Substance Addiction

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Understanding the intoxicated brain is important for addiction treatment

Addiction is the psychological, physiological dependence on a substance or activity that progresses through compulsion and interferes with life responsibilities.[1][2] There are various forms of addiction including substance abuse, sex, gambling, and internet addiction. Among these forms, substance addiction is one of the most prevalent in terms of research and common misuse.

The study of addiction is significant because of its wide correlation to neurological, behavioural and psychological studies. It is also very complex as it involves not only the biological aspects like genetics and cellular tolerance, but also environmental factors. The interplay between biological and environmental aspects of addiction is seen with its high comorbidity prevalence with psychiatric disorders, which influences addiction treatment. This highlights that addiction is difficult to treat, as a lot of money, time and effort go towards treatment. Furthermore, consequences of addiction are not only physiological and can be detrimental socially and economically. Thus, better understanding of addiction can provide more efficient treatment. Finally, it is important to study addiction because it can happen to anyone (commonality) in many different forms.

Bibliography
2. Lippincott Williams & Wilkins. Addiction Definition. http://www.medilexicon.com/medicaldictionary.php?t=1061. (2006).


Addiction Comorbidity

main article: Addiction Comorbidity
author: Merovee Dorado

Comorbidity
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www.recoveryconnection.org

Substance addiction, like any other type of addiction, is a form of mental illness, also known as Substance Use Disorder (SUD). Substance addiction comorbidity occurs when an addiction to one substance (ie. cocaine) co-occur with addiction with another substance (ie. opiods). However, SUD can also co-occur with other psychiatric disorders due to significantly similar symptoms. Addiction comorbidity is highly prevalent and can greatly affect treatment for psychiatric disorders and addiction [1]. Studies show that over 50% of individuals with mental illness abuse drugs or alcohol, which is relatively high compared to 15% of the general population [2]. In some cases, drug addiction develops from abuse of or dependence on prescription drugs [3] or as a form of self-medication for psychiatric disorders [4].

Psychiatric disorders comorbid with addiction commonly involves Affective, Anxiety and Mood Disorders. Comorbid disorders can worsen the progression of both disorders.

Bibliography
1. Brady, K., Verdiun, M., and Tolliver, B. Treatment of Patients Comorbid for Addiction and Other Psychiatric Disorders. Current Psychiatry Report 9, 374-380 (2007).
2. Canadian Mental Health Association, BC. Mental Illness and Substance Use Disorders: Key Issues. http://www.cmha.bc.ca/files/7-mi_substance_use.pdf (2005).
3. Egan, M., Moride, Y., Wolfson, C., and Monette, J. Long-term continuous use of benzodiazepines by older adults in Quebec: prevalence, incidence and risk factors. J. Am. Geriatr. Soc. 48, 811-916 (2000).
4. Norman, S., Myers, U., Wilkins, K., Goldsmith, A., Hristova, V., Huang, Z., McCullogh, K., and Robinson, S. Review of biological mechanisms and pharmacological treatments of comorbid PTSD and substance use disorder. Neuropharma. 62, 542-551 (2012).


Genetics of Addiction

main article: Genetics of Addiction
author: YunJoo Lee

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(Fig. 1) Genetic disposition affects brain behavioural outcomes and behaviour [2]

Initially, addiction seems to arise directly as a consequence of an individual’s social setting. Though setting is an influence, there are factors that contribute to peoples’ personalities, behaviours and/or biological functionalities that can reel them an inch closer to addiction development. Meta-analysis of twin studies reveal that heritable genetic factors account for 48-66% of alcohol, 42-79% of cocaine and 51-59% of cannabis addiction.[1] In this sense, genetics can suggest the possibility of addiction development when looking at polymorphic variants of genes for receptors, transporters and enzymes. The presence of different receptor subunits or transporter variants can modulate different amounts of neurotransmitter synthesis, and release affecting behaviours (Fig. 1). Consequently, external behaviours such as impulsiveness, aggression and depression can arise, increasing the risk of individuals resorting to substance-use and compulsory addiction. Some variants of subunits and enzymes can yield less efficient functionality resulting in aversive side effects of drugs (and less risk of addiction) or more efficient functioning driving an individual to consume higher doses of drugs for a satisfactory effect.

