Despite the substantial progress in identifying the genes at which drugs of abuse alter histone acetylation, many questions remain. For example, we still do not know if histone acetylation in brain is a primary cause of changes in gene expression or if it is simply a reflection of such changes. This is complicated by the fact that at most genes identified to date, gene expression and histone acetylation are both elevated and return to baseline with a similar time frame. However, the cocaine-induced regulation of bdnf provides unique insight into the possible interplay between acetylation and transcription in vivo. Rats in withdrawal from cocaine self-administration show a marked increase in histone acetylation in the NAc and dorsal striatum on the bdnf promoter within 24 hrs after the final drug exposure [53]. However, no detectable increases in BDNF protein are observed for nearly a week of drug withdrawal [61]. This is an example where histone acetylation on a gene promoter precedes the induction of gene expression, and suggests that, in addition to marking an actively transcribed gene, histone acetylation may also
