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The Journal of Neuroscience, December 1, 2000, 20(23):8861-8867

Brain-Stimulation Reward Thresholds Raised by an Antisense Oligonucleotide for the M5 Muscarinic Receptor Infused near Dopamine Cells

John S. Yeomans¹, Junichi Takeuchi¹, Marco Baptista¹, Donna D. Flynn², Karen Lepik¹, Jose Nobrega¹, James Fulton¹, and Martin R. Ralph¹

¹ Department of Psychology, University of Toronto, Toronto, Ontario, Canada M5S 3G3, and ² Department of Molecular and Cellular Pharmacology, University of Miami School of Medicine, Miami, Florida 33101

Oligonucleotides targeting M5 muscarinic receptor mRNA were infused for 6 d into the ventral tegmental area of freely behaving rats trained to bar-press for lateral hypothalamic stimulation. The bar-pressing rate was determined at a range of frequencies each day to evaluate the effects of infusions on reward. M5 antisense oligonucleotide (oligo) infusions increased the frequency required for bar pressing by 48% over baseline levels, with the largest increases occurring after 4-6 d of infusion. Two control oligos had only slight effects (means of 5 and 11% for missense and sense oligos, respectively). After the infusion, the required frequency shifted back to baseline levels gradually over 1-5 d. Antisense oligo infusions decreased M5 receptors on the ipsilateral, but not the contralateral, side of the ventral tegmentum, as compared with a missense oligo. Therefore, M5 muscarinic receptors associated with mesolimbic dopamine neurons seem to be important in brain-stimulation reward.

Key words: M5; muscarinic; cholinergic; dopamine; self-stimulation; reward; oligodeoxynucleotide

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Copyright © 2000 Society for Neuroscience  0270-6474/00/20238861-07$05.00/0

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