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Voluntary adolescent drinking enhances excitation by low levels of alcohol in a subset of dopaminergic neurons in the ventral tegmental area.

ABSTRACT: Enhanced dopamine (DA) neurotransmission from the ventral tegmental area (VTA) to the ventral striatum is thought to drive drug self-administration and mediate positive reinforcement. We examined neuronal firing rates in slices of mouse midbrain following adolescent binge-like alcohol drinking and find that prior alcohol experience greatly enhanced the sensitivity to excitation by ethanol itself (10-50 mM) in a subset of ventral midbrain DA neurons located in the medial VTA. This enhanced response after drinking was not associated with alterations of firing rate or other measures of intrinsic excitability. In addition, the phenomenon appears to be specific to adolescent drinking, as mice that established a drinking preference only after the onset of adulthood showed no change in alcohol sensitivity. Here we demonstrate not only that drinking during adolescence induces enhanced alcohol sensitivity, but also that this DA neuronal response occurs over a range of alcohol concentrations associated with social drinking in humans.

SUBMITTER: Avegno EM

PROVIDER: S-EPMC5563459 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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Voluntary adolescent drinking enhances excitation by low levels of alcohol in a subset of dopaminergic neurons in the ventral tegmental area.

Avegno Elizabeth M EM Salling Michael C MC Borgkvist Anders A Mrejeru Ana A Whitebirch Alexander C AC Margolis Elyssa B EB Sulzer David D Harrison Neil L NL

Neuropharmacology 20160727 Pt A

Enhanced dopamine (DA) neurotransmission from the ventral tegmental area (VTA) to the ventral striatum is thought to drive drug self-administration and mediate positive reinforcement. We examined neuronal firing rates in slices of mouse midbrain following adolescent binge-like alcohol drinking and find that prior alcohol experience greatly enhanced the sensitivity to excitation by ethanol itself (10-50 mM) in a subset of ventral midbrain DA neurons located in the medial VTA. This enhanced respon ...[more]

PMID: 27475082

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Project description:The mesocorticolimbic dopamine system mediates the reinforcing effects of salient stimuli, including drugs of abuse. Nondependent chronic alcohol consumption modifies this system, resulting in an increased number of spontaneously active dopamine neurons in the posterior ventral tegmental area (VTA) of alcohol-preferring (P) rats. Enhanced responses of postsynaptic glutamate receptors may contribute to the increase in active dopamine neurons. Thus, excitations of putative dopamine neurons to locally applied N-methyl-d-aspartic acid (NMDA; glutamate receptor subtype agonist) were evaluated.P rats were assigned to alcohol naïve (water only) or alcohol drinking (continuous access to 15% alcohol and water for 8 consecutive weeks) groups. Responses of 23 putative dopamine neurons from naïve rats and 19 putative dopamine neurons from drinking rats were assessed in vivo using microiontophoretically applied NMDA. Current-response curves for firing frequency and burst activity were constructed using nonlinear mixed effects models. Between-group comparisons were made for EC(50) (effective current producing a half maximal excitatory response), E(max) (maximal excitatory effect), and C(DB) (the current at which depolarization block-marked decrease in neuronal activity-occurred).Drinking P rats steadily consumed alcohol over the 8-week protocol and did not exhibit signs of dependence or withdrawal. Putative dopamine neurons from drinking rats exhibited resistance to depolarization block (higher C(DB) values) and required larger doses of NMDA to elicit moderate excitatory responses (higher EC(50) values), consistent with decreased receptor affinity. Maximal excitatory responses (E(max) ) did not differ between the groups, consistent with no change in receptor number. Blood alcohol was at undetectable levels at the time of experimentation.NMDA receptor sensitivity is decreased on posterior VTA putative dopamine neurons in P rats on a nondependent schedule of alcohol consumption. Mechanisms underlying increased spontaneous dopamine neuron activity may be independent of changes in NMDA receptor function. Decreased NMDA receptor sensitivity may precede the development of dependence.

Project description:BackgroundChronic postsurgical pain (CPP) markedly impairs patients' quality of life. Research has shown that chronic stress may extend incisional nociception in male mice. Dopaminergic (DAergic) neurons in the ventral tegmental area (VTA) are integral to stress-related mental disorders (including major depressive disorder, anxiety disorders, and PTSD) and pain. However, the impact of chronic social defeat stress (CSDS) on mesolimbic dopamine (DA) transmission in the development of CPP is yet to be established. It remains uncertain whether the dopamine signals in the rostral anterior cingulate cortex (rACC), which regulate pain, derive from the VTA. This study aims to explore the role of VTA-rACC dopaminergic circuits in a mouse model of CPP induced by CSDS.MethodsWe conducted CSDS on C57BL/6 J wild-type male mice (n = 12-16 mice/group) and DAT-cre male mice (n = 10-12 mice/group). After 10 days of CSDS, a left posterior plantar incision was made to establish a mouse model of CPP. Paw withdrawal thresholds (PWTs) were evaluated using Von-Frey fibre stimulation. The open field test (OFT) and elevated plus maze test (EPM) were used to assess pain-related negative emotions. We used immunofluorescence staining and Western Blot to analyse D1, D2, c-Fos, and TH expression. DAergic fibre projections in the VTA-rACC neural pathway were traced using retrograde tracing and immunofluorescence staining. Optogenetics and Chemogenetics were employed to manipulate DAergic neurons in the VTA and their axons in the rACC.ResultsThe ipsilateral PWTs in male C57BL/6 J mice significantly decreased after surgery, returning to baseline after seven days. Conversely, in CSDS mice, ipsilateral PWTs remained reduced for at least 30 days post-incision. A significant reduction in TH-positive neurons expressing c-Fos in the VTA of CPP mice was observed 15 days post-incision. Activating DAergic neurons significantly improved ipsilateral PWTs and locomotor performance in the OFT and EPM in CPP mice post-incision. Additionally, D1 expression in the rACC was found to decrease in CPP mice, and this reduction counteracted the increase in PWTs caused by activating DAergic neuron axon terminals in the rACC.ConclusionCSDS results in chronicity of postsurgical nociception and anxiety-like negative emotions, with alterations in DA transmission playing a role in CPP. Specific activation of DAergic neurons mitigates nociceptive responses and anxiety-like bahaviors, possibly mediated by D1 receptors in the rACC.

Dataset Information

Voluntary adolescent drinking enhances excitation by low levels of alcohol in a subset of dopaminergic neurons in the ventral tegmental area.

Publications

Voluntary adolescent drinking enhances excitation by low levels of alcohol in a subset of dopaminergic neurons in the ventral tegmental area.

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