Role of D 1 -like receptors in amphetamine-induced behavioral sensitization: a study using D 1A receptor knockout mice

Rationale: The role played by D1-like receptors in amphetamine-induced behavioral sensitization has been examined using both the D1-like receptor antagonist, SCH 23390, and the D1A receptor knockout mouse (i.e. D1A-deficient mice). Studies using these two approaches have provided conflicting evidence about the importance of D1-like receptors for amphetamine-induced behavioral sensitization. Objective: The purpose of the present study was to determine: (a) whether D1A-deficient mice exhibit amphetamine-induced locomotor sensitization after 3 and 17 drug abstinence days, and (b) whether SCH 23390, which binds to both D1A and D1B receptor subtypes, blocks development of amphetamine sensitization in wild-type and D1A-deficient mice. Methods: In the first experiment, adult wild-type and D1A-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 D1A-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 1 mg/kg amphetamine and locomotion was measured for 120 min. Results: Both wild-type and D1A-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 D1A-deficient mice. Conclusions: It appears that D1-like receptors are necessary for the development of amphetamine sensitization in wild-type mice, while neither the D1A nor D1B receptor subtypes are necessary for the amphetamine-induced locomotor sensitization of D1A-deficient mice. A possible explanation for these conflicting results is that D1A-deficient mice may have a compensatory mechanism (not involving D1B receptors) that allows them to exhibit amphetamine-induced behavioral sensitization in the absence of the D1A receptor.