Brain-stimulation reward thresholds raised by an antisense oligonucleotide for the M5 muscarinic receptor infused near dopamine cells.
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.
Yeomans
J S
JS
Department of Psychology, University of Toronto, Toronto, Ontario, Canada M5S 3G3. yeomans@psych.utoronto.ca
Takeuchi
J
J
Baptista
M
M
Flynn
D D
DD
Lepik
K
K
Nobrega
J
J
Fulton
J
J
Ralph
M R
MR
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D002404:Catheterization; D004558:Electric Stimulation; D004567:Electrodes, Implanted; D007026:Hypothalamic Area, Lateral / Q000502:physiology / Q000601:surgery; D015918:Infusion Pumps, Implantable; D007263:Infusions, Parenteral; D008474:Medial Forebrain Bundle / Q000502:physiology / Q000601:surgery; D018727:Muscarinic Antagonists / Q000008:administration & dosage; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage*; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D043642:Receptor, Muscarinic M5; D011954:Receptors, Dopamine / Q000378:metabolism; D011976:Receptors, Muscarinic / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D012201:Reward; D012653:Self Stimulation / Q000187:drug effects; D012684:Sensory Thresholds / Q000187:drug effects* / Q000502:physiology; D017557:Ventral Tegmental Area / Q000187:drug effects / Q000502:physiology; D014851:Wakefulness / Q000502:physiology
D018727:Muscarinic Antagonists; D016376:Oligonucleotides, Antisense; D012333:RNA, Messenger; D043642:Receptor, Muscarinic M5; D011954:Receptors, Dopamine; D011976:Receptors, Muscarinic