Novel transcription factors are induced by chronic cocaine treatment.
There are many other transcription factors that are regulated by cocaine, and there are several nontranscriptional mechanisms of regulating protein levels as well. However, the induction of the chronic AP-1 complex and the chronic Fras provides a mechanism capable of underlying long-lasting alterations in gene expression following chronic cocaine treatment. We hypothesize that while the well-known acute effects of cocaine are occurring, the acutely induced cAMP pathway, possibly in conjunction with other second messenger pathways, is also inducing two general types of alterations in gene expression. 1. Acutely induced significant alterations in gene expression are rapidly induced and relatively short-lived. These alterations in gene expression would allow the cell to rapidly adapt to cocaine in its environment without committing to long-term changes. 2. Additional alterations in gene expression are induced by each acute administration during chronic cocaine exposure. These latter alterations are gradually induced and long-lasting. With each acute activation, the level of induction of these latter longer-lasting alterations in gene expression would be relatively small and insignificant compared to the rapidly induced acute alterations in gene expression. Therefore, with each acute administration, the cell does not commit itself to long-term alterations. However, these small but longer lasting changes in gene expression would accumulate with each acute administration during chronic cocaine treatment, similar to the accumulation of the chronic AP-I complex (FIG. 4). The cumulative alterations which occur during repeated administrations eventually reach a level where they produce significant and long-lasting alterations in gene expression different from those induced acutely. This incremental induction of long-lasting alterations in gene expression would allow the cell to gradually commit to long-term alterations for the purpose of adapting to repeated long-term exposure to cocaine in its environment. These long-lasting alterations in gene expression may underlie the gradual induction of persistent changes in protein levels, neuronal signaling, and related behaviors. This hypothesis allows for the different adaptations observed following acute versus chronic cocaine administration at the biochemical, physiological, and behavioral levels. We hope these investigations provide ideas for specific pharmacological blockade or reversal of the long-term, versus short-term, alterations in gene expression that lead to addiction, without interfering with the animal's or human's ability to experience reward. This would be important for ensuring both efficacy and compliance.
Hope
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Department of Psychiatry, Massachusetts General Hospital East, Charlestown 02129, USA.
D003042:Cocaine / Q000008:administration & dosage / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics*
D014157:Transcription Factors; D003042:Cocaine