Glutamate plasticity woven through the progression to alcohol use disorder: a multi-circuit perspective

Abstract

Glutamate signaling in the brain is one of the most studied targets in the alcohol research field. Here, we report the current understanding of how the excitatory neurotransmitter glutamate, its receptors, and its transporters are involved in low, episodic, and heavy alcohol use. Specific animal behavior protocols can be used to assess these different drinking levels, including two-bottle choice, operant self-administration, drinking in the dark, the alcohol deprivation effect, intermittent access to alcohol, and chronic intermittent ethanol vapor inhalation. Importantly, these methods are not limited to a specific category, since they can be interchanged to assess different states in the development from low to heavy drinking. We encourage a circuit-based perspective beyond the classic mesolimbic-centric view, as multiple structures are dynamically engaged during the transition from positive- to negative-related reinforcement to drive alcohol drinking. During this shift from lower-level alcohol drinking to heavy alcohol use, there appears to be a shift from metabotropic glutamate receptor-dependent behaviors to N-methyl-D-aspartate receptor-related processes. Despite high efficacy of the glutamate-related pharmaceutical acamprosate in animal models of drinking, it is ineffective as treatment in the clinic. Therefore, research needs to focus on other promising glutamatergic compounds to reduce heavy drinking or mediate withdrawal symptoms or both.

Keywords: addiction; alcohol; chronic intermittent ethanol vapor; drinking in the dark; glutamate; intermittent access to alcohol; self-administration; two-bottle choice.

Figure 1.. A sagittal representation of subcortical structures and their circuitry related to different stages during the transition from low-level drinking to heavy alcohol use.

Regions of interest in red indicate involvement in heavy drinking, yellow in episodic drinking, and green in lower-level drinking. Known connections start with the black circle and finish with the black arrowhead. Animal drinking protocols are depicted in blue italics. ACC, anterior cingulate cortex; BLA, basolateral amygdala; BNST, bed nucleus of the stria terminalis; CeA, central amygdala; HIPP, hippocampus; NAc, nucleus accumbens; PFC, prefrontal cortex; VTA, ventral tegmental area.