IRS2-Akt pathway in midbrain dopamine neurons regulates behavioral and cellular responses to opiates.
Chronic morphine administration (via subcutaneous pellet) decreases the size of dopamine neurons in the ventral tegmental area (VTA), a key reward region in the brain, yet the molecular basis and functional consequences of this effect are unknown. In this study, we used viral-mediated gene transfer in rat to show that chronic morphine-induced downregulation of the insulin receptor substrate 2 (IRS2)-thymoma viral proto-oncogene (Akt) signaling pathway in the VTA mediates the decrease in dopamine cell size seen after morphine exposure and that this downregulation diminishes morphine reward, as measured by conditioned place preference. We further show that the reduction in size of VTA dopamine neurons persists up to 2 weeks after morphine withdrawal, which parallels the tolerance to morphine's rewarding effects caused by previous chronic morphine exposure. These findings directly implicate the IRS2-Akt signaling pathway as a critical regulator of dopamine cell morphology and opiate reward.
Russo
Scott J
SJ
Department of Psychiatry and Center for Basic Neuroscience, The University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390-9070, USA.
Bolanos
Carlos A
CA
Theobald
David E
DE
DeCarolis
Nathan A
NA
Renthal
William
W
Kumar
Arvind
A
Winstanley
Catharine A
CA
Renthal
Nora E
NE
Wiley
Matthew D
MD
Self
David W
DW
Russell
David S
DS
Neve
Rachael L
RL
Eisch
Amelia J
AJ
Nestler
Eric J
EJ
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001522:Behavior, Animal / Q000187:drug effects; D015153:Blotting, Western; D048429:Cell Size / Q000187:drug effects; D003216:Conditioning, Operant / Q000187:drug effects* / Q000502:physiology; D004298:Dopamine / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007150:Immunohistochemistry; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology; D008297:Male; D008636:Mesencephalon / Q000166:cytology*; D009020:Morphine / Q000008:administration & dosage*; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D009294:Narcotics / Q000008:administration & dosage*; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D051058:Oncogene Protein v-akt / Q000502:physiology; D010750:Phosphoproteins / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013997:Time Factors
D004791:Enzyme Inhibitors; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; C526299:Irs2 protein, rat; D009294:Narcotics; D010750:Phosphoproteins; D009020:Morphine; D051058:Oncogene Protein v-akt; D004298:Dopamine