The release of dopamine from the mesolimbic pathway into the nucleus accumbens regulates incentive salience (e.g. motivation and desire for rewarding stimuli) and facilitates reinforcement and reward-related motor function learning;[3][4][5] it may also play a role in the subjective perception of pleasure.[3][5] The dysregulation of the mesolimbic pathway and its output neurons in the nucleus accumbens plays a significant role in the development and maintenance of an addiction.[1][6][7][8]
The mesolimbic pathway and its positioning in relation to the other dopaminergic pathways
The mesolimbic pathway regulates incentive salience, motivation, reinforcement learning, and fear, among other cognitive processes.[14][15][16]
The mesolimbic pathway is involved in motivational cognition. Depletion of dopamine in this pathway, or lesions at its site of origin, decrease the extent to which an animal is willing to go to obtain a reward (e.g. the number of lever presses for intravenous nicotine delivery in rats or time spent searching for food). Dopaminergic drugs are also able to increase the extent an animal is willing to go to obtain a reward. Moreover, the firing rate of neurons in the mesolimbic pathway increases during anticipation of reward, which may explain craving.[17] Mesolimbic dopamine release was once thought to be the primary mediator of pleasure, but is now believed to have only a minor or secondary role in pleasure perception.[18][19]
Mechanisms of addiction
The mesolimbic pathway and a specific set of the pathway's output neurons (e.g. D1-typemedium spiny neurons within the nucleus accumbens) play a central role in the neurobiology of addiction.[20][21][22] Drug addiction is an illness caused by habitual substance use that induces chemical changes in the brain's circuitry.[23] An addictive drug is defined as a substance that affects the mesolimbic system directly or indirectly by increasing extracellular levels of dopamine.[24]
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).[25]
More information Type, Target ...
Addictive Drugs and their Molecular Interactions[24]
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.[26] 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.[27][28]
Relation to other neurological and psychological disorders
Ikemoto S (2010). "Brain reward circuitry beyond the mesolimbic dopamine system: a neurobiological theory". Neurosci Biobehav Rev. 35 (2): 129–50. doi:10.1016/j.neubiorev.2010.02.001. PMC2894302. PMID20149820. 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
Malenka RC, Nestler EJ, Hyman SE (2009). Sydor A, Brown RY (eds.). Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nded.). New York: McGraw-Hill Medical. pp.147–148, 367, 376. ISBN978-0-07-148127-4. VTA DA neurons play a critical role in motivation, reward-related behavior (Chapter 15), attention, and multiple forms of memory. This organization of the DA system, wide projection from a limited number of cell bodies, permits coordinated responses to potent new rewards. 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). In this example, dopamine modulates the processing of sensorimotor information in diverse neural circuits to maximize the ability of the organism to obtain future rewards.... The brain reward circuitry that is targeted by addictive drugs normally mediates the pleasure and strengthening of behaviors associated with natural reinforcers, such as food, water, and sexual contact. Dopamine neurons in the VTA are activated by food and water, and dopamine release in the NAc is stimulated by the presence of natural reinforcers, such as food, water, or a sexual partner.... The NAc and VTA are central components of the circuitry underlying reward and memory of reward. As previously mentioned, the activity of dopaminergic neurons in the VTA appears to be linked to reward prediction. The NAc is involved in learning associated with reinforcement and the modulation of motoric responses to stimuli that satisfy internal homeostatic needs. The shell of the NAc appears to be particularly important to initial drug actions within reward circuitry; addictive drugs appear to have a greater effect on dopamine release in the shell than in the core of the NAc.
Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter 10: Neural and Neuroendocrine Control of the Internal Milieu". In Sydor A, Brown RY (eds.). Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nded.). New York: McGraw-Hill Medical. p.266. ISBN978-0-07-148127-4. Dopamine acts in the nucleus accumbens to attach motivational significance to stimuli associated with reward.
Berridge KC, Kringelbach ML (May 2015). "Pleasure systems in the brain". Neuron. 86 (3): 646–664. doi:10.1016/j.neuron.2015.02.018. PMC4425246. PMID25950633. 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.
Robison AJ, Nestler EJ (November 2011). "Transcriptional and epigenetic mechanisms of addiction". Nat. Rev. Neurosci. 12 (11): 623–637. doi:10.1038/nrn3111. PMC3272277. PMID21989194. 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. PMC4040958. PMID22641964. 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.
Ikemoto S (2010). "Brain reward circuitry beyond the mesolimbic dopamine system: a neurobiological theory". Neurosci Biobehav Rev. 35 (2): 129–50. doi:10.1016/j.neubiorev.2010.02.001. PMC2894302. PMID20149820. 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 accumbensFigure 3: The ventral striatum and self-administration of amphetamine
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. doi:10.1016/s0306-4522(01)00379-7. PMID11720786. S2CID33615497.
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 (2): 215–38. doi:10.1016/j.neubiorev.2005.04.016. PMID16099045. S2CID39886286.
Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter 6: Widely Projecting Systems: Monoamines, Acetylcholine, and Orexin". In Sydor A, Brown RY (eds.). Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nded.). New York: McGraw-Hill Medical. pp.147–148, 154–157. ISBN9780071481274. 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.
Berridge KC, Kringelbach ML (May 2015). "Pleasure systems in the brain". Neuron. 86 (3): 646–664. doi:10.1016/j.neuron.2015.02.018. PMC4425246. PMID25950633. 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.
Robison AJ, Nestler EJ (November 2011). "Transcriptional and epigenetic mechanisms of addiction". Nat. Rev. Neurosci. 12 (11): 623–637. doi:10.1038/nrn3111. PMC3272277. PMID21989194. 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. PMC4040958. PMID22641964. 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.
Di Chiara, Gaetano; Bassareo, Valentina (1 February 2007). "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. ISSN1471-4892. PMID17174602.
