European Neuropsychopharmacology 7 (1997) 1–7 Review Basic aspects of GABA-transmission in alcoholism, with particular reference to GABA-transaminase a, a a b * Fathi M. Sherif , Ahmed M. Tawati , Saleem S. Ahmed , Suleiman I. Sharif a Department of Pharmacology, Al-Fateh Medical University, Tripoli, Libya b Department of Pharmacology, Al- Arab Medical University, Benghazi, Libya Received 1 May 1996; accepted 19 September 1996 Abstract Neuronal dysfunction is the neurobiological basis for alcoholic behaviour, and ethanol craving seems related to hypofunction of the GABA-ergic activity. Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the central nervous system (CNS). In several studies, GABA has been shown to be an important target of ethanol in the CNS, partly, as a consequence of damage to membrane-bound enzymes and receptors. GABA is involved in mediating pre- and post-synaptic inhibition of neuronal activity. It is speculated that the initial excitatory effects of ethanol may be due to inhibition of GABA-ergic activity whereas the sedative effects of the higher doses may be mediated by the activation of this inhibitory system. In the CNS, GABA is synthesised from glutamic acid by the enzyme glutamate decarboxylase (GAD) and catabolized into succinic semialdehyde by the enzyme GABA-transaminase (GABA-T), which are pyridoxal phosphate (PLP) dependent enzymes. Platelet GABA-T was characterized as being similar to central GABA-T. Inhibition of GABA-T with certain potent and selective compounds markedly increases the levels of brain GABA. Experimentally, acute ethanol treatment does not alter GABA-T activity whereas chronic treatment produces an increase in the activity, though, with some reservations since a bimodal effect has been found in chronically ethanol-treated rats. Thus, as it will be discussed below, it may be suggested that GABA-T inhibitors (e.g. vigabatrin) could have a potential role in the treatment of alcoholism and in some of the problems of ethanol withdrawal and of other drugs of abuse. Related studies on metabolism and concentrations of GABA are also promising and show a greater increase in our understanding of the aetiology and treatment of ethanol dependence and withdrawal. In general, this article also reviews both the animal and clinical observations in the field of alcoholism with regard to the GABA system.  1997 Elsevier Science B.V. All rights reserved. Keywords: GABA; GABA-T; Alcohol; Alcoholism; Dependence; Tolerance 1. General introduction as monoamines and gamma-aminobutyric acid (GABA) (Ollat et al., 1988). For many years, it has been thought In many parts of the world, alcoholism is the major that ethanol and other aliphatic alcohols exerted their social, economic and public health problem. Social use and depressant effects on the CNS by dissolving lipid mem- abuse of alcohol are associated with the development of branes, thereby perturbing the function of ion channels and tolerance and dependence. Alcohol tolerance is demon- other proteins embedded therein. In recent years, attention strated by a reduced effect at a given blood or tissue has been focused on the effects of ethanol on the function concentration and could be developed after a single or a of both excitatory (glutamate) and inhibitory (GABA) period of chronic exposure (for references, see, e.g., Buck amino-acid-activated ion channels. Ethanol augments and Harris, 1991). In the central nervous system (CNS), GABA-mediated synaptic inhibition and fluxes of chloride ethanol alters the activity of various neurotransmitters such (Tiku and Kulkarni, 1988; see also below). Although ethanol can inhibit glutamate-activated ion currents, etha- * Corresponding author. Tel.: 1218 21 620301; fax: 1218 21 606486. nol affects predominantly N-methyl-D-aspartate (NMDA) 0924-977X / 97 / $17.00  1997 Elsevier Science B.V. All rights reserved PII S0924-977X(96)00383-5