Receptors and Research in Addiction

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].

Introduction to neurotransmitters and receptors associated with addiction

1. Serotonin

Serotonin or 5-hydroxytryptamine (5-HT) is a neurotransmitter in the brain used for relay of messages through neuronal transmission. In a normal brain its functions include mood, appetite and sleep regulation. Intoxication affects serotonin regulation by increasing or decreasing its uptake and/or metabolic degradation such as increased serotonin concentration, degeneration or loss of receptors[5][6].

In an addicted brain the 5-HT(1A) receptor has been found to be hyperactive due to an increase in serotonin as a result of drug-monoamine transporter interactions[3]. Most substances associated with addiction are speculated to target these receptors in the ventral tegmental area, resulting in elevated dopamine concentration in the nucleus accumbens[4].

2. Dopamine

Dopamine is also a neurotransmitter in the brain used for neuronal transmission of messages. Out of the many receptors, the dopamine-2 (D2) receptor specifically regulates locomotion, hormone concentrations and behaviours associated with addiction[8]. Although dopamine is usually associated with the rewarding effects of addictive drugs, usually thought to be the sole mechanism behind substance addiction, Sora et al (2001) demonstrate that mice with genetic knockout of the dopamine receptor exhibit addictive behaviours such as self-administration of drugs. Drug preference is completely lost with the exclusion of both dopamine and serotonin receptors through gene-knockout experiments[3][10].

Dopamine receptors interact within a number of signalling pathways called G protein-coupled receptors (GPCRs). Activation of the receptors triggers a cascade of signalling events resulting in protein structure modifications and ion release, translating to altered behaviour or disorders associated with addiction[11].

To learn more about the role of D2 receptors in addiction, refer to :Food Addiction

3. GABA

Gamma-aminobutyric acid (GABA) is an inhibitory neurotransmitter, uptake of which causes the hyperpolarization of cells. Enhanced uptake of this neurotransmitter by the GABAA receptors results in anesthesia, sedation, hypnosis and anxiolysis. The GABA receptors consist of heterogenous subunits which means they are diverse[12]. GABA release and uptake in an intoxicated brain is regulated via interactions between the substance and GPCRs consisting of serotonin and dopamine receptors among other subunits[13].

For more on receptors and the reward pathway refer to: Reward Pathway and Behavior in Addiction

Addiction Research

Purpose

Addiction research today comprises of two broad areas: detection of genetic predisposition to addiction and addiction treatment. In order to understand the genetic component of receptors in addiction scientists primarily rely on observational studies by process of elimination of genes associated with specific receptors that mediate addiction behaviours. This type of gene-knockout studies serve two purposes; understanding mechanisms by which substances cause addiction and identifying target pathways to be inhibited/enhanced using drug therapy to treat addiction.

Animal Models for Research
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Gene-knockout studies are common in addiction research

1. Gene Knock-outs and Selective Breeding

Observational studies require animal models to replicate the biological and behavioural conditions of the human addicted brain. Studies such as the one done by Hernandez et al. (2006) exhibit concrete observations through measurement of chemical concentrations prior to and after external cranial stimulations, similar to the role of a psychostimulant[14]. Other studies require physical administering of drugs to induce addiction mechanisms in the animal followed by observation of self-administration patterns and withdrawal behaviour. These studies allow researchers to control multiple variants to observe target variant or control single variant to observe multiple effects due to its absence to identify its function. An example is the study by Sim et al.(2013) in which they analyze ‘anxiety-like behaviours’ in dopamine-2 receptor knockout mice and observe suppression of sensitization and drug-seeking and relapse activities leading them to conclude that the dopamine-2 receptor plays a major role in regulating addiction mechanisms[15]. Such animal models are developed by isolating totipotent embryonic stem cells and inserting the designed gene agonist or antagonist for target gene into the locus through homologous recombination[16]. The developed animal will contain the target mutation in every cell. Producing such an animal model is termed selective breeding. In addiction research and specifically alcohol addiction, animal models are selectively bred to be substance preferring (P) and non-substance preferring (NP). In a study by Sari et al. (2013), P rats are used to study the effects of ceftriaxone on alcohol intake[17].

Conditioned Animal Model
A video on how an animal can be conditioned or trained using
various techniques such as satiety and shock
Please click link above to be view in new window or click below
Conditioned Animal Model Video

2. Current Research

Papers recently published by Pentkowski and his colleagues are vital to the understanding of specific addiction behaviours that can result from the up or down-regulation of specific receptors. The study utilizes cutting-edge technology such as viral vector microinfusion and fluorescent proteins as opposed to gene-knockout animal models[19]. This technology, compared to gene-knockout techniques, is more efficient as viral vectors can be used to deliver gene agonists and antagonists to target sites on a locus in a fully developed animal. This method is convenient for studying the biological and physiological effects of reduced receptor or neurotransmitter concentrations after prolonged administration of addictive substances in adult animals. Current addiction research is aimed toward receptor modulation and addiction-behaviour correlation studies, the ultimate goal being the discovery of therapeutic solutions for addicts, and the techniques and methods used to achieve the task is an integral part of the research.

