PERMANENT DOPAMINE HYPERSENSITIVITY-A UNIQUE MODEL

广泛的长期目标是(1)在分子层面上理解

The broad long-term objectives are (i) to understand at a molecular level how a behavioral supersensitivity (SS) to a neurotransmitter such as striatal dopamine (DA) might become permanent, especially through up-regulation of D2DA receptors (DA-R): both pre-synaptic auto-receptors (DA-R auto)and post-synaptic DA-R (DA-R post), and (ii) to create drug development strategies aimed at down-regulating both kinds of SS DA-R. In rodents, prolonged block of striatal D2 DA-R by antispsychotic drugs such an haloperidol (HAL) causes a compensatory up-regulation of those DA-R post and results in a transient behavioral SS to DA agonists. Chronic neuroieptics also cause tardive dyskinesia (TD) in man. Yet TD symptoms can become permanent remaining long after neuroleptic withdrawal. Our hypothesis to explain the apparent irreversibility is: (1) to compensate for DA-R post SS. DA release decreases; (2) DA-R auto, which inhibit DA synthesis and release, also up-regulate due to HAL and to declining levels of cleft DA; (3) this DA-R auto SS now shuts off DA release at a new, lower set point which further which further increases DA-R auto SS; (4) this vicious cycle "bottoms out" and "locks in " at a constant (lower) level of DA release; (5) now, as the a of DA-R post increases because there is no way to increase to further decrease DA release; (6) the system remains permanently SS because there is also no way to increase DA release to down-regulate SS DA-R; (7) only artificial (pharmacologic) maneuvers to temporarily increase cleft DA can break the cycle. Our model is the ovariectomized (OVX) rat exposed to Hal, which rapidly develops a PERMANENT DA SS; controls are non-OVX, HAL- exposed rats, which develop only a TRANSIENT SS. This model of permanent DA-R SS is unique in that the nigrostriatal DA neurons survive (unlike SS from 60HDA lesions) and compensatory changes can be followed. We will show that a permanent SS of PRE-synaptic DA- R auto precedes or at least accompanies to permanent phase of DA- R post SS> These studies model only ONE aspect of TD - the permanence of the SS. But this one aspect is essential to rational drug development. Other models, e.g. the chronic neuroleptic- treated monkey, appear to more closely resemble many behavioral aspects of TD (e.g. spontaneity, anatomy) but are not economically feasible for our studies. The specific aims are: (I) to confirm the time course for the development of pregnant an transient behavioral SS DA agonists; (II) to evaluate specific neural mechanism during developing and maintenance phases of the permanent striatal SS: (A) postsynaptic: DA-R binding (B) presynaptic: (1) DA-R auto SS (inhibition, of (3H)DA release from slices); (2) DA release (3MT levels; in vivo microdialysis/HPLC); (C) nigral mechanisms: DA-R binding an GAD activity; (III) To determine whether agents that reverse the permanent behavioral SS in the OVX rat (Cyclo(leucyl-glycyl), DA agonist) do so by reversing the same neurochemical changes (above) that appear to cause the permanent SS.