D1 agonist-induced tolerance in a rodent model of Parkinson's disease: Behavioral and molecular characterization of the underlying mechanisms.

摘要

Full D1 dopamine agonists have unparalleled antiparkinson efficacy in primates, yet several promising D1 dopamine agonists have failed as drugs because they elicit a rapid behavioral tolerance within 1--2 days. Using the 6-OHDA-lesioned rat model of Parkinson's disease, the current studies sought to identify key behavioral characteristics of the development of tolerance induced by D1 agonists, and explored some of the obvious molecular changes that might be expected to be involved (e.g. desensitization). Three structurally dissimilar full D1 agonists (dinapsoline, dihydrexidine, or A77636), or the low intrinsic activity partial agonist SKF38393, were administered either by subcutaneous injection using various inter-injection intervals, or via minipumps to achieve continuous receptor occupation. Continuous receptor occupancy of about 24 hr duration (whether achieved via injections or minipump administration) resulted in the development of rapid behavioral tolerance that is identical in time course and degree to that seen in MPTP-lesioned primates, regardless of chemical structure or molecular properties of the D1 agonist administered (i.e., both full and partial agonists caused tolerance). In addition, we demonstrated that administration regimens that cause a complete loss of motor response do not correlate with decreases in striatal D1 receptor density or the ability of these receptors to signal through adenylate cyclase, the classic D1-mediated signal transduction pathway. Moreover, cross-tolerance occurs between all of these D1 agonists, providing strong evidence that the underlying molecular mechanisms in the induction of tolerance are similar between D1 agonists, and independent of the activation of adenylate cyclase. It is clear that contrary to current dogma, D1 agonist-induced tolerance involves temporally delayed mechanisms distinct from the well-characterized mechanisms responsible for receptor desensitization. Finally, our data suggest that cAMP signaling is not a critical mechanism in the induction of tolerance by D1 agonists. Dopamine D1 agonists have demonstrated great promise not only for treatment in Parkinson's disease, but also for schizophrenia, drug addiction, and learning and memory disorders. The potential impact of D1 agonists on these therapeutic areas makes understanding the consequences of long-term receptor occupancy a critical neurobiological issue.