Transient neuronal inhibition reveals opposing roles of indirect and direct pathways in sensitization.
Dorsal striatum is important for the development of drug addiction; however, a precise understanding of the roles of striatopallidal (indirect) and striatonigral (direct) pathway neurons in regulating behaviors remains elusive. Using viral-mediated expression of an engineered G protein-coupled receptor (hM(4)D), we found that activation of hM(4)D receptors with clozapine-N-oxide (CNO) potently reduced striatal neuron excitability. When hM(4)D receptors were selectively expressed in either direct or indirect pathway neurons, CNO did not change acute locomotor responses to amphetamine, but did alter behavioral plasticity associated with repeated drug treatment. Specifically, transiently disrupting striatopallidal neuronal activity facilitated behavioral sensitization, whereas decreasing excitability of striatonigral neurons impaired its persistence. These findings suggest that acute drug effects can be parsed from the behavioral adaptations associated with repeated drug exposure and highlight the utility of this approach for deconstructing neuronal pathway contributions to behavior.
Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, Washington, USA.
Susan M
SM
Ferguson
Daniel
D
Eskenazi
Masago
M
Ishikawa
Matthew J
MJ
Wanat
Paul E M
PE
Phillips
Yan
Y
Dong
Bryan L
BL
Roth
John F
JF
Neumaier
D000661:Amphetamine / Q000494:pharmacology; D000818:Animals; D002461:Cell Line, Transformed; D003024:Clozapine / Q000031:analogs & derivatives / Q000494:pharmacology; D003342:Corpus Striatum / Q000187:drug effects / Q000502:physiology*; D004298:Dopamine / Q000378:metabolism; D005822:Genetic Vectors; D006561:Herpes Simplex / Q000235:genetics; D006801:Humans; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D009433:Neural Inhibition / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D009434:Neural Pathways / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D043588:Receptor, Muscarinic M4 / Q000819:agonists / Q000235:genetics / Q000502:physiology*; D012201:Reward; D017557:Ventral Tegmental Area / Q000378:metabolism / Q000502:physiology
D043588:Receptor, Muscarinic M4; D000661:Amphetamine; D003024:Clozapine; C079149:clozapine N-oxide; D004298:Dopamine