State-dependent behavioural sensitization: evidence from a chlordiazepoxide state.

The present study investigated the hypothesis that behavioural sensitization to psychomotor stimulants is expressed only if the internal state of the animal is the same as it was at the time of sensitization development. This state-dependency hypothesis has previously been put forward to explain the apparent blockade of sensitization by N-methyl-D-aspartate (NMDA) receptor antagonists. The present study used amphetamine (0.375 mg/kg) as the stimulant and chlordiazepoxide (CDP) as a secondary stimulus. Mice were given double injections of either amphetamine + CDP, amphetamine + saline, CDP + saline, or saline + saline daily over 8 days. On the ninth and tenth days, all mice were challenged with amphetamine + saline and with CDP + saline, in a counterbalanced design. CDP does not show evidence of locomotor sensitization and does not act at NMDA receptors, but in other studies it has been shown to give rise to state-dependent-like effects. Thus any progressive augmentation of the response to repeated amphetamine + CDP treatment would be attributable to amphetamine sensitization, and any blockade of sensitization would not be due to NMDA receptor antagonism. Both groups receiving amphetamine became sensitized over the first 8 days (shown by progressive increases in locomotion). When challenged with amphetamine alone, the amphetamine + CDP group failed to show a sensitized response. This observation supports the state-dependency hypothesis and emphasizes the importance of considering the context provided by drug-induced internal states in studies of sensitization.