Circuit specificity in the inhibitory architecture of the VTA regulates cocaine-induced behavior

Edwards, Nicholas J.; Tejeda, Hugo A.; Pignatelli, Marco; Zhang, Shiliang; McDevitt, Ross A.; Wu, Jocelyn; Bass, Caroline E.; Bettler, Bernhard; Morales, Marisela; Bonci, Antonello

doi:10.1038/nn.4482

Cited by 119 publications

(157 citation statements)

References 56 publications

Supporting

Mentioning

145

Contrasting

Order By: Relevance

“…Previous studies including more recent optogenetic approaches have suggested that GABA B receptor-targeting neurons arise from the nucleus accumbens and regulate drug-induced behaviors (Sugita et al, 1992; Cameron and Williams, 1993; McCall et al, 2017; Edwards et al, 2017). However, our earlier work found no LTP GABA at GABA B synapses on dopamine neurons (Nugent et al, 2009), suggesting that the effects of persistently activated κORs are unlikely to involve the nucleus accumbens-VTA GABAergic afferents.…”

Section: Discussionmentioning

confidence: 99%

Constitutive activation of kappa opioid receptors at ventral tegmental area inhibitory synapses following acute stress

Polter

Barcomb

Chen

et al. 2017

eLife

View full text Add to dashboard Cite

Stressful experiences potently activate kappa opioid receptors (κORs). κORs in the ventral tegmental area regulate multiple aspects of dopaminergic and non-dopaminergic cell function. Here we show that at GABAergic synapses on rat VTA dopamine neurons, a single exposure to a brief cold-water swim stress induces prolonged activation of κORs. This is mediated by activation of the receptor during the stressor followed by a persistent, ligand-independent constitutive activation of the κOR itself. This lasting change in function is not seen at κORs at neighboring excitatory synapses, suggesting distinct time courses and mechanisms of regulation of different subsets of κORs. We also provide evidence that constitutive activity of κORs governs the prolonged reinstatement to cocaine-seeking observed after cold water swim stress. Together, our studies indicate that stress-induced constitutive activation is a novel mechanism of κOR regulation that plays a critical role in reinstatement of drug seeking.DOI: http://dx.doi.org/10.7554/eLife.23785.001

show abstract

Section: Discussionmentioning

confidence: 99%

Constitutive activation of kappa opioid receptors at ventral tegmental area inhibitory synapses following acute stress

Polter

Barcomb

Chen

et al. 2017

eLife

View full text Add to dashboard Cite

show abstract

“…Indeed, evidence supports neurochemical and physiological heterogeneity of VTA GABAergic neurons (Margolis et al, 2012; Morales and Margolis, 2017). In particular, GABA A receptors may be expressed by VTA DA neurons as well as local GABAergic interneurons (Edwards et al, 2017). Therefore, depending on the population of intra-VTA GABA A receptors activated, one can have an inhibitory or permissive effect on firing of VTA DA neurons.…”

Section: Discussionmentioning

confidence: 99%

Activation of extrasynaptic δ-GABAA receptors globally or within the posterior-VTA has estrous-dependent effects on consumption of alcohol and estrous-independent effects on locomotion

Melón

Nolan

Colar

et al. 2017

Hormones and Behavior

View full text Add to dashboard Cite

Recent reports support higher than expected rates of binge alcohol consumption among women and girls. Unfortunately, few studies have assessed the mechanisms underlying this pattern of intake in females. Studies in males suggest that alcohol concentrations relevant to the beginning stages of binge intoxication may selectively target tonic GABAergic inhibition mediated by GABAA receptor subtypes expressing the δ-subunit protein (δ-GABAAR). Indeed, administration of agonists that interact with these δ-GABAAR prior to alcohol access can abolish binge drinking behavior in male mice. These δ-GABAAR have also been shown to exhibit estrous-dependent plasticity in regions relevant to drug taking behavior, like the hippocampus and periaqueductal grey. The present experiments were designed to determine whether the estrous cycle would alter binge drinking, or our ability to modulate this pattern of alcohol use with THIP, an agonist with high selectivity and efficacy at δ-GABAAR. Using the Drinking-in-the-Dark (DID) binge-drinking model, regularly cycling female mice were given 2 hours of daily access to alcohol (20%v/v). Vaginal cytology or vaginal impedance was assessed after drinking sessions to track estrous status. There was no fluctuation in binge drinking associated with the estrous cycle. Both Intra-posterior-VTA administration of THIP and systemic administration of the drug was also associated with an estrous cycle dependent reduction in drinking behavior. Pre-treatment with finasteride to inhibit synthesis of 5α-reduced neurosteroids did not disrupt THIP’s effects. Analysis of δ-subunit mRNA from posterior-VTA enriched tissue samples revealed that expression of this GABAA receptor subunit is elevated during diestrus in this region. Taken together, these studies demonstrate that δGABAARs in the VTA are an important target for binge drinking in females and confirm that the estrous cycle is an important moderator of the pharmacology of this GABAA receptor subtype.

show abstract

“…For example, both cocaine and morphine increase locomotor activity but through different mechanisms. That is, activation of GABA B receptors expressed in dopaminergic neurons in the VTA is involved in the regulation of cocaine‐induced locomotion but not affects morphine‐induced locomotion . Therefore, although both morphine and cocaine increase locomotor activity, the downstream signaling that underlies this phenomenon may be quite different.…”

Section: Strategy To Investigate Dopamine‐independent Opioid Rewardmentioning

confidence: 99%

Opioid and nondopamine reward circuitry and state‐dependent mechanisms

Fujita

Ide

Ikeda

2018

Annals of the New York Academy of Sciences

View full text Add to dashboard Cite

A common notion is that essentially all addictive drugs, including opioids, activate dopaminergic pathways in the brain reward system, and the inappropriate use of such drugs induces drug dependence. However, an opioid reward response is reportedly still observed in several models of dopamine depletion, including in animals that are treated with dopamine blockers, animals that are subjected to dopaminergic neuron lesions, and dopamine-deficient mice. The intracranial self-stimulation response is enhanced by stimulants but reduced by morphine. These findings suggest that dopaminergic neurotransmission may not always be required for opioid reward responses. Previous findings also indicate the possibility that dopamine-independent opioid reward may be observed in opioid-naive states but not in opioid-dependent states. Therefore, a history of opioid use should be considered when evaluating the dopamine dependency of opioid reward.

show abstract

Circuit specificity in the inhibitory architecture of the VTA regulates cocaine-induced behavior

Cited by 119 publications

References 56 publications

Constitutive activation of kappa opioid receptors at ventral tegmental area inhibitory synapses following acute stress

Constitutive activation of kappa opioid receptors at ventral tegmental area inhibitory synapses following acute stress

Activation of extrasynaptic δ-GABAA receptors globally or within the posterior-VTA has estrous-dependent effects on consumption of alcohol and estrous-independent effects on locomotion

Opioid and nondopamine reward circuitry and state‐dependent mechanisms

Contact Info

Product

Resources

About