Psychological Mood disorders such as Anxiety, are one of the most prevalent disorders in the world, with most individuals admitting to feeling anxious or stressed for a prolonged time at least once in they’re lifetime (Mental and substance use disorders in Canada, 2012). With an estimated 3 million (11%) of Canadians over the age of 18 years, having mood disorders (Fast facts from the 2014 Survey on Living with Chronic Diseases in Canada, 2014), its no wonder why science that analyzes the mechanisms underlying stress are so important. Moreover, since stress is the combination of both genetic factors as well as environmental, it is permanent to look into the interaction between the two. Finding the underlying mechanisms of stress disorders, and how It predicts substance abuse, can help single out individualized treatment that takes into account multitude of factors. One of the common experimental models testing for the gene x environment interaction are drug models. These models an test the comorbidity between genetic interaction with environmental factors of stress, and its relation to susceptibility of substance abuse. In this paper review, we will look into how FKBP5, a gene haploid involved in modulating effects of stress, is responsible for the correlation between anxiety and addiction disorders.

Stress is an important risk factor that affects both the development of drug addiction, as well as withdrawal symptoms and relapse (Levran, et al., 2014) (Huang, et al., 2014). Stress can affect substance abuse by causing an increase of reward-seeking behaviour (Levran, et al., 2014), with high comorbidity between individuals who experienced childhood traumas or have anxiety disorders (Mental Illness & Addiction: Facts and Statistics, n.d.) such as post-traumatic stress disorder (PTSD), and substance abuse (Levran, et al., 2014). One of the major physiological mechanisms modulating stress response is the hypothalamic-pituitary-adrenal (HPA) axis. The HPA axis is a feedback loop that, when introduced to a stressful stimulus releases corticotrophin-releasing hormones (CRH) from the hypothalamus that trigger the release of adrenocorticotropic hormone (ACTH) from the pituitary gland. From there, the pituitary signals the release of cortisol by the adrenal glands located over the kidneys. The cortisol, a glucocorticoid, binds to glucocorticoid receptors (GR), located on the cytosol of many cells of the body, binding to GR (WBLifeSciences, 2016). This binding causes transformational changes that allow the GR complex to bind to DNA within the cell nucleus to moderate stress-related gene transcription (Julia K Gjerstad, 2018) (Binder, 2009). The affects of modulating GR has thus been of prime interest to scientist researching the impact of HPA disruption on human behaviour.

Heat shock proteins (hsp) are one of the molecular mechanisms involved in normal nucleic translocation of GR which controls activation of gene transcription, whereas FKBP5 is a co-chaperone protein that binds to these hsp and kinases (Julia K Gjerstad, 2018). Studies have shown that FKBP5 is a gene haploid that has been linked to individual susceptibility to drug addictions such as opioids or increased drinking, in correlation to anxiety disorders such as PTSD and early life stress (ELS) (Levran, et al., 2014) (Nylander, et al., 2016). FKBP5 is a co-chaperone for heat shock protein (specifically Hsp70, Hsp90) that regulates the GR complex, preventing normal translocation into the nucleus in association to stress (Julia K Gjerstad, 2018) (WBLifeSciences, 2016). In the presence of FKBP5 binding to the GR complex site, stops normal transcription of glucocorticoid-responsive genes (Levran, et al., 2014). This causes an extra short negative feedback loop where cortisol outside the cell is increased due to decrease of GR complex translocation efficiency. Meaning; decrease of cortisol binding and gene-related transcription reduces efficiency of negative feedback, resulting in overproduction of cortisol by the HPA axis (Binder, 2009) (Levran, et al., 2014). The decrease in GR efficiency caused by FKBP5, can help explain the mechanisms that underlie disruption of normal HPA function and stress response. For example, in attempts to correlate the affects of stress on substance abuse, studies have shown that individuals exposed to chronic morphine had an increase of FKBP5 activation and thus a higher stress response (Levran, et al., 2014). Moreover, the blunting of the HPA axis showed a correlation with reward sensitization (Levran, et al., 2014), explaining the role of stress on how addiction is developed physiologically. The studies have shown that relapse was increased in individuals with blunted HPA axis, probably in attempts to return stress to baseline (Binder, 2009) (Julia K Gjerstad, 2018). Therefore, FKBP5 increase in individuals with opioid addiction can help explain the reasons behind risk of relapse (Levran, et al., 2014; Binder, 2009), by examining individual stress modulation on a molecular level.

