Addiction-related structural neuroplasticity

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Addiction is a state characterized by compulsive engagement in rewarding stimuli, despite adverse consequences. The process of developing an addiction occurs through instrumental learning, which is otherwise known as operant conditioning.

Neuroscientists believe that drug addicts’ behavior is a direct correlation to some physiological change in their brain, caused by using drugs. This view believes there is a bodily function in the brain causing the addiction. This is brought on by a change in the brain caused by brain damage or adaptation from chronic drug use.[1][2]

In humans, addiction is diagnosed according to diagnostic models such as the Diagnostic and Statistical Manual of Mental Disorders, through observed behaviors. There has been significant advancement in understanding the structural changes that occur in parts of the brain involved in the reward pathway (mesolimbic system) that underlies addiction.[3] Most research has focused on two portions of the brain: the ventral tegmental area, (VTA) and the nucleus accumbens (NAc).[4]

The VTA is the portion of the mesolimbic system responsible for spreading dopamine to the whole system. The VTA is stimulated by ″rewarding experiences″. The release of dopamine by the VTA induces pleasure, thus reinforcing behaviors that lead to the reward.[5] Drugs of abuse increase the VTA's ability to project dopamine to the rest of the reward circuit.[6] These structural changes only last 7–10 days,[7] however, indicating that the VTA cannot be the only part of the brain that is affected by drug use, and changed during the development of addiction.

The nucleus accumbens (NAc) plays an essential part in the formation of addiction. Almost every drug with addictive potential induces the release of dopamine into the NAc.[8] In contrast to the VTA, the NAc shows long-term structural changes. Drugs of abuse weaken the connections within the NAc after habitual use,[9] as well as after use then withdrawal.[10]

Structural changes of learning

Learning by experience occurs through modifications of the structural circuits of the brain. These circuits are composed of many neurons and their connections, called synapses, which occur between the axon of one neuron and the dendrite of another. A single neuron generally has many dendrites which are called dendritic branches, each of which can be synapsed by many axons.

Along dendritic branches there can be hundreds or even thousands of dendritic spines, structural protrusions that are sites of excitatory synapses. These spines increase the number of axons from which the dendrite can receive information. Dendritic spines are very plastic, meaning they can be formed and eliminated very quickly, in the order of a few hours.[citation needed] More spines grow on a dendrite when it is repetitively activated. Dendritic spine changes have been correlated with long-term potentiation (LTP) and long-term depression (LTD).[11][12]

LTP is the way that connections between neurons and synapses are strengthened. LTD is the process by which synapses are weakened. For LTP to occur, NMDA receptors on the dendritic spine send intracellular signals to increase the number of AMPA receptors on the post synaptic neuron. If a spine is stabilized by repeated activation, the spine becomes mushroom shaped and acquires many more AMPA receptors. This structural change, which is the basis of LTP, persists for months and may be an explanation for some of the long-term behavioral changes that are associated with learned behaviors including addiction to drugs.[13]

Research methodologies

Animal models

Animal models, especially rats and mice, are used for many types of biological research. The animal models of addiction are particularly useful because animals that are addicted to a substance show behaviors similar to human addicts. This implies that the structural changes that can be observed after the animal ingests a drug can be correlated with an animal's behavioral changes, as well as with similar changes occurring in humans.

Administration protocols

Administration of drugs that are often abused can be done either by the experimenter (non-contingent), or by a self-administration (contingent) method. The latter usually involves the animal pressing a lever to receive a drug. Non-contingent models are generally used for convenience, being useful for examining the pharmacological and structural effects of the drugs. Contingent methods are more realistic because the animal controls when and how much of the drug it receives. This is generally considered a better method for studying the behaviors associated with addiction. Contingent administration of drugs has been shown to produce larger structural changes in certain parts of the brain, in comparison to non-contingent administration.[14]

Types of drugs

All abused drugs directly or indirectly promote dopamine signaling in the mesolimbic dopamine neurons which project from the ventral tegmental area to the nucleus accumbens (NAc).[8] The types of drugs used in experimentation increase this dopamine release through different mechanisms.

