Addiction vulnerability

Addiction and dependence glossary[1][2][3][4]
  • addiction – a biopsychosocial disorder characterized by persistent use of drugs (including alcohol) despite substantial harm and adverse consequences
  • addictive drug – psychoactive substances that with repeated use are associated with significantly higher rates of substance use disorders, due in large part to the drug's effect on brain reward systems
  • dependence – an adaptive state associated with a withdrawal syndrome upon cessation of repeated exposure to a stimulus (e.g., drug intake)
  • drug sensitization or reverse tolerance – the escalating effect of a drug resulting from repeated administration at a given dose
  • drug withdrawal – symptoms that occur upon cessation of repeated drug use
  • physical dependence – dependence that involves persistent physical–somatic withdrawal symptoms (e.g., fatigue and delirium tremens)
  • psychological dependence – dependence that involves emotional–motivational withdrawal symptoms (e.g., dysphoria and anhedonia)
  • reinforcing stimuli – stimuli that increase the probability of repeating behaviors paired with them
  • rewarding stimuli – stimuli that the brain interprets as intrinsically positive and desirable or as something to approach
  • sensitization – an amplified response to a stimulus resulting from repeated exposure to it
  • substance use disorder – a condition in which the use of substances leads to clinically and functionally significant impairment or distress
  • tolerance – the diminishing effect of a drug resulting from repeated administration at a given dose

Addiction vulnerability is an individual's risk of developing an addiction during his or her lifetime. There are a range of genetic and environmental risk factors for developing an addiction that vary across the population.[2][5][6] Genetic and environmental risk factors each account for roughly half of an individual's risk for developing an addiction;[2] the contribution from epigenetic (inheritable traits)[7] risk factors to the total risk is unknown.[5] Even in individuals with a relatively low genetic risk, exposure to sufficiently high doses of an addictive drug for a long period of time (e.g., weeks–months) can result in an addiction.[2] In other words, anyone can become an addict under particular circumstances. Research is working toward establishing a comprehensive picture of the neurobiology of addiction vulnerability, including all factors at work in propensity for addiction.

Three-factor model

Accepted research now shows that some people have vulnerabilities to addiction and has established a three-factor standard for vulnerability to drug addiction: genetic factors, environmental factors, and repeated exposure to drugs of abuse.[8] Being vulnerable to addiction means that there exists some factor which makes one individual more likely to develop an addiction than another individual. Additionally, many in the science community agree that addiction is not simply just a result of desensitized neural receptors but also a corollary of long-term associated memories (or cues) of substance use and self-administration.[9] Vulnerability to addiction has both physiological and biological components.

Genetic factors

Contemporary research in neurobiology (a branch of science that deals with the anatomy,[10] physiology, and pathology of nervous system) of addiction points to genetics as a major contributing factor to addiction vulnerability. It has been estimated that 40–60% of the vulnerability to developing an addiction is due to genetics.[11][12] One gene in particular, the D2 subtype of dopamine receptor, has been studied at length in association to substance addiction. The D2 receptor responds to the chemical dopamine which produces rewarding and pleasurable feelings in the brain. Through mice studies, agreeing contemporary research has shown that individuals with a deficiency in this dopamine receptor exhibit not only a preference for and increased consumption of alcohol over their genetically normal peers,[13] but also compensated levels of the cannabinoid receptor type CB1.[13]

This suggests that both of these genetic factors work together in the regulation of alcohol and cocaine in the brain and in the normal regulation of dopamine. Individuals with this genetic deficiency in the D2 dopamine receptor may be more likely to seek out these recreational pleasure/reward producing substances as they are less receptive to the natural “feel good’’ effects of dopamine.[13] This naturally occurring deficiency is one of the most studied genetic vulnerabilities to substance abuse across the field. Recent studies show that GABA also plays a role in vulnerability to addiction. When alcohol is consumed it affects GABA by mimicking its effects on the brain, such as basic motor functions.[14]

Additionally, genetics play a role on individual traits, which may put one at increased risk for experimentation with drugs, continued use of drugs, addictions, and potential for relapse. Some of these individual personality traits, such as impulsivity, reward-seeking, and response to stress, may lead to increased vulnerability to addiction.[15]

