A glutamatergic hypothesis of drug dependence: extrapolations from benzodiazepine receptor ligands

This article explores some of the data available on processes underlying dependence and withdrawal following chronic treatment with substances acting at GABA(A) receptors. It is argued that adaptations arising from chronic treatment with benzodiazepines (BZs) and ethanol, on the one hand, and inverse agonists at BZ receptors, on the other, cannot be explained by changes primarily in GABAergic systems, and that compensatory changes in glutamatergic transmission account at least partially for tolerance to, and dependence on, BZs and ethanol. The literature on ethanol dependence also points to sensitisation following repeated withdrawals (i.e. increasing intensity of certain withdrawal symptoms and signs) as a potentially important factor in ethanol dependence. It is predicted that a similar sensitisation may also result from repeated BZ withdrawal. In the case of ethanol, this kindling-like process is also dependent on glutamatergic neurotransmission. Parallels are drawn between changes underlying the increase in sensitivity to repeated withdrawal and kindling to BZ receptor inverse agonists. The involvement of glutamatergic mechanisms in the development of tolerance to and dependence on other abused drugs is also explored. The role of glutamate in the development of behavioural sensitisation to psychomotor stimulants and other abused drugs is addressed, and the possibility raised that similar processes may be involved in both behavioural sensitisation and withdrawal sensitisation.