Effects of repeated administration of the preferential dopamine autoreceptor antagonist, (+)-AJ76, on locomotor activity and brain DA metabolism in the rat

AJ76, the cis-(+)-(1S,2R) enantiomer of 5-methoxy-1-methyl-2-(n-propyl-amino) tetralin is a dopamine autoreceptor antagonist which has shown locomotor stimulatory properties, especially in habituated rats. AJ76 was given repeatedly to male rats at different time intervals and different doses to investigate if tachyphylaxis/tolerance would develop. Tolerance did not occur if AJ76 (300 mumol/kg p.o.) was administered once daily for 7 days, (regarding both stimulation of locomotor activity and increase in brain DOPAC levels). Tolerance occurred after a single dose of 52 mumol/kg s.c. given in the morning followed by the same challenge dose 4 but not 24 h later. When the first dose was decreased to 13 mumol/kg s.c. no tachyphylaxis could be demonstrated regarding stimulation of locomotor activity. It is concluded that AJ76 induces a dose-dependent and short lasting tachyphylaxis, while no tolerance is observed after one week repeated administration. The possible mechanism behind these effects are discussed.