Susceptibility to psychological stress disorders such as PTSD has been linked to HPA dysfunctions due to GR hypersensitivity due to prolonged periods of stress (Binder, 2009). Studies have shown that individuals who had experienced prolonged periods of stress during development, had blunted HPA and increase in FKBP5 genetic variances, which helped predict risk of experiencing PTSD following stressful stimuli (Binder, 2009). In particular, since FKBP5 had been impairing regular GR function long-term, these individuals had higher cortisol levels. It can thus be assumed that the high cortisol level unable to be metabolized by the HPA axis, causes increased stress responses in these individuals. These inhibitions of the normal HPA functioning has been correlated by these studies to FKBP5 variants, that all showed to increase in individuals with ELS and PTSD (Nylander, et al., 2016) (Binder, 2009). Therefore, it can thus be interpreted that FKBP variation alters sensitization to stress, blunting the normal HPA stress response system. When these changes occur during development, it puts those individuals at risk of developing anxiety disorders such as PTSD, following a stressor.

A high correlation has been shown to exists between stress and drug addiction, with overlapping genetic and environmental effectors. Blunted HPA has been linked to one of the mechanisms underlying drug addiction. In this review, both the environmental and genetic influences of both stress and addiction disorders are analyzed. Chronic drug abuse has been shown to increase stress response in association to an increase of FKBP5, which interacts with the GR complex to decrease its transcription effects, affecting the HPA by decreasing GR efficiency thus increasing cortisol in the cytoplasm (Levran, et al., 2014). Such a process causes an increase of stress response. This stress response can increase reward-seeking behaviour, and increases the chance of substance abuse (Levran, et al., 2014). Moreover, the increase in susceptibility to stress due to the already increased cortisol in individuals expressing high FKBP5, can also lead to a highly stressful response to withdrawal of the drug, and thus cause relapse due to the state of emergency even small stressors cause these individuals (Binder, 2009) (Levran, et al., 2014). In fact, as mentioned above, individuals who experience ELS during development, can create an adaptive response that causes an ultra fast negative feedback for the HPA axis due to overexpressed levels of FKBP5 (Binder, 2009) (Nylander, et al., 2016) (Huang, et al., 2014). Interestingly, studies that looked at the effect of FKBP5 knockout mice on alcohol withdrawal, found that there was an increase in severity following knockout and withdrawal from alcohol administration (Huang, et al., 2014). This suggests that FKBP5 affects withdrawal in a positive way in individuals with the protein overexpression. The results included cortisol binding and upregulating FKBP5 expression, acting as an ultra short negative feedback loop for GR. This in turn, allows for an increase in GR resistance, which, if disrupts for a long enough duration, creates an adaptive response (WBLifeSciences, 2016)(Huang, et al., 2014) that compensated for the modulation of stress through the FKBP5 cycle. In fact, to confirm these conclusions, when studying the affects of the alleles associated with the T/TT genome of FKBP5, have been correlated to an increase in both cortisol and  FKBP5 protein mRNA in association to a blunted HPA (Huang, et al., 2014). This suggests that the overexpression of FKBP5, increase of cortisol and stress response over a long duration, creates a compensatory mechanism that assists with stress processing such as alcohol withdrawal.