Brain Stimulation to Activate Reward Pathway
Information on deep brain stimulation and its use in research.
Please click link above to be view in new window or click link below
Brain Stimulation Video

Additional Links of Interest:

Tolerance
Treatment of Addiction
Heroine Addiction and Crime
Sexual Addiction
Genetics of Addiction
Video Game Addiction

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
3. Müller CP, Carey RJ, Huston JP, De Souza Silva MA. Serotonin and psychostimulant addiction: focus on 5-HT1A-receptors.
Prog Neurobiol. 2007 Feb; 81(3):133-78.
4. Mateo Y, Budygin EA, John CE, Jones SR. Role of serotonin in cocaine effects in mice with reduced dopamine transporter function.Proc Natl Acad Sci U S A. 2004 Jan 6; 101(1):372-7. Epub 2003 Dec 22.
5. Steinkellner T, Freissmuth M, Sitte HH, Montgomery T. The ugly side of amphetamines: short- and long-term toxicity of 3,4-methylenedioxymethamphetamine (MDMA, 'Ecstasy'), methamphetamine and D-amphetamine. Biological Chemistry. 2011;392:103–115.
6. Yamamoto BK, Moszczynska A, Gudelsky GA. Amphetamine toxicities: classical and emerging mechanisms. Annals of the New York Academy of Sciences. 2010;1187:101–121.
7. Parastoo Hashemi, Elyse C. Dankoski, Rinchen Lama, Kevin M. Wood, Pavel Takmakov, R. Mark Wightman. Brain dopamine and serotonin differ in regulation and its consequences. Proc Natl Acad Sci U S A. 2012 July 17; 109(29): 11510–11515. Published online 2012 July 9. doi: 10.1073/pnas.1201547109
8. Usiello A., Baik J., Rougé-Pont F., Picetti R., Dierich A., LeMeur M., Piazza P. & Borrelli E. Distinct functions of the two isoforms of dopamine D2 receptors.Nature 408, 199-203
9. Rocha BA, Fumagalli F, Gainetdinov RR, Jones SR, Ator R, Giros B, Miller GW, Caron MG. Cocaine self-administration in dopamine-transporter knockout mice. Nature Neuroscience. 1998;1:132–137.
10. Sora I, Hall FS, Andrews AM, Itokawa M, Li XF, Wei HB, Wichems C, Lesch KP, Murphy DL, Uhl GR. Molecular mechanisms of cocaine reward: combined dopamine and serotonin transporter knockouts eliminate cocaine place preference. Proceedings of the National Academy of Science U.S.A. 2001;98:5300–5305.
11. Kreitzer AC, Malenka RC. Striatal plasticity and basal ganglia circuit function. Neuron. 2008 Nov 26; 60(4):543-54.
12. Ingrid A. Lobo, R. Adron Harris. GABAA receptors and alcohol .Pharmacol Biochem Behav. 2008 July; 90(1): 90–94
13. M. Katherine Kelm, Hugh E. Criswell, George R. Breese. Ethanol-enhanced GABA release: A focus on G protein-coupled receptors.Brain Res Rev. 2011 January 1; 65(2): 113–123
14. Hernandez G, Hamdani S, Rajabi H, Conover K, Stewart J, Arvanitogiannis A, Shizgal P. Prolonged rewarding stimulation of the rat medial forebrain bundle: neurochemical and behavioral consequences. Behav Neurosci. 2006 Aug; 120(4):888-904.
15. Sim HR, Choi TY, Lee HJ, Kang EY, Yoon S, Han PL, Choi SY, Baik JH. Role of dopamine D2 receptors in plasticity of stress-induced addictive behaviours. Nat Commun. 2013;4:1579.
16. Hall B, Limaye A, Kulkarni AB. Overview: generation of gene knockout mice.Curr Protoc Cell Biol. 2009 Sep; Chapter 19:Unit 19.12 19.12.1-17
17. Sari Y, Franklin KM, Alazizi A, Rao PS, Bell RL. Effects of ceftriaxone on the acquisition and maintenance of ethanol drinking in peri-adolescent and adult female alcohol-preferring (P) rats.Neuroscience. 2013 Mar 25. doi:pii: S0306-4522(13)00231-5.
18. Pentkowski et al. Protracted withdrawal from cocaine self-administration flips the switch on 5-HT(1B) receptor modulation of cocaine abuse-related behaviors. Biol Psychiatry. Vol. 75(5), 396-404 (2012)
19. Pentkowski et al. Protracted withdrawal from cocaine self-administration flips the switch on 5-HT(1B) receptor modulation of cocaine abuse-related behaviors. Biol Psychiatry. Vol. 75(5), 396-404 (2012)
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