Synaptic Mechanisms of Ethanol Tolerance and Neuroplasticity: Insights from Invertebrate Models

Abstract

Alcohol tolerance is a neuroadaptive response that leads to a reduction in the effects of alcohol caused by previous exposure. Tolerance plays a critical role in the development of alcohol use disorder (AUD) because it leads to the escalation of drinking and dependence. Understanding the molecular mechanisms underlying alcohol tolerance is therefore important for the development of effective therapeutics and for understanding addiction in general. This review explores the molecular basis of alcohol tolerance in invertebrate models, Drosophila and C. elegans, focusing on synaptic transmission. Both organisms exhibit biphasic responses to ethanol and develop tolerance similar to that of mammals. Furthermore, the availability of several genetic tools makes them a great candidate to study the molecular basis of ethanol response. Studies in invertebrate models show that tolerance involves conserved changes in the neurotransmitter systems, ion channels, and synaptic proteins. These neuroadaptive changes lead to a change in neuronal excitability, most likely to compensate for the enhanced inhibition by ethanol.

Keywords: AUD; C. elegans; Drosophila; alcohol tolerance; invertebrates; neuroplasticity; neurotransmission.

Figure 1

Dynamics of inhibitory (I) and excitatory (E) state of a neural circuit in response to ethanol (EtOH). Neuronal excitation and inhibition are balanced in the naive state (a). Exposure to ethanol alters this balance by increasing inhibition in the CNS, leading to sedation (b). To counteract the increased inhibition caused by ethanol, the CNS responds by increasing excitation (c). This adaptation leads to a new state where the balance between excitation and inhibition is achieved (d). This rebalanced state, achieved through the compensatory increase in excitation, is known as tolerance.

Figure 2

Different types of tolerance determined in invertebrates. (A) Schematic of development of acute functional tolerance in C. elegans during a single session of ethanol exposure. C. elegans respond to ethanol by first increasing their movement (or body bends) followed by progressive lack of coordination and eventual immobility within 10 min of exposure. After 30 min, they recover their locomotion speed despite the continued presence of ethanol on the agar plate, indicating the development of acute tolerance. (B) Schematic of rapid tolerance in Drosophila. The flies are exposed to ethanol vapor by pipetting it onto the vial plugs. After 22 min of exposure, all the flies become sedated. Flies are left to recover for 4 h, which allows the ethanol from the first exposure to be fully metabolized. When the flies are re-exposed to the same dose of ethanol, they take longer to be sedated than the first exposure, indicating the development of rapid tolerance.