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

• Published in: The Journal of neuroscience 2000-12, Vol.20 (23), p.8861-8867
• Main Authors: Yeomans, John S, Takeuchi, Junichi, Baptista, Marco, Flynn, Donna D, Lepik, Karen, Nobrega, Jose, Fulton, James, Ralph, Martin R
• Format: Article
• Language: English
• Subjects: Animals; Behavior, Animal - drug effects; Brain - drug effects; Brain - metabolism; Catheterization; Electric Stimulation; Electrodes, Implanted; Hypothalamic Area, Lateral - physiology; Hypothalamic Area, Lateral - surgery; Infusion Pumps, Implantable; Infusions, Parenteral; Medial Forebrain Bundle - physiology; Medial Forebrain Bundle - surgery; Muscarinic Antagonists - administration & dosage; Neurons - drug effects; Neurons - metabolism; Oligonucleotides, Antisense - administration & dosage; Rats; Receptor, Muscarinic M5; Receptors, Dopamine - metabolism; Receptors, Muscarinic - drug effects; Receptors, Muscarinic - genetics; Receptors, Muscarinic - metabolism; Reward; RNA, Messenger - antagonists & inhibitors; RNA, Messenger - metabolism; Self Stimulation - drug effects; Sensory Thresholds - drug effects; Sensory Thresholds - physiology; Ventral Tegmental Area - drug effects; Ventral Tegmental Area - physiology; Wakefulness - physiology
• ISSN: 0270-6474; 1529-2401
• DOI: 10.1523/jneurosci.20-23-08861.2000

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.