Hope B T
Department of Psychiatry, Massachusetts General Hospital East, Charlestown 02129, USA.
Ann N Y Acad Sci. 1996 Oct 31;801:1-12. doi: 10.1111/j.1749-6632.1996.tb17427.x.
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.
还有许多其他受可卡因调控的转录因子，并且也存在几种调节蛋白质水平的非转录机制。然而，慢性AP-1复合物和慢性Fras的诱导提供了一种机制，能够成为慢性可卡因治疗后基因表达长期改变的基础。我们假设，在可卡因产生众所周知的急性效应时，急性诱导的cAMP途径，可能与其他第二信使途径一起，也在诱导基因表达的两种一般类型的改变。1. 急性诱导的基因表达显著改变被快速诱导且相对短暂。这些基因表达的改变将使细胞能够快速适应其环境中的可卡因，而无需进行长期改变。2. 在慢性可卡因暴露期间，每次急性给药都会诱导基因表达的额外改变。这些后期改变是逐渐诱导且持久的。与快速诱导的急性基因表达改变相比，每次急性激活时，这些后期持久的基因表达改变的诱导水平相对较小且不显著。因此，每次急性给药时，细胞不会进行长期改变。然而，这些基因表达中微小但持久的变化会在慢性可卡因治疗期间随着每次急性给药而积累，类似于慢性AP-I复合物的积累（图4）。在重复给药期间发生的累积改变最终达到一个水平，在该水平上它们会产生与急性诱导不同的显著且持久的基因表达改变。这种基因表达长期改变的渐进性诱导将使细胞能够逐渐进行长期改变，以适应其环境中反复长期暴露于可卡因的情况。这些基因表达的长期改变可能是蛋白质水平、神经元信号传导及相关行为中持续变化逐渐诱导的基础。该假设解释了在生化、生理和行为水平上急性与慢性可卡因给药后观察到的不同适应性。我们希望这些研究为特异性药理阻断或逆转导致成瘾的基因表达的长期与短期改变提供思路，同时不干扰动物或人类体验奖励的能力。这对于确保疗效和依从性都很重要。
