Basic aspects of GABA-transmission in alcoholism, with particular reference to GABA-transaminase.
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.
Sherif
F M
FM
Department of Pharmacology, Al-Fateh Medical University, Tripoli, Libya.
Tawati
A M
AM
Ahmed
S S
SS
Sharif
S I
SI
D000612:4-Aminobutyrate Transaminase / Q000502:physiology*; D000437:Alcoholism / Q000201:enzymology / Q000503:physiopathology*; D000818:Animals; D006801:Humans; D051381:Rats; D009435:Synaptic Transmission / Q000502:physiology*; D005680:gamma-Aminobutyric Acid / Q000502:physiology*
D005680:gamma-Aminobutyric Acid; D000612:4-Aminobutyrate Transaminase