Striatal regulation of ΔFosB, FosB, and cFos during cocaine self-administration and withdrawal.
Chronic drug exposure induces alterations in gene expression profiles that are thought to underlie the development of drug addiction. The present study examined regulation of the Fos-family of transcription factors, specifically cFos, FosB, and ΔFosB, in striatal subregions during and after chronic intravenous cocaine administration in self-administering and yoked rats. We found that cFos, FosB, and ΔFosB exhibit regionally and temporally distinct expression patterns, with greater accumulation of ΔFosB protein in the nucleus accumbens (NAc) shell and core after chronic cocaine administration, whereas ΔFosB increases in the caudate-putamen (CPu) remained similar with either acute or chronic administration. In contrast, tolerance developed to cocaine-induced mRNA for ΔFosB in all three striatal subregions with chronic administration. Tolerance also developed to FosB expression, most notably in the NAc shell and CPu. Interestingly, tolerance to cocaine-induced cFos induction was dependent on volitional control of cocaine intake in ventral but not dorsal striatal regions, whereas regulation of FosB and ΔFosB was similar in cocaine self-administering and yoked animals. Thus, ΔFosB-mediated neuroadaptations in the CPu may occur earlier than previously thought with the initiation of intravenous cocaine use and, together with greater accumulation of ΔFosB in the NAc, could contribute to addiction-related increases in cocaine-seeking behavior.
Larson
Erin B
EB
The Seay Center for Basic and Applied Research in Psychiatric Illness, UT Southwestern Medical Center, Dallas, Texas 75390, USA.
Akkentli
Fatih
F
Edwards
Scott
S
Graham
Danielle L
DL
Simmons
Diana L
DL
Alibhai
Imran N
IN
Nestler
Eric J
EJ
Self
David W
DW
D000818:Animals; D015153:Blotting, Western; D003042:Cocaine / Q000009:adverse effects* / Q000494:pharmacology*; D019970:Cocaine-Related Disorders / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects*; D007275:Injections, Intravenous; D008297:Male; D017072:Neostriatum / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000235:genetics; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D012054:Reinforcement, Psychology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012646:Self Administration; D015819:Substance Abuse, Intravenous; D013375:Substance Withdrawal Syndrome / Q000378:metabolism*
C483820:Fosb protein, rat; D009419:Nerve Tissue Proteins; D016760:Proto-Oncogene Proteins c-fos; D012333:RNA, Messenger; D003042:Cocaine