GABA-A and NMDA receptor subunit mRNA expression is altered in the caudate but not the putamen of the postmortem brains of alcoholics

Abstract

Chronic consumption of alcohol by humans has been shown to lead to impairment of executive and cognitive functions. Here, we have studied the mRNA expression of ion channel receptors for glutamate and GABA in the dorsal striatum of post-mortem brains from alcoholics (n = 29) and normal controls (n = 29), with the focus on the caudate nucleus that is associated with the frontal cortex executive functions and automatic thinking and on the putamen area that is linked to motor cortices and automatic movements. The results obtained by qPCR assay revealed significant changes in the expression of specific excitatory ionotropic glutamate and inhibitory GABA-A receptor subunit genes in the caudate but not the putamen. Thus, in the caudate we found reduced levels of mRNAs encoding the GluN2A glutamate receptor and the δ, ε, and ρ2 GABA-A receptor subunits, and increased levels of the mRNAs encoding GluD1, GluD2, and GABA-A γ1 subunits in the alcoholics as compared to controls. Interestingly in the controls, 11 glutamate and 5 GABA-A receptor genes were more prominently expressed in the caudate than the putamen (fold-increase varied from 1.24 to 2.91). Differences in gene expression patterns between the striatal regions may underlie differences in associated behavioral outputs. Our results suggest an altered balance between caudate-mediated voluntarily controlled and automatic behaviors in alcoholics, including diminished executive control on goal-directed alcohol-seeking behavior.

Glutamatergic plasticity and alcohol dependence-induced alterations in reward, affect and cognition

“…For the most part, these studies have generally supported the animal work demonstrating an up-regulation in glutamate receptors following chronic alcohol exposure (Breese et al, 1995; Jin et al, 2014b; Enoch et al, 2014; Bhandage et al, 2014; Laukkanen et al, 2015). Together with the animal studies described above, these data suggest that glutamatergic alterations within these regions likely plays a role in the impaired cognitive function and the transition from goal-direct to habitual behavior that is characteristic of alcohol addiction.…”

“…In fact, withdrawal from alcohol is associated with increased glutamate concentration in both humans and rodents (Hermann et al, 2012) and severity of alcohol dependence is positively correlated with CSF glutamate (Umhau et al, 2010). Furthermore, a growing body of literature is emerging indicating that significant glutamatergic adaptations occur in brain regions underlying reward, cognition, and affect in alcohol-dependent individuals (Jin et al, 2014a, 2014b; Enoch et al, 2014; Bhandage et al, 2014; Laukkanen et al, 2015). While human studies are critical to our understanding of the neuroadaptive processes that occur in addicted individuals, animal models have been essential to our appreciation of the cellular adaptations that occur within the neural circuits underlying dependence-induced symptomology, which may help to uncover pharmacological targets for the treatment of alcoholism.…”

Mechanisms of Action and Persistent Neuroplasticity by Drugs of Abuse

“…The same situation was found for other drugs of abuse (Albertson et al, 2004(Albertson et al, , 2006. Significant alterations in glutamate and GABA receptor mRNAs were found in postmortem brains of alcohol-dependent subjects, but the changes differed from one brain region to another (Jin et al, 2011(Jin et al, , 2014aBhandage et al, 2014). For these obvious reasons, we reviewed the literature for each drug according to the specific brain regions where alterations have been observed most commonly in preclinical experiments.…”

“…Moreover, the changes were dependent on the length of ethanol exposure. Recent data from human postmortem brain areas from controls and alcoholics have also revealed brain region-specific changes in GABA A and glutamate receptor subunit expression in alcoholics (Jin et al, 2011;Bhandage et al, 2014;Jin et al, 2014a,b).…”

Alteration in AMPA receptor subunit expression and receptor binding among patients with addictive disorders: A systematic review of human postmortem studies

“…Jin et al demonstrated that mRNA expressions of AMPA receptor subunits were lower in the central amygdala (n = 9) and higher in the hippocampus dentate gyrus (n = 13) in the patient group, while there were no differences in the dorsolateral prefrontal cortex (DLPFC) (n = 14) or the orbitofrontal cortex (OFC) (n = 11). Bhandage et al found that mRNAs expression levels were not different among any of the glutamate receptor subunits in the caudate and the putamen (n = 29). Farris et al showed higher gene connectivity including GRIA1 in the prefrontal cortex (n = 16).…”