Further studies on the interaction between bromocriptine and SKF38393 in reserpine and alpha methyl-para-tyrosine-treated mice

Abstract

In a previous report, we showed that the relatively selective dopamine (DA) D-2 agonist bromocriptine (BRC), when combined with the selective D-1 agonist SKF38393, produced in DA-depleted mice a marked locomotor stimulation, despite BRC and SKF38393 being inactive by themselves (Jackson and Hashizume 1986). The present series of experiments was designed to further explore this interaction. In all experiments, mice were pretreated with reserpine and/or alpha methyl-p-tyrosine (AMPT). In mice pretreated with reserpine, AMPT or reserpine plus AMPT, BRC plus SKF38393 produced marked excitation whether the BRC was given 3 or 1 h prior to the SKF38393 challenge. However, while there was no absolute requirement that BRC be given a certain time before SKF38393, this factor was of some importance, with the onset of locomotor stimulation produced by the combination being much more rapid if the BRC was given 3 h rather than 1 h before the SKF38393. Interestingly, the degree of locomotor stimulation produced by the combination was always greatest in the animals premedicated with reserpine alone. If AMPT was also used (with or without reserpine), the stimulation produced by the combination was reduced, which may have resulted in part from a non-specific depressant effect of the AMPT. From these results, it seems as though endogenous DA is not required for BRC to work, provided that D-1 receptors are stimulated. The BRC/SKF38393 stimulation lasted for about 4 h, but could be extended for another 3 h with a second injection of SKF38393, indicating that the biological half-life of SKF38393 is the limiting factor in the duration of stimulation produced by the combination. The stimulation produced by the combination was completely blocked by the D-1 antagonist SCH23390. The data confirm the importance of D-1 receptors for the locomotor stimulant effects of BRC.