Repeated SKF 38393 and nigrostriatal system neuronal responsiveness: functional down-regulation is followed by up-regulation after withdrawal.

The effects of chronic administration of the D1 dopamine (DA) agonist SKF 38393 on the basal activity and electrophysiological and pharmacological responsiveness of nigrostriatal DA neurons were examined by means of extracellular, single-unit recording techniques. Chronic D1 stimulation failed to alter either the basal activity of DA neurons or the potency of quinpirole to induce inhibition of these cells. However, 28-day SKF 38393 treatment (but not 14-day treatment) eliminated the ability of subsequent (24 h later) acute SKF 38393 to alter the rate-dependent nature of quinpirole-induced inhibition. In contrast, one week after a 28-day SKF 38393 treatment we found that quinpirole-induced inhibition by itself was no longer rate-dependent, an effect which was reversed by acute pretreatment with the D1 antagonist SCH 23390. This latter finding is suggestive of enhanced endogenous D1 tone. Similarly, 28-day SKF 38393 treatment eliminated the effect of subsequent acute SKF 38393 on sciatic nerve stimulation-induced inhibition of nigrostriatal DA neurons, whereas one week after the chronic D1 regimen these cells were highly sensitive to acute D1 enhancement of the response to sciatic nerve stimulation. In order to address the postsynaptic effects of chronic D1 stimulation, the influence of iontophoretically administered SKF 38393 was examined on type I caudate neurons. Again, 28-day SKF 38393 treatment resulted in reduced sensitivity of caudate neurons tested 24 h later, and an enhanced sensitivity was observed one week after the completion of chronic SKF 38393 administration. Thus, chronic SKF 38393 induced functional desensitization of D1 receptors, but one-week withdrawal was followed by sensitization.