Environmental factors

A major environmental factor that increases vulnerability to developing addiction is availability of drugs. Additionally, other environmental factors come into play, such as socioeconomic status and poor familial relationships, and have been shown to be contributing factors in the initiation (and continued use) of drug abuse.[16] Neurobiology again plays a role in addiction vulnerability when in combination with environmental factors. The main risk of chronic stressors contributing to vulnerability is that they can put the brain in a compromised state. External stressors (such as financial concerns and family problems) can, after repeated exposure, affect the physiology of the brain.[17]

Chronic stress or trauma has been shown to have neuroadaptive effects such that the brain can essentially physically “rewire” itself to accommodate for the increase in cortisol produced by the stressors. Evidence has also shown that a great amount of stress hinders your prefrontal functioning as well causes an increased limbic-stratal level responding. This can lead to low behavioral and cognitive control.[17] Additionally, when the brain is put under severe stress due to repeated drug use, it has been shown to be physiologically altered.[9][18] This compromised neural state plays a large role in perpetuating addiction and in making recovery more difficult.

Repeated exposure

Repeated exposure to a drug is one of the determining factors in distinguishing recreational substance use from chronic abuse. Many neurobiological theories of addiction place repeated or continued use of the drug in the path of addiction development. For example, researchers have theorized that addiction is the result of the shift from goal-directed actions to habits and ultimately, to compulsive drug-seeking and taking.[19][20]

In other words, repeated, deliberate use of the drug plays a role in the eventual compulsory drug-taking and/or habitual drug-taking associated with addiction. Another theory suggests that through repeated use of the drug, individuals become sensitized to drug-associated stimuli which may result in compulsive motivation and desire for the drug.[21]

Additionally, a third neurobiological theory highlights the changes in brain reward circuitry following repeated drug use that contributes to the development of addiction such that addiction is conceptualized as being a progression of allostatic changes in which the addicted individual is able to maintain stability but at a pathological set point.[22] Experience-dependent neural plasticity is a hallmark of repeated drug exposure and refers to the adaptation of the brain due to increased levels of the drug in the body.[23] In this sense, repeated exposure falls under both physiological vulnerability and behavioral/psychological vulnerability to addiction.

Although many variables individually contribute to an increased risk of developing a substance use disorder, no single vulnerability guarantees the development of addiction. It is the combination of many factors (e.g. genetics, environmental stressors, initiation and continued use of the drug) that culminates in the development of this disorder.

Adolescence

Previous research has examined the increased risk of substance use initiation during adolescence. Many factors have been identified as being associated with increased risk of substance use during this period of development including individual differences (e.g., negative affect, decreased harm avoidance, and low motivation for achievement), biological (e.g., genetic predisposition and neurological development), and environmental factors (e.g., high levels of stress, peer influences, availability of substances, etc.) [24][25][26] Rat studies provide behavioral evidence that adolescence is a period of increased vulnerability to drug-seeking behavior and onset addiction.[27]

The mesolimbic dopamine system of the brain is undergoing reorganization and functional changes during adolescence. Rat studies have demonstrated that adolescents have tendencies and abilities to drink more than adults due to minimal disruption to their motor functions and also due to minimal sensitivity to sedation.[28] As a result, it is more susceptible to become addicted in the wake of drug use during this developmental period.[27] Overall, social, behavioral and developmental factors in adolescence make individuals more liable to drug seeking behavior, and as a result, addiction.

Epigenetic factors

Transgenerational epigenetic inheritance

Epigenetic genes and their products (e.g., proteins) are the key components through which environmental influences can affect the genes of an individual;[5] they also serve as the mechanism responsible for transgenerational epigenetic inheritance, a phenomenon in which environmental influences on the genes of a parent can affect the associated traits and behavioral phenotypes of their offspring (e.g., behavioral responses to environmental stimuli).[5] In addiction, epigenetic mechanisms play a central role in the pathophysiology of the disease;[2] it has been noted that some of the alterations to the epigenome which arise through chronic exposure to addictive stimuli during an addiction can be transmitted across generations, in turn affecting the behavior of one's children (e.g., the child's behavioral responses to addictive drugs and natural rewards).[5][29]

