Amphetamine exposure selectively enhances hippocampus-dependent spatial learning and attenuates amygdala-dependent cue learning.

Behaviorally sensitizing regimen of amphetamine (AMPH) exposure has diverse effects on learning, memory, and cognition that are likely to be a consequence of long-term neural adaptations occurring in the cortico-limbic-striatal circuitry. In particular, altered dopamine signaling in the nucleus accumbens and medial prefrontal cortex has been implicated to underlie AMPH-induced changes in behavior. This study sought to test the hypothesis that repeated AMPH exposure disrupts the regulation of limbic information processing and the balance of competing limbic control over appetitive behavior. Mice received seven intraperitoneal injections of D-AMPH (2.5 mg/kg or 5 mg/kg) or vehicle solution (saline) and were trained in (1) a simultaneous conditioned cue and place preference task using a six-arm radial maze, found to depend on the integrity of the hippocampus (HPC) and basolateral amygdala (BLA), respectively and (2) a conditional BLA-dependent cue, and HPC-dependent place learning task using an elevated T-maze. In both tasks, the vehicle pretreatment group initially acquired cue learning, followed by the emergence of significant place/spatial learning. In contrast, pretreatment with repeated AMPH caused marked deviations from normal acquisition patterns of place and cue conditioning, significantly facilitating HPC-dependent place conditioning in the first task while attenuating BLA-dependent cue conditioning in both tasks. These findings provide the first demonstration of an aberrant regulation of HPC- and BLA-dependent learning as a result of AMPH exposure, highlighting the importance of the meso-coticolimbic dopamine system in maintaining the balance of limbic control over appetitive behavior.