Brain transcription factor expression: effects of acute and chronic amphetamine and injection stress.
Amphetamine influences behaviors and the expression of transcription factor genes in the central nervous system (CNS). A single d-amphetamine dose (7.5 mg/kg, i.p.) enhances behavioral stereotypy and augments brain expression of c-fos, fos-B, fra-1, zif268, jun-B, and c-jun by 2-11 fold. When the single amphetamine dose is preceded by 28 saline injections over 14 days, it is half as effective in enhancing expression of these genes. Rats injected with 7.5 mg/kg i.p. twice daily for 2 weeks and sacrificed after the last injection reveal further attenuation or abolition of the amphetamine-induced mRNA upregulation. These stigmata of 'tolerance' in gene expression display partial overlap with behavioral tolerance, manifest as changes in locomotor activity. Rats receiving low (2 mg/kg) amphetamine challenge doses following the 2-week 7.5 mg/kg b.i.d. amphetamine treatment show tolerance to the locomotor activating effects of the drug; no tolerance is evident following a high (7.5 mg/kg) challenge dose. These data suggest that amphetamine-induced alterations in brain transcription factor gene expression can display 'tolerance' and possibly 'cross-tolerance' with the stress caused by i.p. injection.
Persico
A M
AM
Molecular Neurobiology Branch, Addiction Research Center, National Institute on Drug Abuse, Baltimore, MD 21224.
Schindler
C W
CW
O'Hara
B F
BF
Brannock
M T
MT
Uhl
G R
GR
D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000096:biosynthesis; D003913:Dextroamphetamine / Q000008:administration & dosage*; D051766:Early Growth Response Protein 1; D017874:Immediate-Early Proteins; D007274:Injections, Intraperitoneal; D008297:Male; D009043:Motor Activity / Q000502:physiology; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis; D016755:Proto-Oncogene Proteins c-jun / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D013239:Stereotyped Behavior / Q000502:physiology; D013312:Stress, Physiological / Q000378:metabolism*; D013997:Time Factors; D014157:Transcription Factors / Q000096:biosynthesis*; D015854:Up-Regulation / Q000502:physiology; D016335:Zinc Fingers
D004268:DNA-Binding Proteins; D051766:Early Growth Response Protein 1; C486110:Egr1 protein, rat; D017874:Immediate-Early Proteins; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D014157:Transcription Factors; D003913:Dextroamphetamine