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Volume 17, Number 7, Issue of April 1, 1997 pp. 2519-2530
Copyright ©1997 Society for Neuroscience

Functional Roles of Dopamine D₂ and D₃ Autoreceptors on Nigrostriatal Neurons Analyzed by Antisense Knockdown In Vivo

Received Nov. 27, 1996; revised Jan. 21, 1997; accepted Jan. 22, 1997.

James M. Tepper, Bao-Cun Sun, Lynn P. Martin, and Ian Creese

Center for Molecular and Behavioral Neuroscience, Aidekman Research Center, Program in Cellular and Molecular Biodynamics, Rutgers, The State University of New Jersey, Newark, New Jersey 07102

Two different 19-mer antisense oligodeoxynucleotides complementary to the initial coding regions of dopamine D₂ or D₃ receptor mRNA were infused unilaterally into the substantia nigra of rats for 3-6 d to suppress synthesis of D₂ and/or D₃ receptors on substantia nigra dopaminergic neurons, thereby producing specific reductions of D₂ and/or D₃ receptors. Autoradiographic receptor binding revealed that D₂ and D₃ antisense oligodeoxynucleotides specifically and significantly reduced D₂ or D₃ binding in the ipsilateral substantia nigra, respectively, without affecting dopamine receptor binding in the neostriatum. Either D₂ or D₃ antisense oligodeoxynucleotides greatly attenuated the ability of apomorphine to inhibit dopaminergic neurons in vivo, an effect that was potentiated by simultaneous administration of D₂ and D₃ antisenses. Despite these effects, neither the rate nor the pattern of spontaneous activity of antisense-treated nigrostriatal neurons differed from those in the control groups. The proportion of antidromic responses consisting of full spikes from antisense-treated rats was significantly greater, and the mean antidromic threshold was significantly lower than in controls, indicating that autoreceptor knockdown increased both somatodendritic and terminal excitability. These data demonstrate that selective reduction of specific dopamine receptor subtypes by antisense infusion can be effected in vivo, and that nigrostriatal neurons express both D₂ and D₃ autoreceptors at their somatodendritic and axon terminal regions. Although the somatodendritic and terminal autoreceptors modulate dendritic and terminal excitability, respectively, the interaction of endogenously released dopamine with somatodendritic autoreceptors does not appear to exert a significant effect on spontaneous activity in anesthetized rats.

Key words: antisense oligodeoxynucleotide; autoreceptor; dopamine receptor subtype; D₂ receptor; D₃ receptor; electrophysiology; substantia nigra

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