D1 dopamine receptor activation is necessary for the induction of sensitization by amphetamine in the ventral tegmental area.

Repeated intermittent exposure to amphetamine produces long-term enhancements in the ability of this drug to produce locomotion and increase extracellular dopamine (DA) in the nucleus accumbens (NAcc). Three experiments were conducted to evaluate the role played by D1 DA receptors in the production of these changes in response to amphetamine. Rats were preexposed to amphetamine, alone or with a DA receptor antagonist, and tested for sensitization 1-3 weeks after the last drug injection. On the test for sensitization, locomotor (experiments 1 and 2) and NAcc DA (experiment 3) responses of the animals to a systemic amphetamine injection were assessed. In the first experiment, systemic injections of the D1 DA receptor antagonist SCH23390, but not other DA receptor antagonists with greater affinity for D2 DA and 5-HT2 receptors, blocked the development of locomotor sensitization produced by systemic injections of amphetamine. In the second experiment, locomotor sensitization induced by infusion of amphetamine into the ventral tegmental area (VTA) was blocked when these injections were preceded by systemic injections of SCH23390. Finally, in experiment three, co-injecting SCH23390, but not its inactive enantiomer, with amphetamine into the VTA during preexposure prevented sensitization of the NAcc DA response to this drug. These results indicate that while D2 DA receptor activation is not necessary for the induction of locomotor sensitization to amphetamine, D1 DA receptors located in the VTA play a critical role in the development of sensitized locomotor and NAcc DA response to this drug.