Regardless of whether a variant manifests to diminish or enhance risk of addiction development, it’s inevitably the interplay of gene-gene, gene-environment interactions and the polygenic nature that makes it so difficult to tease apart the causal associations of addiction development. Thus, genes thought to contribute to addiction development are upheld only as vulnerability factors and not causes since addiction is not as simple as one or a few genes giving rise to addiction.

Genes and Addiction. Prod. by Seastage & Dr. T. Wilens
(Massachusetts General Hospital)

These candidate or implicated genes may increase susceptibility of an individual to addiction and provide an idea or path for future studies to explore but it does not determine whether he or she will develop addiction. Even if specific genes were directly correlated, there would still be uncertainties in predictive abilities because of the complex interactions giving different behaviours and gene expression. Many studies investigate and suggest possible genes associated with addiction but inconsistencies in results exist because of the elaborate influences of social, economic, and psychological environments on an individual’s genetic expression.

Bibliography
1. Agrawal, A. et al. The genetics of addiction- a translational perspective. Transl Psychiatry. 2, 1-14 (2012).
2. Volkow, N. D. & Muenke, M. The genetics of addiction. Hum Genet 131, 773-777 (2012).


Receptors and Research in Addiction

main article: Receptors and Research in Addiction
author: Tabassum Rahim

Receptors in the Intoxicated Brain
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Receptors aid the intoxicated brain by negative
feedback and population regulation[1]

Why are they important?

The brain consists of specific receptors that play a major role in regulating addiction and are the highlight of most research regarding addiction mechanisms in the brain. These receptors are the brain’s own way of compensating for excess neurotransmitter release due to intoxication. Research on these receptors is valuable to society as the information gained on how they work can be used for addiction treatment. There are specific mechanisms by which these receptors have been found to aid the intoxicated brain, such as negative feedback and regulation of receptor populations[1]. Exploring and understanding such mechanisms that may help find new addiction treatments is possible due to the use of animal models. Today, most research on addiction consist of receptor knockout and conditioned animal model studies[2].

Bibliography
1. McBRIDE, W.J. , MURPHY, J.M. , LUMENG, L. , LI , T.K. Serotonin, Dopamine and GAB A Involvement in Alcohol Drinking of Selectively Bred Rats. Alcohol. Vol. 7, 199-205
2. Bell, R.L., Rodd, Z.A., Lumeng, L., Murphy, J.M., McBride, W.J. The alcohol-preferring P rat and animal models of excessive alcohol drinking. Addiction Biology. Vol. 11, 270–288


Reward Pathway and Behavior in Addiction

main article: Reward Pathway and Behavior in Addiction
author: Chang Woo Park

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The mesolimbic reward pathway and the alteration of the dopamine neuromodulators. [4]

Human survival mandates us to sustain our vital functions of our lives by nourishing ourselves with food and water and engaging in sexual activity to avoid human extinction by reproducing. All of these factors have an effect on the reward circuit, triggering pleasurable stimulations in our brains. As humans, it is psychological for us to seek pleasurable stimulations while avoiding pain as much as possible.[1] Therefore when the reward circuit is exploited by abusive behaviors and addictive substances via substance, social and sexual addictions, the reward circuit is dramatically affected and altered. The reward circuit is composed of 3 major dopaminergic pathways of which one, the mesocorticolimbic, is largely associated with reward stimulation and reward-seeking behaviors. With any addiction, it alters this pathway, affecting reward regulation, motivation and behaviors. This happens by modifying the level of dopamine neuromodulators and its receptors. One of the main sources of the dopaminergic neurons is located in the ventral tegmental area (VTA). When an individual is exposed to addictive substance, the activity of the VTA dopaminergic neurons are affected which contributes to the overall change in the level of dopamine, modulated by the activity of GABAergic neurons.[2] Changes in the reward pathway also affects behavior; specifically in the nucleus accumbens that leads to craving and pleasure-seeking behavior through synaptic plasticity.[3]

