Abstract
Alcohol use disorder (AUD) is a debilitating condition marked by cyclic patterns of craving, use, and withdrawal. These pathological behaviors are mediated by multiple neurotransmitter systems utilizing glutamate, GABA, dopamine, ATP, and adenosine. In particular, purines such as ATP and adenosine have been demonstrated to alter the phase and function of the circadian clock and are reciprocally regulated by the clock itself. Importantly, chronic ethanol intake has been demonstrated to disrupt the molecular circadian clock and is associated with altered circadian patterns of activity and sleep. Moreover, ethanol has been demonstrated to disrupt purinergic signaling, while dysfunction of the purinergic system has been implicated in conditions of drug abuse such as AUD. In this review, we summarize our current knowledge regarding circadian disruption by ethanol, focusing on the reciprocal relationship that exists between oscillatory neurotransmission and the molecular circadian clock. In particular, we offer detailed explanations and hypotheses regarding the concerted regulation of purinergic signaling and circadian oscillations by neurons and astrocytes, and review the diverse mechanisms by which purinergic dysfuction may contribute to circadian disruption or alcohol abuse. Finally, we describe the mechanisms by which ethanol may disrupt or hijack endogenous circadian rhythms to induce the maladaptive behavioral patterns associated with AUD.
Highlights
Specialty section: This article was submitted to Integrative Physiology, a section of the journal Frontiers in Physiology
We describe the mechanisms by which ethanol may disrupt or hijack endogenous circadian rhythms to induce the maladaptive behavioral patterns associated with Alcohol use disorder (AUD)
Clock mutant mice exhibit increased locomotor activity, reduced anxiety-like and depression-like behaviors, and more frequent intracranial self-stimulation at a lower threshold (McClung et al, 2005; Roybal et al, 2007). These behaviors are associated with an increase in dopaminergic activity in the VTA and a general increase in glutamatergic tone, suggesting that circadian disruption may induce both region-specific and global changes in synaptic signaling which may further desynchronize circadian rhythms and contribute to the behavioral manifestations of AUD (McClung et al, 2005; Beaule et al, 2009). These results suggest that circadian rhythms and reward-regulated behaviors exist in a reciprocal relationship wherein molecular circadian oscillations dictate rhythms of anticipation and reward seeking, which may be re-entrained by ethanol and drugs of abuse
Summary
Time is an important factor governing human behavior. Each day we engage in repeated patterns of activity regarding work, sleep, and eating. Artificial and cultural traditions may inform our daily schedules and activities, robust, intrinsic physiological rhythms heavily influence our thoughts and behaviors. These circadian rhythms are entrained by external lighting cues and are reciprocally modified by our behaviors and environment, which may alter the phase and amplitude of biological rhythms controlling sleep, consumption, and other behaviors (Partch et al, 2014)
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