Opiates

Opiates are a class of sedative with the capacity for pain relief. Morphine is an opiate that is commonly used in animal testing of addiction. Opiates stimulate dopamine neurons in the brain indirectly by inhibiting GABA release from modulatory interneurons that synapse onto the dopamine neurons. GABA is an inhibitory neurotransmitter that decreases the probability that the target neuron will send a subsequent signal.

Stimulants

Stimulants used regularly in neuroscience experimentation are cocaine and amphetamine. These drugs induce an increase in synaptic dopamine by inhibiting the reuptake of dopamine from the synaptic cleft, effectively increasing the amount of dopamine that reaches the target neuron.

Form of neuroplasticity
or behavioral plasticity 		Type of reinforcer Sources
Opiates Psychostimulants High fat or sugar food Sexual intercourse Physical exercise
(aerobic) 		Environmental
enrichment
ΔFosB expression in
nucleus accumbens D1-type MSNsTooltip medium spiny neurons 		↑ ↑ ↑ ↑ ↑ ↑ [15]
Behavioral plasticity
Escalation of intake Yes Yes Yes [15]
Psychostimulant
cross-sensitization 		Yes Not applicable Yes Yes Attenuated Attenuated [15]
Psychostimulant
self-administration 		↑ ↑ ↓ ↓ ↓ [15]
Psychostimulant
conditioned place preference 		↑ ↑ ↓ ↑ ↓ ↑ [15]
Reinstatement of drug-seeking behavior ↑ ↑ ↓ ↓ [15]
Neurochemical plasticity
CREBTooltip cAMP response element-binding protein phosphorylation
in the nucleus accumbens 		↓ ↓ ↓ ↓ ↓ [15]
Sensitized dopamine response
in the nucleus accumbens 		No Yes No Yes [15]
Altered striatal dopamine signaling ↓DRD2, ↑DRD3 ↑DRD1, ↓DRD2, ↑DRD3 ↑DRD1, ↓DRD2, ↑DRD3 ↑DRD2 ↑DRD2 [15]
Altered striatal opioid signaling No change or
↑μ-opioid receptors		 ↑μ-opioid receptors
↑κ-opioid receptors		 ↑μ-opioid receptors ↑μ-opioid receptors No change No change [15]
Changes in striatal opioid peptides ↑dynorphin
No change: enkephalin		 ↑dynorphin ↓enkephalin ↑dynorphin ↑dynorphin [15]
Mesocorticolimbic synaptic plasticity
Number of dendrites in the nucleus accumbens ↓ ↑ ↑ [15]
Dendritic spine density in
the nucleus accumbens 		↓ ↑ ↑ [15]

The reward pathway

The reward pathway, also called the mesolimbic system of the brain, is the part of the brain that registers reward and pleasure. This circuit reinforces the behavior that leads to a positive and pleasurable outcome. In drug addiction, the drug-seeking behaviors become reinforced by the rush of dopamine that follows the administration of a drug of abuse. The effects of drugs of abuse on the ventral tegmental area (VTA) and the nucleus accumbens (NAc) have been studied extensively.[16]

Drugs of abuse change the complexity of dendritic branching as well as the number and size of the branches in both the VTA and the NAc.[17] [7] By correlation, these structural changes have been linked to addictive behaviors. The effect of these structural changes on behavior is uncertain and studies have produced conflicting results. Two studies[18][19] have shown that an increase in dendritic spine density due to cocaine exposure facilitates behavioral sensitization, while two other studies[20][21] produce contradicting evidence.

In response to drugs of abuse, structural changes can be observed in the size of neurons[22] and the shape and number of the synapses between them.[23] The nature of the structural changes is specific to the type of drug used in the experiment. Opiates and stimulants produce opposite effects in structural plasticity in the reward pathway. It is not expected that these drugs would induce opposing structural changes in the brain because these two classes of drugs, opiates and stimulants, both cause similar behavioral phenotypes.

