title: Overexpression of CREB in the nucleus accumbens shell increases cocaine reinforcement in self-administering rats.
abstract: Chronic exposure to addictive drugs enhances cAMP response element binding protein (CREB)-regulated gene expression in nucleus accumbens (NAc), and these effects are thought to reduce the positive hedonic effects of passive cocaine administration. Here, we used viral-mediated gene transfer to produce short- and long-term regulation of CREB activity in NAc shell of rats engaging in volitional cocaine self-administration. Increasing CREB expression in NAc shell markedly enhanced cocaine reinforcement of self-administration behavior, as indicated by leftward (long-term) and upward (short-term) shifts in fixed ratio dose-response curves. CREB also increased the effort exerted by rats to obtain cocaine on more demanding progressive ratio schedules, an effect highly correlated with viral-induced modulation of BDNF protein in the NAc shell. CREB enhanced cocaine reinforcement when expressed either throughout acquisition of self-administration or when expression was limited to postacquisition tests, indicating a direct effect of CREB independent of reinforcement-related learning. Downregulating endogenous CREB in NAc shell by expressing a short hairpin RNA reduced cocaine reinforcement in similar tests, while overexpression of a dominant-negative CREB(S133A) mutant had no significant effect on cocaine self-administration. Finally, increasing CREB expression after withdrawal from self-administration enhanced cocaine-primed relapse, while reducing CREB levels facilitated extinction of cocaine seeking, but neither altered relapse induced by cocaine cues or footshock stress. Together, these findings indicate that CREB activity in NAc shell increases the motivation for cocaine during active self-administration or after withdrawal from cocaine. Our results also highlight that volitional and passive drug administration can lead to substantially different behavioral outcomes.
authors.affiliation: Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
authors.forename: Erin B
authors.initials: EB
authors.lastname: Larson
authors.forename: Danielle L
authors.initials: DL
authors.lastname: Graham
authors.forename: Rose R
authors.initials: RR
authors.lastname: Arzaga
authors.forename: Nicole
authors.initials: N
authors.lastname: Buzin
authors.forename: Joseph
authors.initials: J
authors.lastname: Webb
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Green
authors.forename: Caroline E
authors.initials: CE
authors.lastname: Bass
authors.forename: Rachael L
authors.initials: RL
authors.lastname: Neve
authors.forename: Ernest F
authors.initials: EF
authors.lastname: Terwilliger
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Nestler
authors.forename: David W
authors.initials: DW
authors.lastname: Self
mesh_terms: D000779:Anesthetics, Local / Q000008:administration & dosage*; D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D050882:CREB-Binding Protein / Q000235:genetics / Q000378:metabolism*; D003042:Cocaine / Q000008:administration & dosage* / Q000009:adverse effects; D003216:Conditioning, Operant / Q000187:drug effects; D004333:Drug Administration Routes; D005108:Extinction, Psychological / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects*; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D009154:Mutation / Q000235:genetics; D009714:Nucleus Accumbens / Q000187:drug effects* / Q000378:metabolism; D034622:RNA Interference / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012055:Reinforcement Schedule; D012054:Reinforcement, Psychology; D012646:Self Administration; D013223:Statistics as Topic; D013375:Substance Withdrawal Syndrome / Q000503:physiopathology; D014162:Transfection / Q000379:methods
chemical_list: D000779:Anesthetics, Local; D019208:Brain-Derived Neurotrophic Factor; D049452:Green Fluorescent Proteins; D050882:CREB-Binding Protein; D003042:Cocaine
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