensitization. Overall, while the results of the study suggest that NMDARs with reduced sensitivity to ethanol favor the development of locomotor sensitization, they also show that intrinsic ethanol sensitivity is not the sole determinant underlying changes in NMDAR expression following repeated exposures to ethanol.
Insights
Chronic ethanol exposure alters brain N-methyl-D-aspartate receptors (NMDARs). Reduced ethanol sensitivity in NMDARs may promote locomotor sensitization, but intrinsic sensitivity isn't the only factor influencing NMDAR expression changes.
Area of Science:
- Neuroscience
- Pharmacology
- Genetics
Background:
- Chronic drug abuse, including ethanol, alters glutamatergic transmission in brain reward and behavior control regions.
- N-methyl-D-aspartate receptors (NMDARs) are crucial for neuronal activity and plasticity, and are inhibited by ethanol.
- Ethanol-induced NMDAR changes may contribute to alcohol dependence, including increased drinking and cognitive deficits.
Purpose of the Study:
- To investigate how ethanol affects NMDAR subunit expression in various brain regions.
- To determine if the intrinsic ethanol sensitivity of NMDARs modulates ethanol-induced expression changes.
- To examine these effects in mice genetically engineered for ethanol-resistant NMDARs (F639A mice).
Main Methods:
- Compared NMDAR subunit expression (GluN1, GluN2A, GluN2B) in cortical, striatal, and limbic brain areas of wild-type and F639A mice.
- Utilized long-term voluntary ethanol consumption and repeated ethanol injections (2-3.5 g/kg) as exposure protocols.
- Assessed behavioral responses, including motor activity, following ethanol exposure.
Main Results:
- F639A mice showed increased GluN2A expression after voluntary ethanol drinking compared to wild-type mice.
- Repeated ethanol injections induced complex changes in NMDAR expression, varying by genotype, brain region, subunit, and protocol.
- F639A mice exhibited enhanced motor activity after repeated ethanol injections, linked to altered NMDAR subunit expression in specific brain areas.
Conclusions:
- NMDARs with reduced ethanol sensitivity appear to facilitate locomotor sensitization.
- Intrinsic ethanol sensitivity of NMDARs is not the sole factor determining NMDAR expression changes after repeated ethanol exposure.
- These findings offer insights into the neurobiological mechanisms underlying alcohol dependence and drug sensitization.