Both of these drugs induce increased locomotor activity acutely, escalated self-administration chronically, and dysphoria when the drug is taken away.[24] Although their effects on structural plasticity are opposite, there are two possible explanations as to why these drugs still produce the same indicators of addiction: Either these changes produce the same behavioral phenotype when any change from baseline is produced, or the critical changes that cause the addictive behavior cannot be quantified by measuring dendritic spine density.[citation needed]

Opiates decrease spine density and dendrite complexity in the nucleus accumbens (NAc).[24] Morphine decreases spine density regardless of the treatment paradigm (with one exception: "chronic morphine increases spine number on orbitofrontal cortex (oPFC) pyramidal neurons").[24] Either chronic or intermittent administration of morphine will produce the same effect.[14] The only case where opiates increase dendritic density is with chronic morphine exposure, which increases spine density on pyramidal neurons in the orbitofrontal cortex.[25] Stimulants increase spinal density and dendritic complexity in the nucleus accumbens (NAc),[21][23][26][27] ventral tegmental area (VTA),[28] and other structures in the reward circuit.[23][26][27]

Ventral tegmental area

Main article: Ventral tegmental area

There are neurons with cell bodies in the VTA that release dopamine onto specific parts of the brain, including many of the limbic regions such as the NAc, the medial prefrontal cortex (mPFC), dorsal striatum, amygdala, and the hippocampus. The VTA has both dopaminergic and GABAergic neurons that both project to the NAc and mPFC.[29][30] GABAergic neurons in the VTA also synapse on local dopamine cells.[31] In non-drug models, the VTA dopamine neurons are stimulated by rewarding experiences.[5] A release of dopamine from the VTA neurons seems to be the driving action behind drug-induced pleasure and reward.

Exposure to drugs of abuse elicits LTP at excitatory synapses on VTA dopamine neurons.[6] Excitatory synapses in brain slices from the VTA taken 24 hours after a single cocaine exposure showed an increase in AMPA receptors in comparison to a saline control.[32] Additional LTP could not be induced in these synapses. This is thought to be because the maximal amount of LTP had already been induced by the administration of cocaine.[citation needed] LTP is only seen on the dopamine neurons, not on neighboring GABAergic neurons. This is of interest because the administration of drugs of abuse increases the excitation of VTA dopamine neurons, but does not increase inhibition.[citation needed] Excitatory inputs into the VTA will activate the dopamine neurons 200%, but do not increase activation of GABA neurons which are important in local inhibition.[33]

This effect of inducing LTP in VTA slices 24 hours after drug exposure has been shown using morphine, nicotine, ethanol, cocaine, and amphetamines. These drugs have very little in common except that they are all potentially addictive. This is evidence supporting a link between structural changes in the VTA and the development of addiction.[citation needed]

Changes other than LTP have been observed in the VTA after treatment with drugs of abuse. For example, neuronal body size decreased in response to opiates.[8][14][22][34]

Although the structural changes in the VTA invoked by exposure to an addictive drug generally disappear after a week or two, the target regions of the VTA, including the NAc, may be where the longer-term changes associated with addiction occur during the development of the addiction.[7][35][36]

Nucleus accumbens

Main article: Nucleus accumbens

The nucleus accumbens plays an integral role in addiction. Almost every addictive drug of abuse induces the release of dopamine into the nucleus accumbens.[8][37][38] The NAc is particularly important for instrumental learning, including cue-induced reinstatement of drug-seeking behavior.[39] It is also involved in mediating the initial reinforcing effects of addictive drugs.[40][41] The most common cell type in the NAc is the GABAergic medium spiny neuron.[42] These neurons project inhibitory connections to the VTA and receive excitatory input from various other structures in the limbic system. Changes in the excitatory synaptic inputs into these neurons have been shown to be important in mediating addiction-related behaviors.[43] It has been shown that LTP and LTD occurs at NAc excitatory synapses.[44]

Unlike the VTA, a single dose of cocaine induces no change in potentiation in the excitatory synapses of the NAc.[45] LTD was observed in the medium spiny neurons in the NAc following two different protocols: a daily cocaine administration for five days[9] or a single dose followed by 10–14 days of withdrawal.[10] This suggests that the structural changes in the NAc are associated with long-term behaviors (rather than acute responses) associated with addiction such as drug seeking.[46]

Human relevance

Relapse

Neuroscientists studying addiction define relapse as the reinstatement of drug-seeking behavior after a period of abstinence. The structural changes in the VTA are hypothesized to contribute to relapse.[47] As the molecular mechanisms of relapse are better understood, pharmacological treatments to prevent relapse are further refined.[48]

Risk of relapse is a serious and long-term problem for recovering addicts.[49][50] An addict can be forced to abstain from using drugs while they are admitted in a treatment clinic, but once they leave the clinic they are at risk of relapse.[51] Relapse can be triggered by stress, cues associated with past drug use, or re-exposure to the substance. Animal models of relapse can be triggered in the same way.[47]

Search for a cure for addiction

The goal of addiction research is to find ways to prevent and reverse the effects of addiction on the brain. Theoretically, if the structural changes in the brain associated with addiction can be blocked, then the negative behaviors associated with the disease should never develop.

