Tolerance, sensitization, withdrawal and craving can be viewed as events requiring storage of information in the central nervous system. Long-term storage of information is increasingly tied to alterations in gene expression which is modulated via alterations in the expression or activities of transcription factors. Changes in the expression of transcription factors following acute amphetamine treatments were documented during the past FY. This year, studies identifying brain-region-specific patterns of change in transcription factor mRNAs were performed, together with specific temporal correlations with behavioral and neurotransmitter turnover measures. Gene transcription was measured using quantitative Northern blotting. Striatal dopamine and serotonin turnover were assessed using HPLC. Locomotor activity and stereotypy time were measured during novelty-response sessions. Evidence for tolerance, sensitization, withdrawal and cross-tolerance with injection stress was recorded at the level of transcription factor gene expression. These temporal patterns closely resembled changes in striatal dopamine turnover, while decreases in novelty-response stereotypy time during withdrawal appear to last longer than both gene expression and dopamine turnover changes. Tyrosine hydroxylase also displays increased expression during amphetamine withdrawal.
