Dopaminergic neurotransmission in the brain modulates a number of important cognitive and behavioral functions. For example, schizophrenia is believed to result from an imbalance in forebrain dopamine systems. Recent advances in molecular biology have led to the identification of 5 different genes coding for dopamine receptors of 2 main families, D1 and D2. Although agonists and antagonists that discriminate between members of the D1 and D2 families exist, drugs do not yet exist that are selective among family members (e.g., D2 vs. D3 vs. D4 or D1 vs. D5). This has resulted in confusion about the sites and mechanisms of action of dopamine in the brain, about precisely which receptor subtypes mediate which cellular effects, and likely also contributes to the mixed therapeutic efficacy and unwanted side effects of antischizophrenic drugs in use today. We have shown that in vivo infusion of specifically designed antisense oligodeoxynucleotides complementary to the mRNA coding for different dopamine receptors produces a highly regional- and receptor-specific pre- or postsynaptic """"""""knockout"""""""" of the dopamine D2 or D3 receptors as indexed by receptor autoradiography. In vivo and in vitro electrophysiological techniques will be used to determine the roles that D2 and D3 dopamine receptors play in the modulation of the electrical activity of substantia nigra dopaminergic neurons and neostriatal neurons. Subsequent experiments will utilize similar methods to achieve knockout of the D1 and D4 receptors. The site and receptor subtype of the dopamine receptor that mediates the inhibitory effects of amphetamine on nigral cell firing will be determined. In vivo extracellular and in vitro intracellular recordings will be used to confirm the identity of the nigral somadendritic autoreceptor and determine the role that it plays in the control of the rate and pattern of firing of nigral dopamine neurons. In vivo and in vitro intracellular recordings will be used to define receptor subtype- specific actions of dopamine on neostriatal neurons, and determine the site and subtype of the receptor that mediates dopamine's effect on corticostriatal synaptic transmission. This research is highly relevant to both basic and applied neuroscience. Validating the antisense approach to selective receptor knockout in vivo by electrophysiological means is a necessary first step towards the application of this technique to a variety of research issues. The identification of the particular dopamine receptor subtype(s) that mediates a number of well-characterized physiological responses to dopamine may provide information that will direct future research towards the design of a new generation of antipsychotic drugs that are simultaneously more effective and lack the often devastating side effects of the neuroleptics in use today.
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