The general classes of epigenetic alterations that have been implicated in transgenerational epigenetic inheritance include DNA methylation, histone modifications, and downregulation or upregulation of microRNAs.[5] With respect to addiction, more research is needed to determine the specific heritable epigenetic alterations that arise from various forms of addiction in humans and the corresponding behavioral phenotypes from these epigenetic alterations that occur in human offspring.[5][29] Based upon preclinical evidence from animal research, certain addiction-induced epigenetic alterations in rats can be transmitted from parent to offspring and produce behavioral phenotypes that decrease the offspring's risk of developing an addiction.[note 1][5] More generally, the heritable behavioral phenotypes that are derived from addiction-induced epigenetic alterations and transmitted from parent to offspring may serve to either increase or decrease the offspring's risk of developing an addiction.[5][29]

Notes

  1. ↑ According to a review of experimental animal models that examined the transgenerational epigenetic inheritance of epigenetic marks that occur in addiction, alterations in histone acetylation – specifically, di-acetylation of lysine residues 9 and 14 on histone 3 (i.e., H3K9ac2 and H3K14ac2) in association with BDNF gene promoters – have been shown to occur within the medial prefrontal cortex (mPFC), testes, and sperm of cocaine-addicted male rats.[5] These epigenetic alterations in the rat mPFC result in increased BDNF gene expression within the mPFC, which in turn blunts the rewarding properties of cocaine and reduces cocaine self-administration.[5] The male but not female offspring of these cocaine-exposed rats inherited both epigenetic marks (i.e., di-acetylation of lysine residues 9 and 14 on histone 3) within mPFC neurons, the corresponding increase in BDNF expression within mPFC neurons, and the behavioral phenotype associated with these effects (i.e., a reduction in cocaine reward, resulting in reduced cocaine-seeking by these male offspring).[5] Consequently, the transmission of these two cocaine-induced epigenetic alterations (i.e., H3K9ac2 and H3K14ac2) in rats from male fathers to male offspring served to reduce the offspring's risk of developing an addiction to cocaine.[5] As of 2018, neither the heritability of these epigenetic marks in humans nor the behavioral effects of the marks within human mPFC neurons has been established.[5]

