DA THERAPY AND BRAIN NEUROTROPHIC ACTIVITY

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Dopaminergic drugs used in the treatment of schizophrenia and Parkinson's disease (PD) are associated with complications which often compromise otherwise efficacious drug therapy (i.e., tardive dyskinesia (TD) and loss of efficacy, respectively). Using a novel approach for studying these drugs, we have demonstrated that cell-free striatal extracts from animals chronically treated with dopaminergic drugs alter the growth of mesencephalic cell cultures containing dopamine (DA) neurons: DA antagonist treatment enhanced, while DA agonist treatment reduced, the effect striatal extracts had on culture growth. These data suggest that drug-sensitive striatal-derived neurotrophic or neuroinhibitory factors influence the growth of DA neurons in culture. These studies have led to an operational hypothesis which states that "the growth promoting effect cell-free striatal extracts have on mesencephalic cultures is inversely related to DA tone." We intend to test this hypothesis directly using the traditional approach of varying the dose and duration of treatment with dopaminergic drugs (haloperidol and levodopa) in well established behavioral models (behavioral hypersensitivity and 6-hydroxydopamine rotation). DA biochemistry, spiroperidol receptor density, as well as stereotypical and rotational behavior alterations induced by these drug treatments will represent the dependent measures of DA tone. A highly sensitive low cell density culture system will be used to identify drug therapies which induce alterations in striatal growth promoting activity (GPA). Whether or not cultures using immunocytochemical stains and cell counts of DA and GABA neurons, as well as astrocytes. The effect this GPA has on neuron sprouting in the cultures will be evaluated by assessing DA and GABA uptake. The dependent measures of DA tone will then be used to predict GPA (defined as cell counts and/or transmitter uptake) using multiple regression analysis. Identifying a statistically significant inverse relationship using this equation will directly support the operational hypothesis. This analysis will take two years to complete. In the third year of the proposal, other dopaminergic drugs with differing pharmacological profiles and clinical activities will then be evaluated using this model system. These analyses will further support or refute the operational hypothesis as well as begin to address the potential relationships between drug treatment and side effects. If these drug sensitive growth factors were to influence DA neuron growth in vivo in a similar fashion (as our preliminary results appear to suggest), the resulting alterations in synaptic architecture could contribute to the complications which attend dopaminergic drug therapy. Thus, increased DA neuron growth associated with DA antagonist treatment could contribute to TD while reduced DA neuron growth associated with DA agonist therapy could contribute to the progression of PD. The results of this proposal would therefore be expected to influence the current therapeutic strategies employed in the treatment of schizophrenia and PD.