These studies showing that in situations of overexpression of stress, FKBP5 can have an opposite affect on GR, increasing ACTH secretion by the HPA, increasing cortisol levels, and increasing FKBP5 transcription. This causes an ultra fast negative feedback that disrupts normal HPA functioning.  Studies have shown that individuals who have experienced ELS, and who reported to have the T/TT genome associated to FKBP5 and its Single Nucleotide Polymorphisms (SNPs), were at higher risk of alcohol addiction (Nylander, et al., 2016). Specifically, those with the associated allele showed to be highly correlated with increased alcohol abuse, decreased withdrawal (analogous to findings of FKBP5 affect on mice knockout and alcohol withdrawal severity, mentioned above (Huang, et al., 2014)), and increased ELS experience (Nylander, et al., 2016). Moreover, the SNPs associated with ELS were correlated to reward-dependent behaviour and blunted HPA (Nylander, et al., 2016); both dysfunctional mechanisms modulated by FKBP5. It is speculated that the T allele enhances FKBP5 transcription (mRNA), that directly modulates regulation of glucocorticoids by enhancing HPA (Julia K Gjerstad, 2018). This increases susceptibility to ELS that has long term affects on development of reward-seeking behaviour moderated by substance abuse (Nylander, et al., 2016). These results suggest that individuals with high predispositions to stress due to overexpression of FKBP5, which is reinforced by compensatory mechanisms due to ELS, can lead to substance abuse such as alcohol. So, the genotype-related impairment of HPA and stress-related cortisol release, suggest that individuals overexpressing FKBP5 are at higher risk of developing anxiety disorders (Julia K Gjerstad, 2018) that correspond to reward-seeking behaviours like substance abuse. Moreover, long-term stress-dependent changes in the regulation of FKBP5 in these individuals, can cause compensatory mechanisms that aid with drug withdrawal severity, furthermore increasing the likelihood of relapse. For example; individuals with anxiety disorders and thus sensitive HPA axis due to FKBP5, show an increase in cortisol levels than individuals with low FKBP5 expression. Its possible to assume that these individuals with increased cortisol levels due to overexpression of FKBP5, results in overexpression of the HPA, which over long periods of time creates an adaptive compensatory response. This response seems to be the decrease of cortisol sensitivity over all, decreasing its affects on mediating negative feedback of stress. This creates an extra short feedback loop mediated by FKBP5, a cortisol-regulated gene, whose expression increases with the increase of inefficient cortisol (Julia K Gjerstad, 2018). Consistent with this are the findings on the FKBP5 knockout models that showed a decrease of cortisol levels (and withdrawal severity) following knockout (Huang, et al., 2014). Therefore, these findings suggest that individuals overexpressing FKBP5 show slower recovery following stressors (Julia K Gjerstad, 2018) (in comparison to individuals with low FKBP5) due to increased cortisol levels and cortisol-dependent FKBP5 transcription that contributes to an ultra-short feedback loop, disrupting normal HPA functioning.

The Gene haploid FKPB5 has been related to problematic modulation of stress responses that risk disturbing normal stress functioning when overexpressed. and thus disrupts normal stress functioning when overexpressed. These normal stress responses have been linked with higher susceptibility to drug addiction and relapse withdrawal symptoms, as well as increased responses to stress that lead to anxiety disorders such as PTSD. The findings that attempt to conclude FKBP5’s role in regulating stress response in association to substance abuse, can be an important discovery to help individualized treatment. Alleles associated with FKBP5 expression, such as the T/TT genotype (WBLifeSciences, 2016) (Binder, 2009), have shown an increase in corticosterone levels, which decreases the return of stress to baseline in those overexpressing FKBP5. Studies have shown that the stress-related modifications caused by gene variances of FKBP5, increases the likelihood of experiencing addictive behaviour or withdrawal symptoms (Huang, et al., 2014). For example, child abuse leading to increased stress, showed to be correlated to variations of the FKBP5 gene (Nylander, et al., 2016), and increased the chances of reward-seeking behaviour such as addiction. This suggests an environment x gene interaction between the mechanisms underlying chronic stress and stress disorders, leading to a high prediction rate of drug abuse. Such regulatory dysfunctions of stress experienced over prolonged periods, can create adaptive compensatory mechanisms that metabolize stress (WBLifeSciences, 2016) (Julia K Gjerstad, 2018). For example, in normal situations, FKBP5 would be represented at normal rates, allowing for a normal decrease in GR transcription. In cases of FKBP overexpression, research has shown an increase of cortisol (also due to dysregulation of HPA caused by FKBP5 SNPs), which increases FKBP5 mRNA, slowing down individual’s ability to react to environmental stressors (Julia K Gjerstad, 2018). These reactions cause an increase likelihood of dysfunctional behaviour that creates a vicious cycle, reinforcing the activation of FKBP5 in already-sensitive individuals. Its unclear the exact mechanisms that underlie the susceptibility of FKBP5 activation, and although it seems like a promising mechanism of research, further studies on the functionality of GR and FKBP5 interaction would contribute to the knowledge of the HPA axis.

