Tolerance, sensitization, withdrawal and craving can be viewed as events acquiring storage of information in the central nervous system. Long- term storage of information is increasingly tied to alterations in gene expression which can be modulated by alterations in the expression or activities of transcription factors. The expression of transcription factors and transcription factor gene targets can change following acute and chronic psychostimulant treatments. These studies have now been extended: 1) Studies identifying brain-region-specific patterns of psychostimulant-induced change in transcription factor MRNAS in single rodent strains were correlated with behavioral and neurotransmitter turnover measures. 2) Since pharmacogenetic techniques have proven valuable in examining mechanisms underlying various drug responses, the effects of psychostimulant treatments on the expression of several transcription factor genes in inbred strains of mice known to differ in their initial sensitivity to cocaine were examined. 3) Modulation of genes of dopaminergic neurotransmission was examined in several psychostimulant paradigms. 4) Since many of the genes whose modulation might be important for drug responses may be currently unknown, Differential Display Polymerase Chain Reaction (DDPCR) has been employed to identify genes whose expression is changed during psychostimulant treatment and withdrawal. 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-responses 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, while dopamine transporter expression was reduced in specific neuronal cell groups of the ventral tegmental area in animals sacrificed during """"""""withdrawal"""""""" from cocaine administration, as noted above. DDPCR has identified several CDNAS whose sequences are known and several CDNAS different from any other sequence in the GenBank database. Northern analyses of these MRNAS are being pursued to reveal which species are altered in expression with three amphetamine treatment and withdrawal.
