title: DeltaFosB induction in orbitofrontal cortex potentiates locomotor sensitization despite attenuating the cognitive dysfunction caused by cocaine.
abstract: The effects of addictive drugs change with repeated use: many individuals become tolerant of their pleasurable effects but also more sensitive to negative sequelae (e.g., anxiety, paranoia, and drug craving). Understanding the mechanisms underlying such tolerance and sensitization may provide valuable insight into the basis of drug dependency and addiction. We have recently shown that chronic cocaine administration reduces the ability of an acute injection of cocaine to affect impulsivity in rats. However, animals become more impulsive during withdrawal from cocaine self-administration. We have also shown that chronic administration of cocaine increases expression of the transcription factor DeltaFosB in the orbitofrontal cortex (OFC). Mimicking this drug-induced elevation in OFC DeltaFosB through viral-mediated gene transfer mimics these behavioural changes: DeltaFosB over-expression in OFC induces tolerance to the effects of an acute cocaine challenge but sensitizes rats to the cognitive sequelae of withdrawal. Here we report novel data demonstrating that increasing DeltaFosB in the OFC also sensitizes animals to the locomotor-stimulant properties of cocaine. Analysis of nucleus accumbens tissue taken from rats over-expressing DeltaFosB in the OFC and treated chronically with saline or cocaine does not provide support for the hypothesis that increasing OFC DeltaFosB potentiates sensitization via the nucleus accumbens. These data suggest that both tolerance and sensitization to cocaine's many effects, although seemingly opposing processes, can be induced in parallel via the same biological mechanism within the same brain region, and that drug-induced changes in gene expression within the OFC play an important role in multiple aspects of addiction.
authors.affiliation: Department of Psychiatry, The University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9070, United States. cwinstanley@psych.ubc.ca
authors.forename: Catharine A
authors.initials: CA
authors.lastname: Winstanley
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Green
authors.forename: David E H
authors.initials: DE
authors.lastname: Theobald
authors.forename: William
authors.initials: W
authors.lastname: Renthal
authors.forename: Quincey
authors.initials: Q
authors.lastname: LaPlant
authors.forename: Ralph J
authors.initials: RJ
authors.lastname: DiLeone
authors.forename: Sumana
authors.initials: S
authors.lastname: Chakravarty
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Nestler
mesh_terms: D000818:Animals; D003042:Cocaine; D003072:Cognition Disorders / Q000139:chemically induced* / Q000523:psychology*; D018765:Dopamine Uptake Inhibitors; D005625:Frontal Lobe / Q000187:drug effects* / Q000378:metabolism*; D015870:Gene Expression / Q000187:drug effects; D008297:Male; D009043:Motor Activity / Q000187:drug effects* / Q000502:physiology*; D017072:Neostriatum / Q000187:drug effects / Q000502:physiology; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis* / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D020318:Rats, Long-Evans; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D018765:Dopamine Uptake Inhibitors; C483820:Fosb protein, rat; D016760:Proto-Oncogene Proteins c-fos; D012333:RNA, Messenger; D003042:Cocaine