BRAIN TRANSCRIPTION FACTOR GENE-EXPRESSION, NEUROTRANSMITTER LEVELS, AND NOVELTY RESPONSE BEHAVIORS - ALTERATIONS DURING RAT AMPHETAMINE WITHDRAWAL AND FOLLOWING CHRONIC INJECTION STRESS

Transcription factors are known to act as gene expression regulators, possibly linking extracellular stimuli to long-term modifications at t he neuronal level. Such modifications may potentially underlie chronic psychostimulant- and stress-induced behavioral alterations. This stud y illustrates how a 2 week, twice daily 7.5 mg/kg d-amphetamine or sal ine regimen alters rat brain regional expression of transcription fact or genes, including c-fos, fos-B, jun-B, c-jun, and zif 268, and seeks potential correlations between those changes and alterations in neuro transmitter levels and behavioral novelty responses. Amphetamine withd rawal-induced decreases in transcription factor mRNA levels, assessed using Northern blot analysis, appear most prominent in prefrontal cort ex, begin approximately 12 h after the last injection, and largely rec over to control levels by 54 h. Prefrontal cortical and striatal dopam ine content, assessed using HPLC, decrease and recover over a similar time course. Behavioral ''stereotypy time'' manifest by animals expose d to a novel environment, a measure sensitive to psychostimulant withd rawal, also decreases beginning 12 h after the last injection, is stil l significantly reduced at 54 h, and recovers at 72 h. Chronic saline injections are followed by a consistent decrease in transcription fact or gene expression, observed 6 h after the last injection, followed by a ''rebound'' increase at 12 h. These changes are accompanied by dram atic, mostly biphasic alterations in prefrontal cortical biogenic amin es and by a short-lived increase in striatal dopamine turnover. At the same time, rats display much longer-lasting decreases in locomotor re sponses when exposed to a novel environment, with recovery occurring o nly 54 h after the last injection. The delayed recovery of behavioral responses to novelty is consistent with potential involvement of chang es in transcription factor-mediated gene expression in neurochemical m echanisms underlying psychostimulant withdrawal and chronic injection stress-induced behavioral alterations. (C) 1995 Wiley-Liss, Inc.