The effects of single nucleotide polymorphisms in glutamatergic neurotransmission genes on neural response to alcohol cues and craving

Bach, Patrick; Kirsch, Peter; Hoffmann, Sabine; Jorde, Anne; Mann, Karl; Frank, Josef; Charlet, Katrin; Beck, Anne; Heinz, Andreas; Walter, Henrik; Rietschel, Marcella; Kiefer, Falk; Vollstädt‐Klein, Sabine

doi:10.1111/adb.12291

Cited by 34 publications

(24 citation statements)

References 37 publications

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“…In a massive genetics study, Schumann et al . 128 reported that genetic variations in GluN2A have the greatest relevance for human alcohol dependence among 10 glutamatergic probe genes, yet increased GluN2B expression and GluN2C in the ACC and dorsolateral PFC during withdrawal can indicate likelihood of alcohol craving and risk for relapse 129, 130 . It appears that the ACC is a distinct site for glutamate plasticity in heavy drinking.…”

Section: Heavy Drinking and Withdrawalmentioning

confidence: 99%

Glutamate plasticity woven through the progression to alcohol use disorder: a multi-circuit perspective

2017

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Glutamate signaling in the brain is one of the most studied targets in the alcohol research field. Here, we report the current understanding of how the excitatory neurotransmitter glutamate, its receptors, and its transporters are involved in low, episodic, and heavy alcohol use. Specific animal behavior protocols can be used to assess these different drinking levels, including two-bottle choice, operant self-administration, drinking in the dark, the alcohol deprivation effect, intermittent access to alcohol, and chronic intermittent ethanol vapor inhalation. Importantly, these methods are not limited to a specific category, since they can be interchanged to assess different states in the development from low to heavy drinking. We encourage a circuit-based perspective beyond the classic mesolimbic-centric view, as multiple structures are dynamically engaged during the transition from positive- to negative-related reinforcement to drive alcohol drinking. During this shift from lower-level alcohol drinking to heavy alcohol use, there appears to be a shift from metabotropic glutamate receptor-dependent behaviors to N-methyl-D-aspartate receptor-related processes. Despite high efficacy of the glutamate-related pharmaceutical acamprosate in animal models of drinking, it is ineffective as treatment in the clinic. Therefore, research needs to focus on other promising glutamatergic compounds to reduce heavy drinking or mediate withdrawal symptoms or both.

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Section: Heavy Drinking and Withdrawalmentioning

confidence: 99%

Glutamate plasticity woven through the progression to alcohol use disorder: a multi-circuit perspective

2017

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“…Other clinical studies have shown that memantine reduces intake and cravings in treatment‐seeking AUD patients with co‐morbid depression (Muhonen et al ), although it had no effect in another study of treatment‐seekers (Evans et al ). Nonetheless, a GluN2C single nucleotide polymorphism linked to risk for alcoholism is associated with greater activation of several cortical areas by alcohol cues, and where brain activity is related to both craving and future relapse (Bach et al ). Taken together, these findings suggest that non‐canonical NMDARs can play a significant role in regulating addiction to alcohol, and perhaps other drugs of abuse (Sedaghati et al ), particularly under conditions where there is conflict regarding intake.…”

Section: Non‐canonical Nmdars and Cocaine And Alcohol Addictionmentioning

confidence: 99%

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

Hopf

2016

Genes Brain and Behavior

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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.

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“…Bach et al . ) and indicated cue‐induced activation of the VS only when comparing alcohol dependent patients and healthy controls after small volume correction analyses (e.g. Vollstädt‐Klein et al .…”

Section: Introductionmentioning

confidence: 99%

Ghrelin modulates mesolimbic reactivity to alcohol cues in alcohol‐addicted subjects: a functional imaging study

et al. 2018

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Ghrelin has been shown to be involved in the pathophysiology of alcohol dependence, affecting alcohol self-administration and craving. However, the mechanism of action in alcohol dependence still has to be determined. We thus investigated whether ghrelin is associated with mesolimbic cue reactivity to alcohol cues and alcohol craving in recently detoxified alcohol-addicted subjects. We included 41 recently detoxified alcohol-dependent individuals. Functional magnetic resonance imaging (fMRI) was used to study mesolimbic cue reactivity during the presentation of alcohol-related pictures. Additionally, we assessed patients' alcohol craving using the Alcohol Urge Questionnaire and a visual analogue scale. Plasma concentrations of total and acylated (activated) ghrelin were measured in parallel to the fMRI session. The association between ghrelin plasma concentrations, mesolimbic cue reactivity and alcohol craving was assessed by performing correlation and mediation analyses. Alcohol-induced brain response in a network of brain clusters, including the right and left ventral striatum, showed a significant positive association with acylated ghrelin plasma concentration. Additionally, acylated ghrelin was significantly associated with craving. Mediation analyses showed that the association between acylated ghrelin plasma concentration and alcohol craving is mediated by a cue-induced brain response in the ventral striatum. Based on the finding that ghrelin modulates mesolimbic reactivity to alcohol cues, the following should be considered: If alcohol craving and the appetitive status were interrelated, this has to be taken into account when implementing fMRI studies for addictive disorders. Moreover, appetite regulation seems to represent a valid treatment target for reducing cue reactivity in addictive disorders.

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The effects of single nucleotide polymorphisms in glutamatergic neurotransmission genes on neural response to alcohol cues and craving

Cited by 34 publications

References 37 publications

Glutamate plasticity woven through the progression to alcohol use disorder: a multi-circuit perspective

Glutamate plasticity woven through the progression to alcohol use disorder: a multi-circuit perspective

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

Ghrelin modulates mesolimbic reactivity to alcohol cues in alcohol‐addicted subjects: a functional imaging study

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