Imbalance between neuroexcitatory and neuroinhibitory amino acids causes craving for ethanol

Abstract

Long-term exposure to ethanol leads to an imbalance in different excitatory and inhibitory amino acids. When ethanol consumption is reduced or completely stopped, these imbalances in different amino acids and neurotransmitters are behaviorally expressed in the form of ethanol withdrawal. Glutamate, a major excitatory amino acid, and GABA, a major inhibitory amino acid, are responsible, at least partly, for ethanol withdrawal symptoms. The hypofunction of GABA_A receptors and enhanced function of NMDA receptors are suggested to be responsible for the increase in the behavioral susceptibility during ethanol withdrawal. This imbalance between receptors may be exacerbated by repeated withdrawal. Because multiple and repeated periods of chronic ethanol consumption and withdrawal often occur in alcohol abusers, animal studies on the neurochemical changes in different amino acids following chronic ethanol treatment (CET) that is interrupted by repeated ethanol withdrawal episodes may be of clinical relevance for the development of treatment strategies. Brain glutamate increases during the first cycle of ethanol withdrawal, and this increase is much higher during the third cycle of ethanol withdrawal. The elevated glutamate released in the hippocampus during the first cycle of ethanol withdrawal episode was exacerbated in subsequent withdrawal episodes. Acamprosate, a drug used during human alcohol detoxification, is able to completely block the glutamate increase observed during the first as well as the third withdrawal of ethanol. In ethanol-naïve rats, there was no change in the glutamate microdialysate content after an acute ethanol injection. However, when repeated ethanol injections were cued with a vinegar stimulus that had previously been associated with the same ethanol injection, a significant increase in glutamate microdialysate content was assayed. Furthermore, when the cue was omitted, the ethanol injection induced no changes in glutamate microdialysate content in rats that had been previously ethanol conditioned. By comparison, a saline injection had no effect on extracellular glutamate concentration in rats naïve for ethanol as well as in rats daily administered with repeated ethanol injections that were not paired with the cue. It appears probable that these conditioned responses by extracellular glutamate concentrations may participate in the environmental cue-induced conditioned cravings for ethanol that are thought to be related to the high frequency of relapse in detoxified alcoholics.

Introduction

There is increasing evidence to suggest that ethanol may affect the central nervous system (CNS) by interfering with amino acid neurotransmitter systems. Among the amino acid neurotransmitter systems are excitatory amino acids (aspartate and glutamate) that activate postsynaptic cells and the inhibitory amino acids (GABA and taurine) that depress the activity of the postsynaptic cells. Glutamate is the major neuroexcitatory amino acid in the CNS. It activates receptors, which are gated to ion channels or activates proteins mediating a second messenger. This neurotransmitter has been reported to play an important role in alcoholism (Tsai et al., 1995, Tsai et al., 1998). Glutamate receptors in the mammalian CNS are divided into ionotropic (NMDA, kainate, and AMPA) and metabotropic receptors. The NMDA receptor, which is coupled to a voltage-sensitive ion channel, is permeable to calcium and monovalent cations Na⁺ and K⁺, and has been implicated in many physiological and pathological processes, including synaptic plasticity, learning and memory, epileptiform seizures, and neurotoxicity.