GABAergic transmission modulates ethanol excitation of ventral tegmental area dopamine neurons

Theile, Jonathan W.; Morikawa, Hitoshi; Gonzales, Rueben A.; Morrisett, Richard A.

doi:10.1016/j.neuroscience.2010.10.046

Cited by 63 publications

(57 citation statements)

References 47 publications

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“…Projections from the VTA extend to regions implicated in the rewarding potential of drugs of abuse, including the NAcc (Van Bockstaele and Pickel, 1995;Olson et al, 2005) and the PFC (Carr and Sesack, 2000). An activation of the caudal VTA dopaminergic neurons, which is mediated by a reduced GABAergic signaling (Theile et al, 2011), is one of the cellular bases for alcohol reinforcement (Brodie et al, 1999;Xiao et al, 2009). Several studies have demonstrated that as the GABAergic activity in rostral VTA increases, the dopaminergic activity decreases, resulting in a diminished experience of reward and reinforcement (Ikemoto et al, 1997;Ding et al, 2009).…”

Section: Discussionmentioning

confidence: 99%

αCaMKII Autophosphorylation Controls the Establishment of Alcohol Drinking Behavior

Easton

Lucchesi

Lourdusamy

et al. 2013

Neuropsychopharmacol

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The a-Ca 2 þ /calmodulin-dependent protein kinase II (aCaMKII) is a crucial enzyme controlling plasticity in the brain. The autophosphorylation of aCaMKII works as a 'molecular memory' for a transient calcium activation, thereby accelerating learning. We investigated the role of aCaMKII autophosphorylation in the establishment of alcohol drinking as an addiction-related behavior in mice. We found that alcohol drinking was initially diminished in aCaMKII autophosphorylation-deficient aCaMKII T286A mice, but could be established at wild-type level after repeated withdrawals. The locomotor activating effects of a low-dose alcohol (2 g/kg) were absent in aCaMKII T286A mice, whereas the sedating effects of high-dose (3.5 g/kg) were preserved after acute and subchronic administration. The in vivo microdialysis revealed that aCaMKII T286A mice showed no dopamine (DA) response in the nucleus accumbens to acute or subchronic alcohol administration, but enhanced serotonin (5-HT) responses in the prefrontal cortex. The attenuated DA response in aCaMKII T286A mice was in line with altered c-Fos activation in the ventral tegmental area after acute and subchronic alcohol administration. In order to compare findings in mice with the human condition, we tested 23 single-nucleotide polymorphisms (SNPs) in the CAMK2A gene for their association with alcohol dependence in a population of 1333 male patients with severe alcohol dependence and 939 controls. We found seven significant associations between CAMK2A SNPs and alcohol dependence, one of which in an autophosphorylation-related area of the gene. Together, our data suggest aCaMKII autophosphorylation as a facilitating mechanism in the establishment of alcohol drinking behavior with changing the DA-5-HT balance as a putative mechanism.

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Section: Discussionmentioning

confidence: 99%

αCaMKII Autophosphorylation Controls the Establishment of Alcohol Drinking Behavior

Easton

Lucchesi

Lourdusamy

et al. 2013

Neuropsychopharmacol

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“…It should be noted that the concentrations of ethanol required to induce these effects are typically higher than those consistent with social drinking (e.g., 25-50 mM, with a BAL of 80 mg/dL corresponding to 17.4 mM), suggesting that the action of ethanol on the mesolimbic DA pathway only partially mediates its reinforcing effects in vivo. The net effect of ethanol on the activity of VTA DA neurons results from the summation of excitatory and inhibitory influences, including (i) direct excitation (23,39); (ii) indirect excitation, via enhancement of glutamatergic input (40); (iii) disinhibition, via suppression of GABAergic input (41)(42)(43); and, in other instances, (iv) indirect inhibition, via enhancement of GABAergic transmission (44)(45)(46)(47). Continuous 2BC 6 days (Fig.…”

