Effects of repeated amphetamine treatment on the locomotor activity of the dopamine D1A-deficient mouse.

The role of dopamine D1A receptors in mediating amphetamine-induced sensitization was investigated using the D1A-deficient mouse. During the drug pre-exposure phase, D1A-deficient and control mice were injected for five consecutive days with saline or amphetamine (2 mg/kg, i.p.). Locomotor activity was measured on the first and fifth pre-exposure day. After three abstinence days, mice were given either amphetamine or saline and locomotor activity was again assessed. Mice were then sacrificed and protein kinase A (PKA) activity was measured. In contrast to control mice, D1A-deficient mice did not show a progressive increase in locomotor activity across days. Importantly, both control and mutant mice did exhibit behavioral sensitization, because mice pre-exposed and tested with amphetamine were more active than mice acutely tested with the drug. Even so, the amphetamine-induced locomotor activity of the mutant mice was significantly reduced when compared with similarly treated control mice, indicating that the sensitized response was less pronounced in the D1A-deficient mouse. PKA activity also varied depending on genotype, since amphetamine decreased PKA activity in control but not D1A-deficient mice.