Structural changes associated with addiction can be inhibited by NMDA receptor antagonists which block the activity of NMDA receptors.[47] NMDA receptors are essential in the process of LTP and LTD.[32] Drugs of this class are unlikely candidates for pharmacological prevention of addiction because these drugs themselves are used recreationally. Examples of NMDAR antagonists are ketamine, dextromethorphan (DXM), phencyclidine (PCP).

References

  1. ^ Foddy, Bennett; Savulescu, Julian (Winter 2017). "A Liberal Account of Addiction". Philosophy, Psychiatry, and Psychology. 17 (1): 1–22. doi:10.1353/ppp.0.0282. PMC 3959650. PMID 24659901.
  2. ^ Leshner, Al (1997). "Addiction is a brain disease, and it matters". Science. 278 (5335): 45–7. doi:10.1126/science.278.5335.45. PMID 9311924. S2CID 35915002.
  3. ^ Kauer, Julie A.; Malenka, Robert C. (November 2007). "Synaptic plasticity and addiction". Nature Reviews Neuroscience. 8 (11): 844–858. doi:10.1038/nrn2234. ISSN 1471-003X. PMID 17948030.
  4. ^ Turner, Brandon D.; Kashima, Daniel T.; Manz, Kevin M.; Grueter, Carrie A.; Grueter, Brad A. (2018-09-19). "Synaptic Plasticity in the Nucleus Accumbens: Lessons Learned from Experience". ACS Chemical Neuroscience. 9 (9): 2114–2126. doi:10.1021/acschemneuro.7b00420. ISSN 1948-7193. PMC 6508969. PMID 29280617.
  5. ^ a b Schultz, W. (1997). "Dopamine neurons and their role in reward mechanisms". Current Opinion in Neurobiology. 7 (2): 191–197. doi:10.1016/s0959-4388(97)80007-4. PMID 9142754. S2CID 31097014.
  6. ^ a b Ungless, M.A. (2001). "Single cocaine exposure in vivo induces long-term potentiation in dopamine neurons". Nature. 411 (6837): 583–87. doi:10.1038/35079077. PMID 11385572. S2CID 4311436.
  7. ^ a b Nestler, EJ (2001). "Molecular basis of longterm plasticity underlying addiction". Nat. Rev. Neurosci. 2 (2): 119–28. doi:10.1038/35053570. PMID 11252991. S2CID 52849205.
  8. ^ a b c d Nestler, E.J. (1992). "Molecular mechanisms of drug addiction". Journal of Neuroscience. 12 (7): 2439–2450. doi:10.1523/JNEUROSCI.12-07-02439.1992. PMC 6575828. PMID 1319476.
  9. ^ a b Kourrich, S. (2007). "Cocaine experience controls bidirectional synaptic plasticity in the nucleus accumbens". J. Neurosci. 27 (30): 7921–7928. doi:10.1523/JNEUROSCI.1859-07.2007. PMC 6672735. PMID 17652583.
  10. ^ a b Thomas, M.J. (2001). "Long-term depression in the nucleus accumbens: a neural correlate of behavioral sensitization to cocaine". Nat. Neurosci. 4 (12): 217–1223. doi:10.1038/nn757. PMID 11694884. S2CID 28573169.
  11. ^ Bourne, J. (2007). "Do thin spines learn to be mushroom spines that remember?". Current Opinion in Neurobiology. 17 (3): 381–386. doi:10.1016/j.conb.2007.04.009. PMID 17498943. S2CID 15510661.
  12. ^ Carlisle, H.J. (2005). "Spine architecture and synaptic plasticity". Trends in Neurosciences. 28 (4): 182–187. doi:10.1016/j.tins.2005.01.008. PMID 15808352. S2CID 29529892.
  13. ^ Zweifel, Larry S.; Argilli, Emanuela; Bonci, Antonello; Palmiter, Richard D. (August 2008). "Role of NMDA Receptors in Dopamine Neurons for Plasticity and Addictive Behaviors". Neuron. 59 (3): 486–496. doi:10.1016/j.neuron.2008.05.028. PMC 2556153. PMID 18701073.
  14. ^ a b c Robinson, T.E. (2004). "Structural plasticity associated with exposure to drugs of abuse". Neuropharmacology. 47: 33–46. doi:10.1016/j.neuropharm.2004.06.025. PMID 15464124. S2CID 1987897.
