Time-dependent alterations in ICSS thresholds associated with repeated amphetamine administrations.

The time interval between successive injections of psychostimulant drugs, such as amphetamine, plays an important role in the development of neuroadaptive responses to these drugs. Changes in reward function were quantified using a discrete-trial current-intensity paradigm to determine thresholds for lateral hypothalamic electrical self-stimulation after experimenter-administered amphetamine injections (4 mg/kg, IP) at 1- and 5-day intervals. Repeated administration of amphetamine produced progressive changes in ICSS behavior that were dependent on the time interval between injections. The acute effects of amphetamine on ICSS thresholds were potentiated, and threshold elevations associated with withdrawal from the drug diminished after repeated drug challenges at 5-day intervals. By contrast, daily injections of the same dose of amphetamine did not alter the acute threshold-lowering effect of the drug, but resulted in progressive increments in thresholds at later time points. Notably, the decreases in response latency produce by acute amphetamine administration were potentiated by both exposure regimens, which indicates a dissociation of drug effects on motor performance and brain stimulation reward. Thus, the distinct components of changes in reward function associated with acute amphetamine administration and subsequent withdrawal were differentially altered by the two exposure regimens, suggesting that the pattern of exposure is an important determinant of neuroadaptive responses to the drug.