Wikipédia

Via mesolímbica

A via mesolímbica, às vezes chamada de via de recompensa, é uma das vias dopaminérgicas do cérebro.[1] A via se inicia na área tegmental ventral do mesencéfalo e forma conexão com o sistema límbico através do núcleo accumbens, a amígdala cerebelosa e o hipocampo, e também com o córtex pré-frontal medial.[2] É sabido estar envolvida na modulação das respostas comportamentais aos estímulos que ativam as sensações de recompensa através do neurotransmissor dopamina.[3]

A via mesolímbica pode ser vista aqui como as projeções azuis da área tegmental ventral (ATV) para o núcleo accumbens.

A liberação de dopamina da via mesolímbica no núcleo accumbens regula a saliência de incentivo (isto é, motivação e desejo) recompensando estímulos, e facilita o aprendizado da função motora de reforço e recompensa; também pode desempenhar um papel importante na percepção subjetiva do prazer.[4] A desregulação da via mesolímbica e seus neurônios de saída no núcleo accumbens desempenha um papel significativo no desenvolvimento e manutenção de uma dependência.[1][5][6][7]

Anatomia

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A via mesolímbica é uma coleção de neurônios dopaminérgicos (isto é, liberadores de dopamina) que se projetam da área tegmental ventral (ATV) para o corpo estriado ventral, que inclui o núcleo accumbens (NAcc) e o tubérculo olfatório.[2] É uma das vias componentes do feixe do prosencéfalo medial, que é um conjunto de vias neurais que medeiam a recompensa da estimulação cerebral.[8]

O VTA está localizado no mesencéfalo e consiste em neurônios dopaminérgicos, GABAérgicos e glutamatérgicos.[9] O núcleo accumbens e o tubérculo olfativo estão localizados no estriado ventral e são compostos principalmente de neurônios espinhosos médios.[2][10][11] O nucleus accumbens é subdividido em sub-regiões límbicas e motoras conhecidas como shell NACC e núcleo NAcc.[9] Os neurônios espinhosos médios no nucleus accumbens recebem informações de ambos os neurônios dopaminérgicos da VTA e dos neurônios glutamatérgicos do hipocampo, da amígdala e do córtex pré-frontal medial. Quando eles são ativados por essas entradas, as projeções dos neurônios espinhais médios liberam GABA no pálido ventral.[9]

Função

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A via mesolímbica regula a saliência de incentivo, motivação, aprendizagem de reforço e medo, entre outros processos cognitivos.[12][13][14]

A via mesolímbica está envolvida na cognição da motivação. A depleção de dopamina nesta via, ou lesões no seu local de origem, diminui a extensão em que um animal está disposto a buscar uma recompensa (por exemplo, o tempo procurando comida). Drogas dopaminérgicas também são capazes de aumentar a taxa de disparo dos neurônios na via mesolímbica, que aumenta durante a antecipação da recompensa.[15] Acredita-se que a liberação de dopamina mesolímbica seja o principal mediador do prazer, mas acredita-se que tenha apenas um papel menor na percepção do prazer.[4][16]

Significado clínico

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A via mesolímbica e um conjunto específico de neurônios de saída da via (ou seja, neurônios espinhosos médios do tipo D1 dentro do núcleo accumbens) desempenham um papel central na neurobiologia da dependência.[5][6][7] Também está implicado na esquizofrenia e depressão.[17][18][19] Dependência, esquizofrenia e depressão envolvem mudanças estruturais distintas dentro da via mesolímbica.[17] O abuso também pode afetar a via mesolímbica. Um estudo de 2017 descobriu que eventos adversos da vida - abuso emocional, físico e sexual - estavam associados a uma resposta límbica aumentada à cocaína. Em outras palavras, os indivíduos que sofreram abuso anteriormente eram mais propensos a ter uma via cerebral preparada para o uso de cocaína ou outras drogas.[20]

