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

Pina, Melanie M.; Cunningham, Christopher L.

doi:10.1016/j.bbr.2016.06.063

Cited by 14 publications

(3 citation statements)

References 54 publications

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“…Stronger support for a role of the dopamine system in alcohol-seeking driven by discrete cues was provided by the finding that chemogenetically silencing VTA dopamine neurons reduced CS-triggered alcohol-seeking in a neutral context. This result corroborates data suggesting a role for cholinergic 72 and glutamatergic 73 signalling within the VTA in cue conditioning with alcohol. Importantly, neither the lowest effective CNO dose in this experiment nor a dose of clozapine that could have been produced through reverse metabolism of CNO impacted CS-triggered alcohol-seeking in rats that did not express designer receptors.…”

Section: Discussionsupporting

confidence: 91%

Dissociable mesolimbic dopamine circuits control responding triggered by alcohol-predictive discrete cues and contexts

et al. 2020

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Context can influence reactions to environmental cues and this elemental process has implications for substance use disorder. Using an animal model, we show that an alcohol-associated context elevates entry into a fluid port triggered by a conditioned stimulus (CS) that predicted alcohol (CS-triggered alcohol-seeking). This effect persists across multiple sessions and, after it diminishes in extinction, the alcohol context retains the capacity to augment reinstatement. Systemically administered eticlopride and chemogenetic inhibition of ventral tegmental area (VTA) dopamine neurons reduce CS-triggered alcohol-seeking. Chemogenetically silencing VTA dopamine terminals in the nucleus accumbens (NAc) core reduces CS-triggered alcohol-seeking, irrespective of context, whereas silencing VTA dopamine terminals in the NAc shell selectively reduces the elevation of CS-triggered alcohol-seeking in an alcohol context. This dissociation reveals new roles for divergent mesolimbic dopamine circuits in the control of responding to a discrete cue for alcohol and in the amplification of this behaviour in an alcohol context.

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Section: Discussionsupporting

confidence: 91%

Dissociable mesolimbic dopamine circuits control responding triggered by alcohol-predictive discrete cues and contexts

et al. 2020

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“…Therefore, Sorcs2 −/− mice stop drinking when they have quenched their thirst, while Wt might continue drinking. Similar behaviors have been reported for mice lacking DRD1 36 , DRD2 37 , 38 , and ionotrophic glutamate receptor signaling 39 . The finding is in accordance with our previous observation that Sorcs2 −/− mice also have reduced intake of alcohol in a two-bottle choice, a behavioral response that also is controlled by the dopaminergic system 40 , 41 .…”

Section: Discussionsupporting

confidence: 80%

Altered dopaminergic firing pattern and novelty response underlie ADHD-like behavior of SorCS2-deficient mice

et al. 2021

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Attention deficit hyperactivity disorder (ADHD) is the most frequently diagnosed neurodevelopmental disorder worldwide. Affected individuals present with hyperactivity, inattention, and cognitive deficits and display a characteristic paradoxical response to drugs affecting the dopaminergic system. However, the underlying pathophysiology of ADHD and how this relates to dopaminergic transmission remains to be fully understood. Sorcs2−/− mice uniquely recapitulate symptoms reminiscent of ADHD in humans. Here, we show that lack of SorCS2 in mice results in lower sucrose intake, indicating general reward deficits. Using in-vivo recordings, we further find that dopaminergic transmission in the ventral tegmental area (VTA) is shifted towards a more regular firing pattern with marked reductions in the relative occurrence of irregular firing in Sorcs2−/− mice. This was paralleled by abnormal acute behavioral responses to dopamine receptor agonists, suggesting fundamental differences in dopaminergic circuits and indicating a perturbation in the balance between the activities of the postsynaptic dopamine receptor DRD1 and the presynaptic inhibitory autoreceptor DRD2. Interestingly, the hyperactivity and drug response of Sorcs2−/− mice were markedly affected by novelty. Taken together, our findings show how loss of a candidate ADHD-risk gene has marked effects on dopaminergic circuit function and the behavioral response to the environment.

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“…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 ).…”

Section: Nmdar Contributions To 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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Involvement of ventral tegmental area ionotropic glutamate receptors in the expression of ethanol-induced conditioned place preference

Cited by 14 publications

References 54 publications

Dissociable mesolimbic dopamine circuits control responding triggered by alcohol-predictive discrete cues and contexts

Dissociable mesolimbic dopamine circuits control responding triggered by alcohol-predictive discrete cues and contexts

Altered dopaminergic firing pattern and novelty response underlie ADHD-like behavior of SorCS2-deficient mice

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

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