Chronic amphetamine transforms the emotional significance of a novel but not a familiar environment: implications for addiction.

Both drug-induced locomotor sensitization and reactivity to novelty in rodents have been related to drug-craving mechanisms in humans. We investigated whether the exposure to a completely novel environment would modulate the expression of locomotor sensitization induced by repeated administration of amphetamine (Amp) in mice. In addition to locomotion, different open-field behavioural parameters were used to evaluate the possible involvement of anxiogenic-like effects induced by Amp, novelty or a combination of the two. In order to avoid misinterpretations due to different locomotor baseline conditions, we used an open-field illumination condition in which previous exposure to the apparatus did not modify locomotion (although it reliably increased grooming behaviour). Acute Amp administration increased locomotion in mice previously habituated to the open field (Hab) but not in mice exposed to the apparatus for the first time (Nov). This absence of Amp-induced locomotor activation in Nov mice may be related to higher anxiety-like levels, because these animals displayed longer freezing duration. However, only Nov mice developed locomotor sensitization. Because Amp challenge in Amp pre-treated Nov mice did not induce an increase in freezing behaviour, the locomotor sensitization in Nov mice might be related to the tolerance of Amp-induced anxiogenic-like behaviour in novel environments. Repeated Amp administration increased motivation to explore the environment in Nov mice in that these animals presented a within-session locomotion-habituation deficit. Our data suggest that a complex and plastic interaction between the anxiogenic and motivational properties of both novelty and Amp can critically modify the behavioural expression of craving-related mechanisms.