Insulin receptor substrate-2 in the ventral tegmental area regulates behavioral responses to cocaine.
Neurotrophic factor signaling modulates cellular and behavioral responses to drugs of abuse. Among other biochemical adaptations, chronic exposure to abused drugs decreases the expression of insulin receptor substrate-2 (IRS-2; a protein involved in neurotrophic signaling) in the ventral tegmental area (VTA), a neural substrate for many drugs of abuse. Using viral-mediated gene transfer to locally alter the activity of IRS-2, the authors show that overexpression of IRS-2 in the VTA results in an enhanced preference for environments previously paired with cocaine, as measured by the place conditioning paradigm, whereas blockade of IRS-2 activity results in avoidance of cocaine-paired compartments. In addition, IRS-2 overexpression leads to enhanced cocaine-induced locomotor activity, and blockade of IRS-2 expression significantly blunts behavioral responses to cocaine. These results demonstrate that levels of IRS-2 in the VTA regulate responsiveness to the behavioral effects of cocaine.
Iñiguez
Sergio D
SD
Department of Psychology, Florida State Universit, FL, USA.
Warren
Brandon L
BL
Neve
Rachael L
RL
Nestler
Eric J
EJ
Russo
Scott J
SJ
Bolaños-Guzmán
Carlos A
CA
D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D003042:Cocaine / Q000494:pharmacology*; D003216:Conditioning, Operant / Q000187:drug effects; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects; D018014:Gene Transfer Techniques; D049452:Green Fluorescent Proteins / Q000096:biosynthesis / Q000235:genetics; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism*; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D017557:Ventral Tegmental Area / Q000187:drug effects*
D018765:Dopamine Uptake Inhibitors; D055504:Insulin Receptor Substrate Proteins; D049452:Green Fluorescent Proteins; D003042:Cocaine