Importance of D(1) receptors for associative components of amphetamine-induced behavioral sensitization and...

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.

The purpose of the present study was to determine whether the absence of the D(1) receptor would disrupt associative processes modulating sensitization and conditioned activity.

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.

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.

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.