  15. ^ a b c d e f g h i j k l m Olsen CM (December 2011). "Natural rewards, neuroplasticity, and non-drug addictions". Neuropharmacology. 61 (7): 1109–1122. doi:10.1016/j.neuropharm.2011.03.010. PMC 3139704. PMID 21459101. Similar to environmental enrichment, studies have found that exercise reduces self-administration and relapse to drugs of abuse (Cosgrove et al., 2002; Zlebnik et al., 2010). There is also some evidence that these preclinical findings translate to human populations, as exercise reduces withdrawal symptoms and relapse in abstinent smokers (Daniel et al., 2006; Prochaska et al., 2008), and one drug recovery program has seen success in participants that train for and compete in a marathon as part of the program (Butler, 2005). ... In humans, the role of dopamine signaling in incentive-sensitization processes has recently been highlighted by the observation of a dopamine dysregulation syndrome in some patients taking dopaminergic drugs. This syndrome is characterized by a medication-induced increase in (or compulsive) engagement in non-drug rewards such as gambling, shopping, or sex (Evans et al., 2006; Aiken, 2007; Lader, 2008).Table 1: Summary of plasticity observed following exposure to drug or natural reinforcers
  16. ^ Fu, Yu; Pollandt, Sebastian; Liu, Jie; Krishnan, Balaji; Genzer, Kathy; Orozco-Cabal, Luis; Gallagher, Joel P.; Shinnick-Gallagher, Patricia (January 2007). "Long-Term Potentiation (LTP) in the Central Amygdala (CeA) Is Enhanced After Prolonged Withdrawal From Chronic Cocaine and Requires CRF 1 Receptors". Journal of Neurophysiology. 97 (1): 937–941. doi:10.1152/jn.00349.2006. ISSN 0022-3077. PMID 17079348.
  17. ^ Russo, S.J. (2010). "The addicted synapse: mechanisms of synaptic and structural plasticity in nucleus accumbens". Trends in Neurosciences. 33 (6): 267–276. doi:10.1016/j.tins.2010.02.002. PMC 2891948. PMID 20207024.
  18. ^ Pulipparacharuvil, S. (2008). "Cocaine regulates MEF2 to control synaptic and behavioral plasticity". Neuron. 59 (4): 621–633. doi:10.1016/j.neuron.2008.06.020. PMC 2626175. PMID 18760698.
  19. ^ Russo, S.J. (2009). "Nuclear factor kappa B signaling regulates neuronal morphology and cocaine reward". Journal of Neuroscience. 29 (11): 3529–3537. doi:10.1523/jneurosci.6173-08.2009. PMC 2677656. PMID 19295158.
  20. ^ Maze, I. (2010). "Essential role of the histone methyltransferase G9a in cocaine-induced plasticity". Science. 327 (5962): 213–216. Bibcode:2010Sci...327..213M. doi:10.1126/science.1179438. PMC 2820240. PMID 20056891.
  21. ^ a b Norrholm, S.D. (2003). "Cocaine-induced proliferation of dendritic spines in nucleus accumbens is dependent on the activity of cyclin-dependent kinase-5". Neuroscience. 116 (1): 19–22. doi:10.1016/s0306-4522(02)00560-2. PMC 4296576. PMID 12535933.
  22. ^ a b Sklair-Tavron, L. (1996). "Chronic morphine induces visible changes in the morphology of mesolimbic dopamine neurons". Proceedings of the National Academy of Sciences of the United States of America. 93 (20): 11202–11207. Bibcode:1996PNAS...9311202S. doi:10.1073/pnas.93.20.11202. PMC 38308. PMID 8855333.