Referências

  1. ↑ a b Dreyer JL (2010). «New insights into the roles of microRNAs in drug addiction and neuroplasticity». Genome Med. 2 (12). 92 páginas. PMC 3025434 . PMID 21205279. doi:10.1186/gm213 
  2. ↑ a b c Ikemoto S (2010). «Brain reward circuitry beyond the mesolimbic dopamine system: a neurobiological theory». Neurosci Biobehav Rev. 35 (2): 129–50. PMC 2894302 . PMID 20149820. doi:10.1016/j.neubiorev.2010.02.001. Recent studies on intracranial self-administration of neurochemicals (drugs) found that rats learn to self-administer various drugs into the mesolimbic dopamine structures–the posterior ventral tegmental area, medial shell nucleus accumbens and medial olfactory tubercle. ... In the 1970s it was recognized that the olfactory tubercle contains a striatal component, which is filled with GABAergic medium spiny neurons receiving glutamatergic inputs form cortical regions and dopaminergic inputs from the VTA and projecting to the ventral pallidum just like the nucleus accumbens 
    Figure 3: The ventral striatum and self-administration of amphetamine
  3. ↑ Tisch S, Silberstein P, Limousin-Dowsey P, Jahanshahi M. 2004. The basal ganglia: anatomy, physiology, and pharmacology. Psychiatric clinincs of North America 27:757+
  4. ↑ a b Berridge KC, Kringelbach ML (2015). «Pleasure systems in the brain». Neuron. 86 (3): 646–664. PMC 4425246 . PMID 25950633. doi:10.1016/j.neuron.2015.02.018. To summarize: the emerging realization that many diverse pleasures share overlapping brain substrates; better neuroimaging maps for encoding human pleasure in orbitofrontal cortex; identification of hotspots and separable brain mechanisms for generating ‘liking’ and ‘wanting’ for the same reward; identification of larger keyboard patterns of generators for desire and dread within NAc, with multiple modes of function; and the realization that dopamine and most ‘pleasure electrode’ candidates for brain hedonic generators probably did not cause much pleasure after all. 
  5. ↑ a b Robison AJ, Nestler EJ (2011). «Transcriptional and epigenetic mechanisms of addiction». Nat. Rev. Neurosci. 12 (11): 623–637. PMC 3272277 . PMID 21989194. doi:10.1038/nrn3111. 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. 
  6. ↑ a b 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». J. Psychoactive Drugs. 44 (1): 38–55. PMC 4040958 . PMID 22641964. doi:10.1080/02791072.2012.662112. 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. 
  7. ↑ a b Olsen CM (2011). «Natural rewards, neuroplasticity, and non-drug addictions». Neuropharmacology. 61 (7): 1109–22. PMC 3139704 . PMID 21459101. doi:10.1016/j.neuropharm.2011.03.010 
  8. ↑ You ZB, Chen YQ, Wise RA (2001). «Dopamine and glutamate release in the nucleus accumbens and ventral tegmental area of rat following lateral hypothalamic self-stimulation». Neuroscience. 107 (4): 629–39. PMID 11720786. doi:10.1016/s0306-4522(01)00379-7 
  9. ↑ a b c Pierce RC, Kumaresan V (2006). «The mesolimbic dopamine system: The final common pathway for the reinforcing effect of drugs of abuse?». Neuroscience and Biobehavioral Reviews. 30: 215–38. doi:10.1016/j.neubiorev.2005.04.016 
  10. ↑ Zhang TA, Maldve RE, Morrisett RA (2006). «Coincident signaling in mesolimbic structures underlying alcohol reinforcement». Biochemical Pharmacology. 72: 919–27. doi:10.1016/j.bcp.2006.04.022 
  11. ↑ Purves D et al. 2008. Neuroscience. Sinauer 4ed. 754-56
  12. ↑ Malenka RC, Nestler EJ, Hyman SE (2009). «Chapter 6: Widely Projecting Systems: Monoamines, Acetylcholine, and Orexin». In: Sydor A, Brown RY. Molecular Neuropharmacology: A Foundation for Clinical Neuroscience 2nd ed. New York: McGraw-Hill Medical. pp. 147–148, 154–157. ISBN 9780071481274. Neurons from the SNc densely innervate the dorsal striatum where they play a critical role in the learning and execution of motor programs. Neurons from the VTA innervate the ventral striatum (nucleus accumbens), olfactory bulb, amygdala, hippocampus, orbital and medial prefrontal cortex, and cingulate cortex. VTA DA neurons play a critical role in motivation, reward-related behavior, attention, and multiple forms of memory. ... Thus, acting in diverse terminal fields, dopamine confers motivational salience ("wanting") on the reward itself or associated cues (nucleus accumbens shell region), updates the value placed on different goals in light of this new experience (orbital prefrontal cortex), helps consolidate multiple forms of memory (amygdala and hippocampus), and encodes new motor programs that will facilitate obtaining this reward in the future (nucleus accumbens core region and dorsal striatum). ... DA has multiple actions in the prefrontal cortex. It promotes the "cognitive control" of behavior: the selection and successful monitoring of behavior to facilitate attainment of chosen goals. Aspects of cognitive control in which DA plays a role include working memory, the ability to hold information "on line" in order to guide actions, suppression of prepotent behaviors that compete with goal-directed actions, and control of attention and thus the ability to overcome distractions. ... Noradrenergic projections from the LC thus interact with dopaminergic projections from the VTA to regulate cognitive control. 
  13. ↑ Engert, Veronika; Pruessner, Jens C (2017). «Dopaminergic and Noradrenergic Contributions to Functionality in ADHD: The Role of Methylphenidate». Current Neuropharmacology. 6 (4): 322–328. ISSN 1570-159X. PMC 2701285 . PMID 19587853. doi:10.2174/157015908787386069 
  14. ↑ Pezze, Marie A.; Feldon, Joram (2004). «Mesolimbic dopaminergic pathways in fear conditioning». Progress in Neurobiology. 74 (5): 301–320. ISSN 0301-0082. PMID 15582224. doi:10.1016/j.pneurobio.2004.09.004 
  15. ↑ Salamone, John D.; Correa, Mercè (2012). «The Mysterious Motivational Functions of Mesolimbic Dopamine». Neuron. 76 (3): 470–485. PMC 4450094 . PMID 23141060. doi:10.1016/j.neuron.2012.10.021 
  16. ↑ Berridge, Kent C; Kringelbach, Morten L (2013). «Neuroscience of affect: brain mechanisms of pleasure and displeasure». Current Opinion in Neurobiology. 23 (3): 294–303. PMC 3644539 . PMID 23375169. doi:10.1016/j.conb.2013.01.017 
  17. ↑ a b Van, den Heuval DMA, Pasterkamp RJ (2008). «Getting connected in the dopamine system». Progress in Neurobiology. 85: 75–93. doi:10.1016/j.pneurobio.2008.01.003 
  18. ↑ Laviolette SR (2007). «Dopamine modulation of emotional processing in cortical and subcortical neural circuits: evidence for a final common pathway in schizophrenia?». Schizoprenia Bulletin. 33: 971–981. doi:10.1093/schbul/sbm048 
  19. ↑ Diaz J. 1996. How Drugs Influence Behavior: A Neurobehavorial Approach. Prentice Hall
  20. ↑ Regier PS, Monge ZA, Franklin TR, Wetherill RR, Teitelman AM, Jagannathan K, et al. Emotional, physical and sexual abuse are associated with a heightened limbic response to cocaine cues. Addiction Biology. 2017 Nov;22(6):1768-177. doi: 10.1111/adb.12445
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