Repeated administration of a dopamine D1 receptor agonist reverses the increased proportions of striatal dopamine D1High and D2High receptors in methamphetamine-sensitized rats

Repeated administration of psychostimulants produces a behavioural sensitization. Amphetamine-sensitized animals are known to have a higher proportion of high-affinity states of dopamine D2 receptors (D2(High) receptors) in the striatum. We recently reported that repeated administration of a dopamine D1 receptor agonist, R-(+)-SKF38393, reverses the established behavioural sensitization to methamphetamine (MAP). To investigate the mechanisms for reversal of behavioural sensitization, we examined the effect of repeated administration of the dopamine D1 receptor agonist on the proportions of D2(High) receptors and the high-affinity states of dopamine D1 receptors (D1(High) receptors) in the striatum. In the striatum from the MAP-sensitized rats, the proportions of D1(High) and D2(High) receptors (28.5 +/- 1.96 and 57.5 +/- 3.58%) were higher than those in the saline-control rats (12.0 +/- 1.01 and 21.9 +/- 1.60%, respectively). Repeated administration of R-(+)-SKF38393 to the MAP-sensitized rats reduced the increased proportions of D1(High) and D2(High) receptors to 12.4 +/- 1.57 and 31.0 +/- 2.14%, respectively, which were similar to the proportions in the saline-control rats. The total densities of dopamine D1 and D2 receptors were not altered in each treatment condition. The results demonstrate that the proportions of D1(High) and D2(High) receptors in the striatum are elevated in MAP-sensitized rats, and that repeated administration of the dopamine D1 receptor agonist to the MAP-sensitized rats reverses the increased proportions of D1(High) and D2(High) receptors. The findings reveal postsynaptic mechanisms for the development of behavioural sensitization to MAP and the reversal of established sensitization by repeated administration of the dopamine D1 receptor agonist.