References

  1. ↑ Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter 15: Reinforcement and Addictive Disorders". In Sydor A, Brown RY (eds.). Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York: McGraw-Hill Medical. pp. 364–375. ISBN 9780071481274.
  2. 1 2 3 4 5 Nestler EJ (December 2013). "Cellular basis of memory for addiction". Dialogues in Clinical Neuroscience. 15 (4): 431–443. PMC 3898681. PMID 24459410. Despite the importance of numerous psychosocial factors, at its core, drug addiction involves a biological process: the ability of repeated exposure to a drug of abuse to induce changes in a vulnerable brain that drive the compulsive seeking and taking of drugs, and loss of control over drug use, that define a state of addiction. ... A large body of literature has demonstrated that such ΔFosB induction in D1-type [nucleus accumbens] neurons increases an animal's sensitivity to drug as well as natural rewards and promotes drug self-administration, presumably through a process of positive reinforcement ... Another ΔFosB target is cFos: as ΔFosB accumulates with repeated drug exposure it represses c-Fos and contributes to the molecular switch whereby ΔFosB is selectively induced in the chronic drug-treated state.41. ... Moreover, there is increasing evidence that, despite a range of genetic risks for addiction across the population, exposure to sufficiently high doses of a drug for long periods of time can transform someone who has relatively lower genetic loading into an addict.
  3. ↑ "Glossary of Terms". Mount Sinai School of Medicine. Department of Neuroscience. Retrieved 9 February 2015.
  4. ↑ Volkow ND, Koob GF, McLellan AT (January 2016). "Neurobiologic Advances from the Brain Disease Model of Addiction". New England Journal of Medicine. 374 (4): 363–371. doi:10.1056/NEJMra1511480. PMC 6135257. PMID 26816013. Substance-use disorder: A diagnostic term in the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) referring to recurrent use of alcohol or other drugs that causes clinically and functionally significant impairment, such as health problems, disability, and failure to meet major responsibilities at work, school, or home. Depending on the level of severity, this disorder is classified as mild, moderate, or severe.
    Addiction: A term used to indicate the most severe, chronic stage of substance-use disorder, in which there is a substantial loss of self-control, as indicated by compulsive drug taking despite the desire to stop taking the drug. In the DSM-5, the term addiction is synonymous with the classification of severe substance-use disorder.
  5. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 Vassoler FM, Sadri-Vakili G (2014). "Mechanisms of transgenerational inheritance of addictive-like behaviors". Neuroscience. 264: 198–206. doi:10.1016/j.neuroscience.2013.07.064. PMC 3872494. PMID 23920159. However, the components that are responsible for the heritability of characteristics that make an individual more susceptible to drug addiction in humans remain largely unknown given that patterns of inheritance cannot be explained by simple genetic mechanisms (Cloninger et al., 1981; Schuckit et al., 1972). The environment also plays a large role in the development of addiction as evidenced by great societal variability in drug use patterns between countries and across time (UNODC, 2012). Therefore, both genetics and the environment contribute to an individual's vulnerability to become addicted following an initial exposure to drugs of abuse. ... The evidence presented here demonstrates that rapid environmental adaptation occurs following exposure to a number of stimuli. Epigenetic mechanisms represent the key components by which the environment can influence genetics, and they provide the missing link between genetic heritability and environmental influences on the behavioral and physiological phenotypes of the offspring.
  6. ↑ R. Maldonado, P. Calvé, A. García-Blanco, L. Domingo-Rodriguez, E. Senabre, E. Martín-García. Vulnerability to addiction, Neuropharmacology, Volume 186, 2021, 108466, ISSN 0028-3908, https://doi.org/10.1016/j.neuropharm.2021.108466.
  7. ↑ "Definition of epigenetic in English". Archived from the original on 29 June 2020.
  8. ↑ Kreek, Mary Jeanne; Nielsen, David A.; LaForge, K. Steven (1 January 2004). "Genes Associated With Addiction: Alcoholism, Opiate, and Cocaine Addiction". NeuroMolecular Medicine. 5 (1): 085–108. doi:10.1385/NMM:5:1:085. PMID 15001815. S2CID 29883440.
  9. 1 2 Hyman, SE; Malenka, RC; Nestler, EJ (2006). "Neural mechanisms of addiction: the role of reward-related learning and memory". Annual Review of Neuroscience. 29: 565–98. doi:10.1146/annurev.neuro.29.051605.113009. PMID 16776597.
  10. ↑ "Neurobiology". Merriam-Webster.
