A working model to account for chemical dependence on ethanol implicates γ-aminobutyrate type A (GABA_A) and N-methyl-D-aspartate (NMDA) receptors. Acute ethanol exposure potentiates inhibitory GABAergic and inhibits excitatory NMDA receptor function. Compensatory changes following chronic ethanol treatment result in downregulation of GABAergic receptor and upregulation of NMDA receptor function, restoring equilibrium in the presence of ethanol, but resulting in hyperactivity on ethanol withdrawal. These effects appear to be mediated by differential expression of the various subunits of the GABA_A receptor and the NMDA receptor. The altered NMDA receptors potentially have increased polyamine sensitivity. Further, brain ornithine decarbozylase activity and polyamine levels are increased during the development of dependence and decrease rapidly during withdrawal suggesting that this compensatory change may act in concert with an altered NMDA receptor to generate receptor hyperactive during withdrawal. Increased calcium flux through upregulated NMDA receptors during withdrawal has two potential consequences; calcium can be excitotoxic and it may act as a second messenger which interacts with calcium-responsive elements, resulting in the activation of genes coding for inducible transcription factors, such as leucine zipper proteins which form the AP-1 complex and the zinc finger protein, Egr-1. AP-1 and Egr DNA-binding activities are selectively activated following withdrawal. The nature of these withdrawal-induced genes remains to be elucidated. However, genes associated with withdrawal-induced kindling and/or delayed cell death may well be expressed under the influence of these inducible transcription factors. If this is so, it could help explain how chronic ethanol exposure predisposes to brain damage.