Synaptic Transmission: Modulation, Plasticity And Effects Of Drugs Of Abuse

National Institute On Alcohol Abuse And Alcoholism

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Abstract

Chronic Alcohol Exposure Alters Acute Alcohol Effects on Dopamine Release: Potential Role in Alcohol Effects on Sleep Acute alcohol exposure is known to produce increases levels of the neuromodulator dopamine in the striatum, with the largest effects in the Nucleus accumbens (NAc)/ventral striatum and the dorsomedial (associative) striatum (DMS). This acute alcohol effect is largely attributed to enhanced activity of midbrain dopaminergic neurons that project to striatum where they release dopamine. The dopamine increase in NAc may contribute to the rewarding effects of the drug. In addition, alcohol has a less potent inhibitory action on dopamine release from terminals in the NAC. There is also considerable interest in how chronic alcohol exposure and regular binge-like alcohol drinking alter the dopaminergic system. To address this latter question with an emphasis on the associative brain circuitry we measured dopamine release following chronic alcohol exposure in the DMS using electrical stimulation and fast-scan cyclic voltammetry in C57Bl6/J mice. We used two alcohol exposure paradigms, chronic intermittent forced inhalational exposure to ethanol (CIE) and the drinking in the dark (DID) voluntary intake procedure. Both paradigms were conducted for 4 weeks, followed by a minimum 6 day forced abstinence period. Brain slices containing DMS were prepared from CIE and DID-exposed mice and appropriate controls beginning 6 days into forced abstinence. Voltammetric recordings in DMS revealed increased dopamine release and prolonged release in CIE-treated mice relative to air-only exposed controls. No such changes were observed in the DID-exposed mice. When acute ethanol application effects on dopamine release were examined, we observed no inhibition in alcohol naive mice, but inhibition by 40 mM ethanol in DMS in both CIE and DID-exposed mice. This finding indicates that the mechanisms underlying this acute alcohol action become stronger after chronic exposure. Such an adaptation could explain how the normal increase in dopamine produced by acute alcohol could be dampened following repeated heavy alcohol intake. We are currently investigating mechanisms that potentially contribute to the acute alcohol inhibition and the increase following chronic exposure. These experiments were carried out as part of a larger study examining alcohol effects on mouse sleep. We used polysomnography and our custom-designed unsupervised sleep scoring system to examine effects of CIE and DID on sleep in cohorts of 20 mice that contained both alcohol-treated animals and controls. Somewhat surprisingly we found that CIE had little effect on sleep, while DID produced increased wake and decreased non-rapid eye movement (NREM) sleep, despite the fact that blood alcohol concentrations were higher in the CIE paradigm. This finding provides an intriguing opportunity to relate the changes in dopamine release to sleep alterations observed in the DID mice. We are also beginning to explore other neural mechanisms that may contribute to the changes in sleep in these mice.