title: Insulin receptor substrate-2 in the ventral tegmental area regulates behavioral responses to cocaine.
abstract: 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.
authors.affiliation: Department of Psychology, Florida State Universit, FL, USA.
authors.forename: Sergio D
authors.initials: SD
authors.lastname: Iñiguez
authors.forename: Brandon L
authors.initials: BL
authors.lastname: Warren
authors.forename: Rachael L
authors.initials: RL
authors.lastname: Neve
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Nestler
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Russo
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Bolaños-Guzmán
mesh_terms: 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*
chemical_list: D018765:Dopamine Uptake Inhibitors; D055504:Insulin Receptor Substrate Proteins; D049452:Green Fluorescent Proteins; D003042:Cocaine