Tuesday, November 15, 2016

A way to lessen withdrawal anxiety?

In a land of plenty where many cases of cancer and other physical illness have become curable due to medical advances, the problem of intractable mental illness is beginning to be far more apparent. One form of mental disorder that seems to be very prevalent is addictive disorders. One study estimated that approximately half the US population suffers from addictive disorder symptoms in the course of a year:
An increasing number of research studies over the last three decades suggest that a wide range of substance and process addictions may serve similar functions. The current article considers 11 such potential addictions (tobacco, alcohol, illicit drugs, eating, gambling, Internet, love, sex, exercise, work, and shopping), their prevalence, and co-occurrence, based on a systematic review of the literature. Data from 83 studies (each study n = at least 500 subjects) were presented and supplemented with small-scale data. Depending on which assumptions are made, overall 12-month prevalence of an addiction among U.S. adults varies from 15% to 61%. The authors assert that it is most plausible that 47% of the U.S. adult population suffers from maladaptive signs of an addictive disorder over a 12-month period and that it may be useful to think of addictions as due to problems of lifestyle as well as to person-level factors.

If nearly half of adults are "addicted" in any given year, then addiction by definition would seem to be a fairly normal process of the brain. When the addiction is to something that helps increase our ability to enjoy and function in life, we call it things like "enthusiasm" or "dedication," but when it robs us of our ability to function productively and healthily, we consider it a disease. (http://www.iflscience.com/health-and-medicine/theres-no-such-thing-as-an-addictive-personality-heres-why/all/) One element of an addictive disorder is that the addicted person suffers from withdrawal symptoms when deprived of the substance or behavior to which he/she is addicted.

What chemically happens in the brain during withdrawal? We know that ΔFosB (delta-FosB), a gene transcription factor is a chemical on-switch for both substance and behavior addictions:
The longevity of some of the behavioral abnormalities that characterize drug addiction has suggested that regulation of neural gene expression may be involved in the process by which drugs of abuse cause a state of addiction. Increasing evidence suggests that the transcription factor ΔFosB represents one mechanism by which drugs of abuse produce relatively stable changes in the brain that contribute to the addiction phenotype. ΔFosB, a member of the Fos family of transcription factors, accumulates within a subset of neurons of the nucleus accumbens and dorsal striatum (brain regions important for addiction) after repeated administration of many kinds of drugs of abuse. Similar accumulation of ΔFosB occurs after compulsive running, which suggests that ΔFosB may accumulate in response to many types of compulsive behaviors. Importantly, ΔFosB persists in neurons for relatively long periods of time because of its extraordinary stability. Therefore, ΔFosB represents a molecular mechanism that could initiate and then sustain changes in gene expression that persist long after drug exposure ceases. Studies in inducible transgenic mice that overexpress either ΔFosB or a dominant negative inhibitor of the protein provide direct evidence that ΔFosB causes increased sensitivity to the behavioral effects of drugs of abuse and, possibly, increased drug seeking behavior. This work supports the view that ΔFosB functions as a type of sustained “molecular switch” that gradually converts acute drug responses into relatively stable adaptations that contribute to the long-term neural and behavioral plasticity that underlies addiction.

When mice are given the opportunity to become addicted to ethanol (alcohol) and then deprived of it, the level of ΔFosB in their brain dramatically rises during the withdrawal period. (http://www.sciencedirect.com/science/article/pii/S0091305713003419) If ΔFosB levels can be kept from rising during the withdrawal period, perhaps that will weaken the power of the addiction and make it easier to get past.

Why does ΔFosB hang around for so long in the brain? Is there a way we can keep it from hanging around for so long so that levels of ΔFosB don't rise as much during withdrawal periods?
The transcription factor ΔFosB (also referred to as FosB2 or FosB[short form]) is an important mediator of the long-term plasticity induced in brain by chronic exposure to several types of psychoactive stimuli, including drugs of abuse, stress, and electroconvulsive seizures. A distinct feature of ΔFosB is that, once induced, it persists in brain for relatively long periods of time in the absence of further stimulation. The mechanisms underlying this apparent stability, however, have remained unknown. Here, we demonstrate that ΔFosB is a relatively stable transcription factor, with a half-life of ∼10 h in cell culture. Furthermore, we show that ΔFosB is a phosphoprotein in brain and that phosphorylation of a highly conserved serine residue (Ser27) in ΔFosB protects it from proteasomal degradation. We provide several lines of evidence suggesting that this phosphorylation is mediated by casein kinase 2. These findings constitute the first evidence that ΔFosB is phosphorylated and demonstrate that phosphorylation contributes to its stability, which is at the core of its ability to mediate long-lasting adaptations in brain.

This suggests that inhibiting casein kinase 2 could diminish the amount by which ΔFosB increases in the brain during withdrawal periods. What inhibits casein kinase 2? Two commonly consumed inhibitors of casein kinase 2 are apigenin (highest in chamomile, parsley, and celery) and ellagic acid (highest in berries and walnuts). Chamomile extract containing apigenin has been observed to reduce anxiety (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3600408/), and ellagic acid has been observed to lessen withdrawal symptoms in nicotine-addicted mice (https://www.uaeh.edu.mx/investigacion/producto.php?producto=5628).

Therefore, if trying to overcome a behavior that has started to drift into "addiction" territory, I would be sure to include high levels of foods containing ellagic acid and apigenin if I felt anxiety at suspending the behavior to which I'd become addicted. Wild strawberries appear to be one of the very best sources of ellagic acid (http://pub.jki.bund.de/index.php/JABFQ/article/viewFile/3114/3485), which tidbit would no doubt please Ingmar Bergman--a Swedish film producer whose film Wild Strawberries is about a very old man overcoming a lifetime of habitual aloofness--were he still alive.

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