  23. ^ a b c Robinson, T.E. (1997). "Persistent structural modifications in nucleus accumbers and prefrontal cortex neurons produced by previous experience with amphetamine". Journal of Neuroscience. 17 (21): 8491–8497. doi:10.1523/JNEUROSCI.17-21-08491.1997. PMC 6573726. PMID 9334421. S2CID 17036577.
  24. ^ a b c Russo, Scott J.; Dietz, David M.; Dumitriu, Dani; Malenka, Robert C.; Nestler, Eric J. (2010). "The Addicted Synapse: Mechanisms of Synaptic and Structural Plasticity in Nucleus Accumbens". Trends in Neurosciences. 33 (6): 267–276. doi:10.1016/j.tins.2010.02.002. ISSN 0166-2236. PMC 2891948. PMID 20207024.
  25. ^ Robinson, T.E. (2002). "Widespread but regionally specific effects of experimenter- versus self-administered morphine on dendritic spines in the nucleus accumbens, hippocampus, and neocortex of adult rats". Synapse. 46 (4): 271–279. doi:10.1002/syn.10146. hdl:2027.42/34996. PMID 12373743. S2CID 16327567.
  26. ^ a b Robinson, T.E. (2001). "Cocaine self-administration alters the morphology of dendrites and dendritic spines in the nucleus accumbens and neocortex" (PDF). Synapse. 39 (3): 257–266. doi:10.1002/1098-2396(20010301)39:3<257::aid-syn1007>3.3.co;2-t. hdl:2027.42/34991. PMID 11169774.
  27. ^ a b Robinson, T.E. (1999). "Alterations in the morphology of dendrites and dendritic spines in the nucleus accumbens and prefrontal cortex following repeated treatment with amphetamine or cocaine" (PDF). European Journal of Neuroscience. 11 (5): 1598–1604. doi:10.1046/j.1460-9568.1999.00576.x. hdl:2027.42/75023. PMID 10215912. S2CID 14635277.
  28. ^ Sarti, F. (2007). "Acute cocaine exposure alters spine density and long-term potentiation in the ventral tegmental area". European Journal of Neuroscience. 26 (3): 749–756. doi:10.1111/j.1460-9568.2007.05689.x. PMID 17686047. S2CID 39333693.
  29. ^ Grace, A.A. (1989). "Morphology and electrophysiological properties of immunocytochemically identified rat dopamine neurons recorded in vitro". Journal of Neuroscience. 9 (10): 3463–3481. doi:10.1523/JNEUROSCI.09-10-03463.1989. PMC 6569889. PMID 2795134.
  30. ^ Johnson, S.W. (1992). "Two types of neurone in the rat ventral tegmental area and their synaptic inputs". Journal of Physiology. 450: 455–468. doi:10.1113/jphysiol.1992.sp019136. PMC 1176131. PMID 1331427.
  31. ^ Johnson, S.W. (1992). "Opioids excite dopamine neurons by hyperpolarization of local interneurons". Journal of Neuroscience. 12 (2): 483–488. doi:10.1523/JNEUROSCI.12-02-00483.1992. PMC 6575608. PMID 1346804.
  32. ^ a b Malinow, R. (2002). "AMPA receptor trafficking and synaptic plasticity". Annu. Rev. Neurosci. 25: 103–26. doi:10.1146/annurev.neuro.25.112701.142758. PMID 12052905.
  33. ^ Cameron, DL (1993). "Dopamine D1 receptors facilitate transmitter release". Nature. 366 (6453): 344–47. Bibcode:1993Natur.366..344C. doi:10.1038/366344a0. PMID 8247128. S2CID 4322939.
  34. ^ Russo, S.J. (2007). "IRS2-Akt pathway in midbrain dopamine neurons regulates behavioral and cellular responses to opiates". Nature Neuroscience. 10 (1): 93–99. doi:10.1038/nn1812. PMID 17143271. S2CID 2887841.
  35. ^ Gerdeman, GL (2003). "It could be habit forming: drugs of abuse and striatal synaptic plasticity". Trends Neurosci. 26 (4): 184–92. doi:10.1016/s0166-2236(03)00065-1. PMID 12689769. S2CID 21003571.
