User:Koberg27/Mesolimbic pathway
Goal: More in depth explanation on how addictive drugs alter the mesolimbic pathway. The section is a little disorganized and needs some work.
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Article Draft
[edit]Lead
[edit]-define addictive drug
-reference addiction page
Article body
[edit]-define how drugs alter VTA
-define how drugs alter Nucleus Accumbens
-Make table for reference to the two bullet points above
-explain synaptic plasticity
The mesolimbic pathway and a specific set of the pathway's output neurons (e.g. D1-type medium spiny neurons within the nucleus accumbens) play a central role in the neurobiology of addiction.[1][2][3] Drug addiction is an illness caused by habitual substance use that induces chemical changes in the brain's circuitry.[4] An addictive drug is defined as a substance that affects the mesolimbic system directly or indirectly by increasing extracellular levels of dopamine.[5]
Common addictive substances such as cocaine, alcohol, and nicotine have been shown to increase extracellular levels of dopamine within the mesolimbic pathway, preferentially within the nucleus accumbens. The mechanisms by which these drugs do so vary depending on the drug prototype. For example, cocaine precludes the re-uptake of synaptic dopamine through blocking the presynaptic dopamine transporter. Another stimulant, amphetamine, reverses the dopamine transporter and induces the release of dopamine from synaptic vesicles. Non-stimulant drugs typically bind with ligand-gated channels or G protein-coupled receptors. Such drugs include alcohol, nicotine, and tetrahydrocannabinol (THC).[6]
| Type | Target | Examples |
|---|---|---|
| Alcohol | GABAA Receptor, NMDA Receptor | Beer, wine, and other beverages |
| Cannabinoids | Cannabinoid Receptor | Marijuana |
| Nicotine | Nicotinic Acetylcholine Receptor | Tobacco |
| Opiates | μ Opioid Receptor | Morphine, heroin |
| Phencyclidine | NMDA Receptor | PCP |
| Stimulants | Dopamine Transporter | Cocaine, amphetamine, methamphetamine |
These dopaminergic activations of the mesolimbic pathway are accompanied by the perception of reward. This stimulus-reward association shows a resistance to extinction and creates an increased motivation to repeat that same behavior that caused it.[7] Additionally, drug intake changes synaptic plasticity in the ventral tegmental area and the nucleus accumbens. Repeated exposure to the drug can lead to lasting changes in the brain that gives rise to addictive behavior.[8][9]
References
[edit]- ^ Robison AJ, Nestler EJ (November 2011). "Transcriptional and epigenetic mechanisms of addiction". Nat. Rev. Neurosci. 12 (11): 623–637. doi:10.1038/nrn3111. PMC 3272277. PMID 21989194.
ΔFosB has been linked directly to several addiction-related behaviors ... Importantly, genetic or viral overexpression of ΔJunD, a dominant negative mutant of JunD which antagonizes ΔFosB- and other AP-1-mediated transcriptional activity, in the NAc or OFC blocks these key effects of drug exposure14,22–24. This indicates that ΔFosB is both necessary and sufficient for many of the changes wrought in the brain by chronic drug exposure. ΔFosB is also induced in D1-type NAc MSNs by chronic consumption of several natural rewards, including sucrose, high fat food, sex, wheel running, where it promotes that consumption14,26–30. This implicates ΔFosB in the regulation of natural rewards under normal conditions and perhaps during pathological addictive-like states.
- ^ Blum K, Werner T, Carnes S, Carnes P, Bowirrat A, Giordano J, Oscar-Berman M, Gold M (2012). "Sex, drugs, and rock 'n' roll: hypothesizing common mesolimbic activation as a function of reward gene polymorphisms". Journal of Psychoactive Drugs. 44 (1): 38–55. doi:10.1080/02791072.2012.662112. PMC 4040958. PMID 22641964.
It has been found that deltaFosB gene in the NAc is critical for reinforcing effects of sexual reward. Pitchers and colleagues (2010) reported that sexual experience was shown to cause DeltaFosB accumulation in several limbic brain regions including the NAc, medial pre-frontal cortex, VTA, caudate, and putamen, but not the medial preoptic nucleus. Next, the induction of c-Fos, a downstream (repressed) target of DeltaFosB, was measured in sexually experienced and naive animals. The number of mating-induced c-Fos-IR cells was significantly decreased in sexually experienced animals compared to sexually naive controls. Finally, DeltaFosB levels and its activity in the NAc were manipulated using viral-mediated gene transfer to study its potential role in mediating sexual experience and experience-induced facilitation of sexual performance. Animals with DeltaFosB overexpression displayed enhanced facilitation of sexual performance with sexual experience relative to controls. In contrast, the expression of DeltaJunD, a dominant-negative binding partner of DeltaFosB, attenuated sexual experience-induced facilitation of sexual performance, and stunted long-term maintenance of facilitation compared to DeltaFosB overexpressing group. Together, these findings support a critical role for DeltaFosB expression in the NAc in the reinforcing effects of sexual behavior and sexual experience-induced facilitation of sexual performance. ... both drug addiction and sexual addiction represent pathological forms of neuroplasticity along with the emergence of aberrant behaviors involving a cascade of neurochemical changes mainly in the brain's rewarding circuitry.
- ^ Olsen CM (December 2011). "Natural rewards, neuroplasticity, and non-drug addictions". Neuropharmacology. 61 (7): 1109–22. doi:10.1016/j.neuropharm.2011.03.010. PMC 3139704. PMID 21459101.
- ^ Administration (US), Substance Abuse and Mental Health Services; General (US), Office of the Surgeon (November 2016). THE NEUROBIOLOGY OF SUBSTANCE USE, MISUSE, AND ADDICTION. US Department of Health and Human Services.
- ^ a b Kandel, Eric R.; Koester, J. D.; Mack, S. H.; Siegelbaum, S. A. (2021). Principles of Neural Science (6e ed.). McGraw Hill.
- ^ Adinoff, Bryon (2004). "Neurobiologic Processes in Drug Reward and Addiction". Harvard Review of Psychiatry. 12 (6): 305–320. doi:10.1080/10673220490910844. ISSN 1067-3229. PMC 1920543. PMID 15764467.
- ^ Di Chiara, Gaetano; Bassareo, Valentina (2007-02-01). "Reward system and addiction: what dopamine does and doesn't do". Current Opinion in Pharmacology. Neurosciences. 7 (1): 69–76. doi:10.1016/j.coph.2006.11.003. ISSN 1471-4892. PMID 17174602.
- ^ Lüscher, Christian; Malenka, Robert C. (2011-02-24). "Drug-Evoked Synaptic Plasticity in Addiction: From Molecular Changes to Circuit Remodeling". Neuron. 69 (4): 650–663. doi:10.1016/j.neuron.2011.01.017. ISSN 0896-6273. PMC 4046255. PMID 21338877.
{{cite journal}}: CS1 maint: PMC format (link) - ^ Gipson, Cassandra D.; Kupchik, Yonatan M.; Kalivas, Peter W. (2014-01). "Rapid, transient synaptic plasticity in addiction". Neuropharmacology. 76: 276–286. doi:10.1016/j.neuropharm.2013.04.032. PMC 3762905. PMID 23639436.
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