Brain transcription factor gene expression, neurotransmitter levels, and novelty response behaviors: Alterations during rat amphetamine withdrawal and following chronic injection stress

Abstract

Transcription factors are known to act as gene expression regulators, possibly linking extracellular stimuli to long-term modifications at the neuronal level. Such modifications may potentially underlie chronic psychostimulant- and stress-induced behavioral alterations. This study illustrates how a 2 week, twice daily 7.5 mg/kg d-amphetamine or saline regimen alters rat brain regional expression of transcription factor genes, including c-fos, fos-B, jun-B, c-jun, and zif 268, and seeks potential correlations between those changes and alterations in neurotransmitter levels and behavioral novelty responses. Amphetamine withdrawal-induced decreases in transcription factor mRNA levels, assessed using Northern blot analysis, appear most prominent in prefrontal cortex, begin approximately 12 h after the last injection, and largely recover to control levels by 54 h. Prefrontal cortical and striatal dopamine content, assessed using HPLC, decrease and recover over a similar time course. Behavioral "stereotypy time" manifest by animals exposed to a novel environment, a measure sensitive to psychostimulant withdrawal, also decreases beginning 12 h after the last injection, is still significantly reduced at 54 h, and recovers at 72 h. Chronic saline injections are followed by a consistent decrease in transcription factor gene expression, observed 6 h after the last injection, followed by a "rebound" increase at 12 h. These changes are accompanied by dramatic, mostly biphasic alterations in prefrontal cortical biogenic amines and by a short-lived increase in striatal dopamine turnover. At the same time, rats display much longer-lasting decreases in locomotor responses when exposed to a novel environment, with recovery occurring only 54 h after the last injection. The delayed recovery of behavioral responses to novelty is consistent with potential involvement of changes in transcription factor-mediated gene expression in neurochemical mechanisms underlying psychostimulant withdrawal and chronic injection stress-induced behavioral alterations.