References

Binder, E. B. (2009, 05). The role of FKBP5, a co-chaperone of the glucocorticoid receptor in the pathogenesis and therapy of affective and anxiety disorders. Elsevier.

Fast facts from the 2014 Survey on Living with Chronic Diseases in Canada. (2014). Retrieved from Government of Canada: https://www.canada.ca/en/public-health/services/publications/diseases-conditions/mood-anxiety-disorders-canada.html

Huang, M.-C., Schwandt, M. L., Chester, J. A., Kirchhoff, A. M., Kao, C.-F., Liang, T., . . . Heilig, M. (2014). FKBP5 Moderates Alcohol Withdrawal Severity: Human Genetic Association and Functional Validation in Knockout Mice. American College of Neuropsychopharmacology.

Julia K Gjerstad, S. L. (2018, 05). Role of glucocorticoid negative feedback in the regulation of HPA axis pulsatility. Retrieved from Talyor & Francis Online: https://www.tandfonline.com/doi/full/10.1080/10253890.2018.1470238

Levran, O., Peles, E., Randesi, M., d, Y. L., Rotrosen, J., Ott, J., . . . Kreek, M. (2014, 03). Stress-related genes and heroin addiction: A role for a functional FKBP5 haplotype.

Mental and substance use disorders in Canada. (2012). Retrieved from Statistics Canada: https://www150.statcan.gc.ca/n1/pub/82-624-x/2013001/article/11855-eng.htm

Mental Illness & Addiction: Facts and Statistics. (n.d.). Retrieved from CAMH: https://www.camh.ca/en/driving-change/the-crisis-is-real/mental-health-statistics

Nylander, I., Todkar, A., Granholm, L., Vrettou, M., Bendre, M., Boon, W., . . . Comasco, E. (2016). Evidence for a Link Between Fkbp5/FKBP5, Early Life Social Relations and Alcohol Drinking in Young Adult Rats andHumans.

WBLifeSciences. (2016, 07). BioEssays: FK506 binding protein 51. Retrieved from Youtube.com: https://www.youtube.com/watch?v=esYNUo801Is

References

Binder, E. B. (2009, 05). The role of FKBP5, a co-chaperone of the glucocorticoid receptor in the pathogenesis and therapy of affective and anxiety disorders. Elsevier.

Fast facts from the 2014 Survey on Living with Chronic Diseases in Canada. (2014). Retrieved from Government of Canada: https://www.canada.ca/en/public-health/services/publications/diseases-conditions/mood-anxiety-disorders-canada.html

Huang, M.-C., Schwandt, M. L., Chester, J. A., Kirchhoff, A. M., Kao, C.-F., Liang, T., . . . Heilig, M. (2014). FKBP5 Moderates Alcohol Withdrawal Severity: Human Genetic Association and Functional Validation in Knockout Mice. American College of Neuropsychopharmacology.

Julia K Gjerstad, S. L. (2018, 05). Role of glucocorticoid negative feedback in the regulation of HPA axis pulsatility. Retrieved from Talyor & Francis Online: https://www.tandfonline.com/doi/full/10.1080/10253890.2018.1470238

Levran, O., Peles, E., Randesi, M., d, Y. L., Rotrosen, J., Ott, J., . . . Kreek, M. (2014, 03). Stress-related genes and heroin addiction: A role for a functional FKBP5 haplotype.

Mental and substance use disorders in Canada. (2012). Retrieved from Statistics Canada: https://www150.statcan.gc.ca/n1/pub/82-624-x/2013001/article/11855-eng.htm

Mental Illness & Addiction: Facts and Statistics. (n.d.). Retrieved from CAMH: https://www.camh.ca/en/driving-change/the-crisis-is-real/mental-health-statistics

Nylander, I., Todkar, A., Granholm, L., Vrettou, M., Bendre, M., Boon, W., . . . Comasco, E. (2016). Evidence for a Link Between Fkbp5/FKBP5, Early Life Social Relations and Alcohol Drinking in Young Adult Rats andHumans.

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