Glutamate Receptors within the Mesolimbic Dopamine System Mediate Alcohol Relapse Behavior

Abstract

Glutamatergic input within the mesolimbic dopamine (DA) pathway plays a critical role in the development of addictive behavior. Although this is well established for some drugs of abuse, it is not known whether glutamate receptors within the mesolimbic system are involved in mediating the addictive properties of chronic alcohol use. Here we evaluated the contribution of mesolimbic NMDARs and AMPARs in mediating alcohol-seeking responses induced by environmental stimuli and relapse behavior using four inducible mutant mouse lines lacking the glutamate receptor genes Grin1 or Gria1 in either DA transporter (DAT) or D1R-expressing neurons. We first demonstrate the lack of GluN1 or GluA1 in either DAT-or D1R-expressing neurons in our mutant mouse lines by colocalization studies. We then show that GluN1 and GluA1 receptor subunits within these neuronal subpopulations mediate the alcohol deprivation effect, while having no impact on context-plus cue-induced reinstatement of alcohol-seeking behavior. We further validated these results pharmacologically by demonstrating similar reductions in the alcohol deprivation effect after infusion of the NMDAR antagonist memantine into the nucleus accumbens and ventral tegmental area of control mice, and a rescue of the mutant phenotype via pharmacological potentiation of AMPAR activity using aniracetam. In conclusion, dopamine neurons as well as D1R-expressing medium spiny neurons and their glutamatergic inputs via NMDARs and AMPARs act in concert to influence relapse responses. These results provide a neuroanatomical and molecular substrate for relapse behavior and emphasize the importance of glutamatergic drugs in modulating relapse behavior.

Striatal H3K27 Acetylation Linked to Glutamatergic Gene Dysregulation in Human Heroin Abusers Holds Promise as Therapeutic Target

“…The AMPA glutamate receptor subunit Gria1 specifically has been implicated in substance use (14, 15, 20, 21) and related neuropsychiatric disorders (17). Our data now provide new insight highlighting the important contribution of specific acetylation disturbances related to transcriptional alterations of striatal GRIA1 in human heroin abusers that is dynamically regulated with repeated use of the drug.…”

Involvement of ventral tegmental area ionotropic glutamate receptors in the expression of ethanol-induced conditioned place preference

“…Cue-induced reinstatement of ethanol seeking was increased by positive allosteric modulation of AMPA receptors [29] and decreased by genetic deletion of the GluR-C AMPA subunit [30], further supporting a role for iGluRs. In addition, recent work has indicated that glutamate inputs to VTA DA neurons influence ethanol relapse through combined action at NMDA and AMPA receptors [31]. …”

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

“…In contrast, NMDAR inhibition within the NAc does strongly inhibit compulsion‐like alcohol consumption that is driven by NAc adaptations in non‐canonical NMDARs (Seif et al , ; see below). Furthermore, NAc NMDARs do not regulate cue‐induced alcohol reinstatement in rats (Backstrom & Hyytia ) or mice (Eisenhardt et al ). In contrast, pharmacological NMDAR inhibition or genetic NMDAR knockdown in direct pathway cells within the NAc strongly reduces the Alcohol Deprivation Effect, a model of relapse where consumption is greatly enhanced by protracted abstinence (Eisenhardt et al ).…”

“…Furthermore, NAc NMDARs do not regulate cue‐induced alcohol reinstatement in rats (Backstrom & Hyytia ) or mice (Eisenhardt et al ). In contrast, pharmacological NMDAR inhibition or genetic NMDAR knockdown in direct pathway cells within the NAc strongly reduces the Alcohol Deprivation Effect, a model of relapse where consumption is greatly enhanced by protracted abstinence (Eisenhardt et al ). Overall, these studies suggest that NAc NMDARs are not required for simpler forms of intake, similar to what is observed for cocaine (see above), but are critical for states of higher motivation, including compulsion‐like drinking and the Alcohol Deprivation Effect.…”

“…Finally, although there are limited studies, inhibition of NMDARs within the VTA decreases both the expression of alcohol CPP (Pina & Cunningham ) and the Alcohol Deprivation Effect (Eisenhardt et al ). In contrast, neither operant nor two‐bottle choice alcohol self‐administration are altered (Eisenhardt et al ).…”