  11. ↑ Goldman, Orozsi; Ducci (2005). "The genetics of addictions: uncovering the genes". Nat Rev Genet. 6 (7): 521–532. doi:10.1038/nrg1635. PMID 15995696. S2CID 3842270.
  12. ↑ Hiroi, Agatsuma (2005). "Genetic susceptibility to substance dependence". Mol Psychiatry. 10 (4): 336–44. doi:10.1038/sj.mp.4001622. PMID 15583701.
  13. 1 2 3 Thanos, Panayotis K.; Gopez, Vanessa; Delis, Foteini; Michaelides, Michael; Grandy, David K.; Wang, Gene-Jack; Kunos, George; Volkow, Nora D. (1 January 2011). "Upregulation of Cannabinoid Type 1 Receptors in Dopamine D2 Receptor Knockout Mice Is Reversed by Chronic Forced Ethanol Consumption". Alcoholism: Clinical and Experimental Research. 35 (1): 19–27. doi:10.1111/j.1530-0277.2010.01318.x. PMC 3004984. PMID 20958329.
  14. ↑ Nestler, Eric J. (November 2000). "Genes and Addiction". Nature Genetics. 26 (3): 277–281. doi:10.1038/81570. PMID 11062465. S2CID 15704258.
  15. ↑ Kreek, M. J.; Nielsen, D. A.; Butelman, E. R.; Laforge, K. S. (2005). "Genetic influences on impulsivity, risk taking, stress responsivity and vulnerability to drug abuse and addiction". Nature Neuroscience. 8 (11): 1450–1457. doi:10.1038/nn1583. PMID 16251987. S2CID 12589277.
  16. ↑ Volkow, N.; Li, T. K. (2005). "The neuroscience of addiction". Nature Neuroscience. 8 (11): 1429–1430. doi:10.1038/nn1105-1429. PMID 16251981. S2CID 7721465.
  17. 1 2 Sinha, Rajita (17 April 2017). "Chronic Stress, Drug Use, and Vulnerability to Addiction". Annals of the New York Academy of Sciences. 1141: 105–130. doi:10.1196/annals.1441.030. ISSN 0077-8923. PMC 2732004. PMID 18991954.
  18. ↑ Sinha, Rajita (1 October 2008). "Chronic Stress, Drug Use, and Vulnerability to Addiction". Annals of the New York Academy of Sciences. 1141 (1): 105–130. doi:10.1196/annals.1441.030. PMC 2732004. PMID 18991954.
  19. ↑ Everitt, B. J.; Robbins, T. W. (2005). "Neural systems of reinforcement for drug addiction: from actions to habits to compulsion". Nature Neuroscience. 8 (11): 1481–1489. doi:10.1038/nn1579. PMID 16251991. S2CID 16941967.
  20. ↑ Goldstein, R. Z. (2002). "Drug Addiction and Its Underlying Neurobiological Basis: Neuroimaging Evidence for the Involvement of the Frontal Cortex". American Journal of Psychiatry. 159 (10): 1642–1652. doi:10.1176/appi.ajp.159.10.1642. PMC 1201373. PMID 12359667.
  21. ↑ Robinson, T. E.; Berridge, K. C. (2008). "The incentive sensitization theory of addiction: Some current issues". Philosophical Transactions of the Royal Society B: Biological Sciences. 363 (1507): 3137–3146. doi:10.1098/rstb.2008.0093. PMC 2607325. PMID 18640920.
  22. ↑ Koob, G. F. (2003). "Alcoholism: Allostasis and Beyond". Alcoholism: Clinical and Experimental Research. 27 (2): 232–243. doi:10.1097/01.ALC.0000057122.36127.C2. PMID 12605072.
  23. ↑ Thomas, Mark J.; Beurrier, Corinne; Bonci, Antonello; Malenka, Robert C. (5 November 2001). "Long-term depression in the nucleus accumbens: A neural correlate of behavioral sensitization to cocaine". Nature Neuroscience. 4 (12): 1217–1223. doi:10.1038/nn757. PMID 11694884. S2CID 28573169.
  24. ↑ Fergusson, D. M.; Boden, J. M.; Horwood, L. J. (2008). "The developmental antecedents of illicit drug use: Evidence from a 25-year longitudinal study". Drug and Alcohol Dependence. 96 (1–2): 165–177. doi:10.1016/j.drugalcdep.2008.03.003. PMID 18423900.
  25. ↑ Nation, M.; Heflinger, C. A. (2006). "Risk Factors for Serious Alcohol and Drug Use: The Role of Psychosocial Variables in Predicting the Frequency of Substance Use Among Adolescents". The American Journal of Drug and Alcohol Abuse. 32 (3): 415–433. doi:10.1080/00952990600753867. PMID 16864471. S2CID 6845644.
  26. ↑ Bates, M. E.; Labouvie, E. W. (1997). "Adolescent Risk Factors and the Prediction of Persistent Alcohol and Drug Use into Adulthood". Alcoholism: Clinical and Experimental Research. 21 (5): 944–950. doi:10.1111/j.1530-0277.1997.tb03863.x.
  27. 1 2 Wong, WC; Ford, KA; Pagels, NE; McCutcheon, JE; Marinelli, M (13 March 2013). "Adolescents are more vulnerable to cocaine addiction: behavioral and electrophysiological evidence". The Journal of Neuroscience. 33 (11): 4913–22. doi:10.1523/JNEUROSCI.1371-12.2013. PMC 3630505. PMID 23486962.
  28. ↑ Winters, Ken C.; Arria, Amelia (2011). "Adolescent brain development and drugs". The Prevention Researcher. 18 (2): 21–24. PMC 3399589. PMID 22822298.
  29. 1 2 3 Yuan TF, Li A, Sun X, Ouyang H, Campos C, Rocha NB, Arias-Carrión O, Machado S, Hou G, So KF (2015). "Transgenerational Inheritance of Paternal Neurobehavioral Phenotypes: Stress, Addiction, Ageing and Metabolism" (PDF). Mol. Neurobiol. 53 (9): 6367–6376. doi:10.1007/s12035-015-9526-2. hdl:10400.22/7331. PMID 26572641. S2CID 25694221.
This article is issued from Offline. The text is licensed under Creative Commons - Attribution - Sharealike. Additional terms may apply for the media files.