Bibliography
1. Bruno Dubuc. The Philosophies of Pleasure. http://thebrain.mcgill.ca/flash/a/a_03/a_03_s/a_03_s_que/a_03_s_que.html (2002)
2. Xiao C, Ye JH. (2008). Ethanol dually modulates GABAergic synaptic transmission onto dopaminergic neurons in ventral tegmental area: role of µ-opioid receptors. Neuroscience. 153(1):240-248.
3. Wolf ME, Ferrario CR. (2010). AMPA receptor plasticity in the nucleus accumbens after repeated exposure to cocaine. Neurosci Biobehav Rev. 35(2):185-211.
4. NIH. Drugs, Brains, and Behavior: The Science of Addiction. http://www.drugabuse.gov/publications/science-addiction/drugs-brain (2010)


Tolerance

main article: Tolerance
author: Linda Cheng

Tolerance
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Figure 1: A pictorial depiction of drug tolerance.
As an individual is repeatedly exposed to the substance,
a greater dose is needed to achieve the same feeling as
before, also known as drug tolerance. [2]

Addiction research has identified tolerance to play a key role in substance addiction and misuse. Tolerance is frequently seen behaviorally as a need to increase the dose to reach the desired effect. Substance tolerance is typically divided into metabolic tolerance and cellular tolerance. Specifically, cellular tolerance includes molecular changes happening at the target site of the drug, and also changes to the learning and reward systems in the brain or sometimes referred to as learned tolerance.

Tolerance to pain managing medications is frequently seen in the clinical setting. A study involving 206 subjects in 2005 found greater than ten-fold dose increase for patients undergoing an opioid pain management program.[1] In illicit opioid users, the amount of dose escalation can be even more drastic as subjects compulsively seek to create the same psychological and physiological effect as the previous dose.

Understanding the role of tolerance in substance dependence can allow for better prevention when medications with high misuse potential are prescribed, and can allow for better treatments for those struggling with substance dependence.

Bibliography
1. Buntin-Mushock, C., Phillip, L., Moriyama, K., Palmer, P.P. Age-dependent opioid escalation in chronic pain patients. Anesth Analg 100, 1740-1745 (2005).
2. Walter, J.P. (2009). From tragedy, Laura found her purpose. KY United Methodist Childrens Homes. Retrieved March 26th, from http://www.kyumh.org/story_laura.htm.


Treatment of Addiction

main article: Treatment of Addiction
author: Ingrid Quevedo

Different medications for different addictions
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Retrieved from http://www.thetimes.co.uk/tto/health/news/article3701440.ece

Producing effective treatment for substance addictions can greatly decrease its prevalence and improve the lives of individuals with addiction. Substance addiction is complex as it encompasses a variation of pathways and structures affected within the brain leading to different behavioural and psychological changes [1]. Medications used to treat addiction reflect this knowledge – different combinations of pharmacological treatments are used depending on the type of addiction [2]. The majority of medications used are effective but there are still some limitations to them. Medications used to treat alcohol, opiate, and stimulant addictions differ due to the different effects these substances produce. Learning and memory also seem to be involved in relapse through the maintenance of drug-cue associations. Targeting these processes could lead to new treatments to prevent the incidence of relapse.

Bibliography
1. Nestler E.J. Is there a common molecular pathway for addiction? Nature. 8: 1445-1449 (2005).
2. Drugs, Brains, and Behavior: The Science of Addiction. http://www.drugabuse.gov/publications/science-addiction/treatment-recovery. (2012)



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