Section: Girk3 Deletion Prevents Ethanol-induced Release Of Da In Thementioning

confidence: 99%

GIRK3 gates activation of the mesolimbic dopaminergic pathway by ethanol

Herman

Sidhu

Stouffer

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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G protein-gated inwardly rectifying potassium (GIRK) channels are critical regulators of neuronal excitability and can be directly activated by ethanol. Constitutive deletion of the GIRK3 subunit has minimal phenotypic consequences, except in response to drugs of abuse. Here we investigated how the GIRK3 subunit contributes to the cellular and behavioral effects of ethanol, as well as to voluntary ethanol consumption. We found that constitutive deletion of GIRK3 in knockout (KO) mice selectively increased ethanol bingelike drinking, without affecting ethanol metabolism, sensitivity to ethanol intoxication, or continuous-access drinking. Virally mediated expression of GIRK3 in the ventral tegmental area (VTA) reversed the phenotype of GIRK3 KO mice and further decreased the intake of their wild-type counterparts. In addition, GIRK3 KO mice showed a blunted response of the mesolimbic dopaminergic (DA) pathway to ethanol, as assessed by ethanol-induced excitation of VTA neurons and DA release in the nucleus accumbens. These findings support the notion that the subunit composition of VTA GIRK channels is a critical determinant of DA neuron sensitivity to drugs of abuse. Furthermore, our study reveals the behavioral impact of this cellular effect, whereby the level of GIRK3 expression in the VTA tunes ethanol intake under binge-type conditions: the more GIRK3, the less ethanol drinking.protein-gated inwardly rectifying potassium (GIRK) channels mediate slow inhibitory postsynaptic potentials following activation of G i/o -coupled receptors, thereby regulating membrane excitability in neuronal, cardiac, and endocrine cells. In neurons, GIRK channels exist as GIRK2 homotetramers or heterotetramers of GIRK1, GIRK2, and/or GIRK3 (reviewed in ref. 1). Despite overlapping distributions in the central nervous system, the three subunits exhibit cell type-specific patterns of expression within some brain regions (2-7). In particular, in the ventral tegmental area (VTA), dopaminergic (DA) neurons express only GIRK2 and GIRK3, whereas non-DA neurons also express GIRK1, a discrepancy that drives differential sensitivity of the two cell populations to G i/o -coupled receptor (e.g., GABA B receptor) activation (8-10).In addition to their activation by G i/o -coupled receptors, GIRK channels also can be directly activated by ethanol (11-14). The behavioral significance of GIRK channel activation by ethanol (either directly or through G proteins) is poorly understood, however. GIRK2 knockout (KO) mice are less sensitive to ethanol's rewarding and aversive effects, as measured in conditioned place preference and conditioned taste aversion tests (15). Ethanol-induced locomotor stimulation, anxiolytic-like effect, and withdrawal severity are also blunted in the absence of GIRK2 (16). Constitutive GIRK2 deletion produces numerous behavioral abnormalities, however, including increased seizure susceptibility, reduced anxiety-like behavior, hyperactivity, hyperalgesia, and enhanced operant response for food, making it difficult to interpre...

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“…GABA-A receptor antagonists, including picrotoxin (Theile et al, 2011) and bicuculline (Westerink et al, 1996), disinhibit VTA-DA release. Similarly, GABA-A receptor inverse agonist, FG7142, has been shown to activate VTA neurons (Murphy et al, 1996).…”

Section: Discussionmentioning

confidence: 99%

Role of GABA Deficit in Sensitivity to the Psychotomimetic Effects of Amphetamine

Ahn

Sewell

Elander

et al. 2015

Neuropsychopharmacol

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Some schizophrenia patients are more sensitive to amphetamine (AMPH)-induced exacerbations in psychosis-an effect that correlates with higher striatal dopamine release. This enhanced vulnerability may be related to gamma-aminobutyric acid (GABA) deficits observed in schizophrenia. We hypothesized that a pharmacologically induced GABA deficit would create vulnerability to the psychotomimetic effects to the 'subthreshold' dose of AMPH in healthy subjects, which by itself would not induce clinically significant increase in positive symptoms. To test this hypothesis, a GABA deficit was induced by intravenous infusion of iomazenil (IOM; 3.7 μg/kg), an antagonist and partial inverse agonist of benzodiazepine receptor. A subthreshold dose of AMPH (0.1 mg/kg) was administered by intravenous infusion. Healthy subjects received placebo IOM followed by placebo AMPH, active IOM followed by placebo AMPH, placebo IOM followed by active AMPH, and active IOM followed by active AMPH in a randomized, double-blind crossover design over 4 test days. Twelve healthy subjects who had a subclinical response to active AMPH alone were included in the analysis. Psychotomimetic effects (Positive and Negative Syndrome Scale (PANSS)), perceptual alterations (Clinician Administered Dissociative Symptoms Scale (CADSS)), and subjective effects (visual analog scale) were captured before and after the administration of drugs. IOM significantly augmented AMPH-induced peak changes in PANSS positive symptom subscale and both subjective and objective CADSS scores. There were no pharmacokinetic interactions. In conclusion, GABA deficits increased vulnerability to amphetamine-induced psychosis-relevant effects in healthy subjects, suggesting that pre-existing GABA deficits may explain why a subgroup of schizophrenia patients are vulnerable to AMPH.

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GABAergic transmission modulates ethanol excitation of ventral tegmental area dopamine neurons

Cited by 63 publications

References 47 publications

αCaMKII Autophosphorylation Controls the Establishment of Alcohol Drinking Behavior

αCaMKII Autophosphorylation Controls the Establishment of Alcohol Drinking Behavior

GIRK3 gates activation of the mesolimbic dopaminergic pathway by ethanol

Role of GABA Deficit in Sensitivity to the Psychotomimetic Effects of Amphetamine

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