Evaluation of unconditioned novelty-seeking and d-amphetamine-conditioned motivation in mice

Following repeated association between psychostimulant drugs and a distinct environment, contextual cues acquire the ability to elicit a conditioned approach response. Further, both rats and mice have a natural drive to seek for the experience of novelty, and a previously unknown environment is able to elicit an unconditioned approach response. Both the experience of novelty and amphetamine (AMPH)-conditioned effects have been associated in rodents with the activation of brain meso-limbic dopaminergic pathways. This study assessed the relative strength of AMPH-conditioned and novelty-induced unconditioned motivations in mice. During the pretreatment period, mice were randomly assigned to three different treatment history groups, and received d-AMPH (0, 2, or 10 mg/kg i.p. once/day) injections for 3 days in the presence of a familiar environment. Following a 48-h washout from the last drug injection, animals were placed in the familiar and pretreatment-paired environment and challenged with either SAL (to evaluate conditioning) or a standard AMPH dose (2 mg/kg, to assess either acute drug effects or carryover influences of each animal's treatment history with the same drug). Following the opening of a partition, animals showed both a clear-cut preference for a novel environment as well as a marked novelty-induced hyperactivity. Interestingly, when mice were tested in a drug-free state in this free-choice paradigm, they expressed neither conditioning to the drug-associated environment nor carry-over effects on the novelty-induced hyperactivity profile. On the other hand, mice injected with AMPH showed a mixed profile, with AMPH 2 treatment history mice showing a conditioned preference for the familiar and drug-paired environment, whereas AMPH 10 animals preferred to spend more time in the novel compartment. Both AMPH doses were associated with an increased locomotion, whereas only the AMPH 10 dose resulted in a stereotyped behavioral syndrome, possibly reminiscent of an aversive "poor welfare" condition. Thus, as a function of the drug dosage, differential positive or negative incentive properties are suggested to be evoked by the AMPH-conditioned environment. In conclusion, a reliable and useful experimental paradigm has been developed to investigate the issue of vulnerability to a variety of habit-forming agents or emotional experiences whose positive reinforcing properties may rely on a common neurobiological mechanism.