Role of D1-like receptors in amphetamine-induced behavioral sensitization:: a study using D1A receptor knockout mice

Rationale: The role played by D-1-like receptors in amphetamine-induced behavioral sensitization has been examined using both the D-1-like receptor antagonist, SCH 23390, and the D-1A receptor knockout mouse (i.e. D-1A-deficient mice). Studies using these two approaches have provided conflicting evidence about the importance of D-1-like receptors for amphetamine-induced behavioral sensitization. Objective: The purpose of the present study was to determine: (a) whether D-1A-deficient mice exhibit amphetamine-induced locomotor sensitization after 3 and 17 drug abstinence days, and (b) whether SCH 23390, which binds to both D-1A and D-1B receptor subtypes. blocks development of amphetamine sensitization in wild-type and D-1A-deficient mice. Methods: In the first experiment, adult wild-type and D-1A-deficient mice were injected with amphetamine (0, 1, 2, 4, or 8 mg/kg, IP) for 7 consecutive days. In the second experiment, wild-type and D-1A-deficient mice were pretreated with SCH 23390 (0, 0.15, or 0.5 mg/kg, IP) 30 min prior to being injected with amphetamine (0 or 8 mg/kg. IP). After each daily amphetamine injection. mice were placed in activity chambers where distance traveled (i.e. horizontal locomotor activity) was measured for 60 min. On the test days, which occurred after 3 or 17 drug abstinence days, mice were injected with I mg/kg amphetamine and locomotion was measured for 120 min. Results: Both wild-type and D-1A-deficient mice exhibited amphetamine-induced locomotor sensitization. Pretreatment with 0.5 mg/kg SCH 23390 blocked the development of locomotor sensitization in wild-type mice, but did not alter the sensitized responding of D-1A-deficient mice. Conclusions: It appears that D-1-like receptors are necessary for the development of amphetamine sensitization in wild-type mice, while neither the D-1A nor D-1B receptor subtypes are necessary for the amphetamine-induced locomotor sensitization of D-1A-deficient mice. A possible explanation for these conflicting results is that D-1A-deficient mice may have a compensatory mechanism (not involving, D-1B receptors) that allows them to exhibit amphetamine-induced behavioral sensitization in the absence of the D-1A receptor.