Repeated stimulation of D1 dopamine receptors causes time-dependent alterations in the sensitivity of both D1 and D2 dopamine receptors within the rat striatum.

Recent evidence suggests that repeated stimulation of D1 dopamine receptors within the rat striatum leads to an enhancement of both D1 and D2 dopamine receptor-mediated responses. The present study used both behavioral observations and extracellular single unit recording techniques to investigate this phenomenon following repeated administration of selective D1 dopamine receptor agonists. Groups of rats received twice daily administration of either saline or the partial D1 dopamine receptor agonist SKF 38393 (8 mg/kg, s.c.) for three weeks. Rats were tolerant to the ability of SKF 38393 to enhance grooming behavior when tested immediately following the last of the 42 treatment injections. However, the ability of this last SKF 38393 injection to potentiate oral stereotyped behavior following administration of the D2 DA agonist quinpirole was still evident. Following a one-day withdrawal, grooming responses to SKF 38393 had returned to normal. At this time, administration of quinpirole, without concomitant SKF 38393, failed to significantly promote oral stereotypies, as is typical of normal rats. Following a one-week withdrawal period, SKF 38393-induced grooming behavior was significantly enhanced and quinpirole, administered without SKF 38393, produced pronounced oral stereotyped behavior in 10 of 12 rats tested. Following a one-month withdrawal, these sensitized responses were no longer evident. Single-cell recordings from rat lateral striatal neurons revealed similar time-dependent alterations in the effects of iontophoretically administered SKF 38393 and quinpirole. Current-response curves revealed that, without a withdrawal period, striatal neurons were subsensitive to the inhibitory effects of SKF 38393 but not quinpirole. The decreased inhibitory responses of striatal neurons to SKF 38393 returned to normal levels after a one-day withdrawal. Following a one-week withdrawal, the effects of both agonists were significantly greater than that in saline-treated controls. Normosensitivity was evident following a one-month withdrawal. Repeated administration of the full D1 DA agonist SKF 81297 (0.5 mg/kg, s.c., twice daily) also resulted in sensitized responses of striatal neurons following a one-week withdrawal, demonstrating that the sensitization to SKF 38393 was not due to its partial agonist character. The present findings provide both behavioral and electrophysiological evidence that repeated stimulation of D2 dopamine receptors results in a brief subsensitivity, followed by transient sensitization of the D1 receptors. The enhanced effects of D2 dopamine agonists might be due to an enhanced synergism (enabling) produced by endogenous dopamine stimulating supersensitive D1 receptors. However, the possibility of a direct change in D2 dopamine receptor sensitivity cannot be eliminated since the D1 receptor appears to regulate D2 receptor sensitivity under certain conditions. Given the similarity of these results to those obtained following repeated administration of psychomotor stimulants, it is argued that striatal D1 receptor supersensitivity may play a role in behavioral sensitization.