  36. ^ Nestler, EJ (2002). "Common molecular and cellular substrates of addiction and memory". Neurobiol. Learn. Mem. 78 (3): 637–47. doi:10.1006/nlme.2002.4084. PMID 12559841. S2CID 38407150.
  37. ^ Di Chiara, G. (1988). "Drugs abused by humans preferentially increase synaptic dopamine concentrations in the mesolimbic system of freely moving rats". Proceedings of the National Academy of Sciences of the United States of America. 85 (14): 5274–5278. doi:10.1073/pnas.85.14.5274. PMC 281732. PMID 2899326.
  38. ^ Koob, G.F. (1992). "Drugs of abuse: anatomy, pharmacology, and function of reward pathways". Trends in Pharmacological Sciences. 13 (5): 177–184. doi:10.1016/0165-6147(92)90060-j. PMID 1604710.
  39. ^ Cardinal, R.N. (2004). "Neural and psychological mechanisms underlying appetitive learning: links to drug addiction". Curr. Opin. Neurobiol. 14 (2): 156–62. doi:10.1016/j.conb.2004.03.004. PMID 15082319. S2CID 15312372.
  40. ^ Kalivas, P.W. (2005). "Unmanageable motivation in addiction: a pathology in prefrontal-accumbens glutamate transmission". Neuron. 45 (5): 647–50. doi:10.1016/j.neuron.2005.02.005. PMID 15748840. S2CID 2803383.
  41. ^ Pierce, R.C. (2006). "The mesolimbic dopamine system: the final common pathway for the reinforcing effect of drugs of abuse?". Neurosci. Biobehav. Rev. 30 (2): 215–238. doi:10.1016/j.neubiorev.2005.04.016. PMID 16099045. S2CID 39886286.
  42. ^ Sesack, R. (2010). "Cortico-Basal Ganglia reward network: microcircuitry". Neuropsychopharmacology. 35 (1): 27–47. doi:10.1038/npp.2009.93. PMC 2879005. PMID 19675534.
  43. ^ Hyman, S.E. (2001). "Addiction and the brain: the neurobiology of compulsion and its persistence". Nat. Rev. Neurosci. 2 (10): 695–703. doi:10.1038/35094560. PMID 11584307. S2CID 3333114.
  44. ^ Yao, R. (2004). "Identification of PSD-95 as a regulator of dopamine-mediated synaptic and behavioral plasticity". Neuron. 41 (4): 625–638. doi:10.1016/s0896-6273(04)00048-0. PMID 14980210. S2CID 6413505.
  45. ^ Luscher, C.J. (2010). "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. PMC 4046255. PMID 21338877.
  46. ^ Kauer, J. (2007). "Synaptic plasticity and addiction". Nat. Rev. Neurosci. 8 (11): 844–858. doi:10.1038/nrn2234. PMID 17948030. S2CID 38811195.
  47. ^ a b c Kauer, J. (2004). "Learning mechanisms in addiction: synaptic plasticity in the ventral tegmental area as a result of exposure to drugs of abuse". Annu. Rev. Physiol. 66: 447–475. doi:10.1146/annurev.physiol.66.032102.112534. PMID 14977410.
  48. ^ Spanagel, Rainer; Vengeliene, Valentina (2013). "New pharmacological treatment strategies for relapse prevention". Current Topics in Behavioral Neurosciences. 13: 583–609. doi:10.1007/7854_2012_205. ISBN 978-3-642-28719-0. ISSN 1866-3370. PMID 22389180.
  49. ^ Guenzel, Nicholas; McChargue, Dennis (2023), "Addiction Relapse Prevention", StatPearls, Treasure Island (FL): StatPearls Publishing, PMID 31855344, retrieved 2024-01-03
  50. ^ "Relapse - Alcohol and Drug Foundation". adf.org.au. Retrieved 2024-01-03.
  51. ^ Friedmann, Peter D.; Saitz, Richard; Samet, Jeffrey H. (1998-04-15). "Management of Adults Recovering From Alcohol or Other Drug ProblemsRelapse Prevention in Primary Care". JAMA. 279 (15): 1227–1231. doi:10.1001/jama.279.15.1227. ISSN 0098-7484. PMID 9555766.
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