Importance of D1 receptors for associative components of amphetamine-induced behavioral sensitization and conditioned activity:: a study using D1 receptor knockout mice

Rationale: Repeated exposure to psychostimulant drugs results in conditioned activity and behavioral sensitization. Nonassociative cellular changes are necessary for behavioral sensitization, while associative processes appear to modify the sensitized response. Objective: The purpose of the present study was to determine whether the absence of the D, receptor would disrupt associative processes modulating sensitization and conditioned activity. Methods: Wild-type and D-1 receptor knockout mice (i.e., D-1-deficient mice) were injected with amphetamine (AMPH; 8 mg/kg, IP) before being placed in a previously novel test chamber (AMPH-Test group) or before being returned to the home cage (AMPH-Home group). Separate groups of mice were injected with saline (SAL) at the same time points. Distance traveled was measured 60 min each day, with the preexposure phase lasting 1 or 7 days. Sensitization was subsequently assessed after an injection of AMPH (1 mg/kg, IP), while conditioned activity was assessed after an injection of SAL. Results: After a 1-day preexposure phase, wild-type and D-1-deficient mice exhibited similar patterns of sensitization and conditioned activity. After a 7-day preexposure phase, (1) D-1-deficient mice exhibited more robust context-specific sensitization than wild-type mice, (2) only D-1-deficient mice showed context-independent sensitization, and (3) only D-1-deficient mice showed conditioned activity. Conclusions: Repeatedly treating D-1-deficient mice with AMPH appears to cause a general increase in responsivity. The reason for this hyper-responsivity is uncertain, but it is possible that cues from the testing environment were unable to inhibit responding (i.e., associative processes were disrupted). Alternatively, compensatory mechanisms (e.g., increases in D-2-like receptors) may affect processes underlying sensitization and conditioned activity.