Targeting glutamate uptake to treat alcohol use disorders

Abstract

Alcoholism is a serious public health concern that is characterized by the development of tolerance to alcohol's effects, increased consumption, loss of control over drinking and the development of physical dependence. This cycle is often times punctuated by periods of abstinence, craving and relapse. The development of tolerance and the expression of withdrawal effects, which manifest as dependence, have been to a great extent attributed to neuroadaptations within the mesocorticolimbic and extended amygdala systems. Alcohol affects various neurotransmitter systems in the brain including the adrenergic, cholinergic, dopaminergic, GABAergic, glutamatergic, peptidergic, and serotonergic systems. Due to the myriad of neurotransmitter and neuromodulator systems affected by alcohol, the efficacies of current pharmacotherapies targeting alcohol dependence are limited. Importantly, research findings of changes in glutamatergic neurotransmission induced by alcohol self- or experimenter-administration have resulted in a focus on therapies targeting glutamatergic receptors and normalization of glutamatergic neurotransmission. Glutamatergic receptors implicated in the effects of ethanol include the ionotropic glutamate receptors (AMPA, Kainate, and NMDA) and some metabotropic glutamate receptors. Regarding glutamatergic homeostasis, ceftriaxone, MS-153, and GPI-1046, which upregulate glutamate transporter 1 (GLT1) expression in mesocorticolimbic brain regions, reduce alcohol intake in genetic animal models of alcoholism. Given the hyperglutamatergic/hyperexcitable state of the central nervous system induced by chronic alcohol abuse and withdrawal, the evidence thus far indicates that a restoration of glutamatergic concentrations and activity within the mesocorticolimbic system and extended amygdala as well as multiple memory systems holds great promise for the treatment of alcohol dependence.

Keywords: EAAT2; GLT1; alcohol; dopamine; glutamate; neurotransmitter.

Figure 1

Diagram of glutamatergic neurocircuits within the mesocorticolimbic system (blue hexagonals and associated arrows), extended amygdala (red rectangles and associated arrows) as well as related memory (green circles and associated arrows) and limbic structures involved in the development of alcohol/drug dependence. The early experimentation/intoxication stage of alcohol/drug abuse is marked by neuroplastic changes in the mesocorticolimbic system. Later, the extended amygdala plays an increasingly greater role, relative to the mesocorticolimbic system (although these systems interact as seen in this Figure), in mediating continued alcohol/drug usage despite physical, emotional, social and/or economic consequences. In later stages of alcohol dependence, most of the neuroplastic changes to the mesocorticolimbic and extended amygdala systems attributed to repeated cycles of alcohol/drug abuse—withdrawal—and relapse have already occurred. While associative learning, contextual conditioning, and habit formation have been occurring throughout the addiction cycle, highlighted are these multiple memory systems (that interact and often overlap) which experience a substantial increase in glutamatergic activity-mediated neuroplastic changes. Basic descriptors of the memory processes mediated by the hippocampus and caudate-putamen, as well as the stages of relapse they influence, are also indicated. ACB, Nucleus Accumbens; AMYG, Amygdala; BNST, Bed Nucleus of the Stria Terminalis; CPU, Caudate Putamen; CTX, Cortex; HIPP, Hippocampus; MDTN, Medial Dorsal Thalamic Nucleus; ML, Mesolimbic; mPFC, Medial Prefrontal Cortex; VTA, Ventral Tegmental Area.