We have systematically defined distinct roles for several in addiction- and depression/anxiety-related behaviors, with some inducing high CREB states, while others inducing low CREB states due to their functions as endogenous dominant negative CREB inhibitors. Studies of CREB Family ProteinsĬREB is just one of several related transcription factors, which include ICER (inducible cAMP early repressor) and several ATFs (activating transcription factors).
Interestingly, antidepressant treatments can normalize both high and low CREB states. High CREB states (chronic exposure to drugs of abuse or to active forms of stress) are associated with depression and low emotional reactivity, while low CREB states (long-term social isolation) are associated with excessive emotional reactivity including anxiety. Together, these observations have suggested that CREB functions as a rheostat of reward. In contrast, inhibition of CREB activity in the nucleus accumbens, which is induced after prolonged periods of social isolation, causes a profound state of anxiety. Unlike most opioid peptides, dynorphin induces a negative emotional state in part by feeding back and suppressing the activity of dopamine neurons. This negative emotional state is mediated in part via CREB’s induction of the opioid peptide dynorphin in this brain region. Indeed it is and increasing evidence now demonstrates that such activation mediates a depression-like state in several animal models. These findings with drugs of abuse led us to investigate whether CREB is also induced in nucleus accumbens by stress. In addition, CREB activation causes a negative emotional state, suggesting that it could mediate depression-like symptoms seen during drug withdrawal. Studies with inducible transgenic mice and viral vectors, combined with an array of behavioral models, has taught us that CREB in this brain region decreases an animal’s sensitivity to the rewarding effects of these drugs of abuse, an indication of tolerance. Interestingly, CREB is activated within the nucleus accumbens not only by opiates, but also by stimulant drugs of abuse such as cocaine and amphetamine. Since that time, we and others have shown that CREB is activated in several other brain regions by chronic exposure to opiates, where it mediates distinct aspects of opiate tolerance and dependence, depending on the brain region involved. A role for CREB in emotional regulation first came from studies of the locus coeruleus, the major noradrenergic nucleus in brain, where we showed that chronic opiate administration induced the CREB pathway to mediate physical aspects of opiate dependence and withdrawal.
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