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Current Psychopharmacology

Editor-in-Chief

ISSN (Print): 2211-5560
ISSN (Online): 2211-5579

Review Article

Dopaminylation in Psychostimulant Use Disorder Protects Against Psychostimulant Seeking Behavior by Normalizing Nucleus Accumbens (NAc) Dopamine Expression

Author(s): Kenneth Blum*, Mark S. Gold, Jean L. Cadet, David Baron, Abdalla Bowirrat, Panayotis K. Thanos, Raymond Brewer, Rajendra D. Badgaiyan and Marjorie C. Gondré-Lewis

Volume 11, Issue 1, 2022

Published on: 08 January, 2021

Page: [11 - 17] Pages: 7

DOI: 10.2174/2211556009666210108112737

Abstract

Background: Repeated cocaine administration changes histone acetylation and methylation on Lys residues and Deoxyribonucleic acid (DNA) within the nucleus accumbens (NAc). Recently Nestler’s group explored histone Arg (R) methylation in reward processing models. Damez- Werno et al. (2016) reported that during human investigations and animal self-administration experiments, the histone mark protein-R-methyltransferase-6 (PRMT6) and asymmetric dimethylation of R2 on histone H3 (H3R2me2a) decreased in the rodent and cocaine-dependent human NAc. Overexpression of PRMT6 in D2-MSNs in all NAc neurons increased cocaine seeking, whereas PRMT6 overexpression in D1-MSNs protects against cocaine-seeking.

Hypothesis: The hypothesis is that dopaminylation (H3R2me2a binding) occurs in psychostimulant use disorder (PSU), and the binding inhibitor Srcin1, like the major DRD2 A2 allelic polymorphism, protects against psychostimulant seeking behavior by normalizing nucleus accumbens (NAc) dopamine expression.

Discussion: Numerous publications confirmed the association between the DRD2 Taq A1 allele (30-40 lower D2 receptor numbers) and severe cocaine dependence. Lepack et al. (2020) found that acute cocaine increases dopamine in NAc synapses, and results in histone H3 glutamine 5 dopaminylation (H3Q5dop) and consequent inhibition of D2 expression. The inhibition increases with chronic cocaine use and accompanies cocaine withdrawal. They also found that the Src kinase signaling inhibitor 1 (Srcin1 or p140CAP) during cocaine withdrawal reduced H3R2me2a binding. Consequently, this inhibited dopaminylation induced a “homeostatic brake.”

Conclusion: The decrease in Src signaling in NAc D2-MSNs, (like the DRD2 Taq A2 allele, a well- known genetic mechanism protective against SUD) normalizes the NAc dopamine expression and decreases cocaine reward and motivation to self-administer cocaine. The Srcin1 may be an important therapeutic target.

Keywords: Src, p140CAP, psychostimulants, cocaine, histone arginine (R) methylation, medium spiny neurons, DRD2 gene.

Graphical Abstract

[1]
Blum K, Giordano J, Morse S, et al. Understanding the high mind Humans are still evolving genetically. IIOAB- India 2010; 1(2): 1-14-4.
[2]
Volkow ND, Blanco C. The changing opioid crisis: development, challenges and opportunities. Mol Psychiatry 2020.
[PMID: 32020048]
[3]
Gold MS, Blum K, Febo M, et al. Molecular role of dopamine in anhedonia linked to reward deficiency syndrome (RDS) and anti- reward systems. Front Biosci (Schol Ed) 2018; 10: 309-25.
[http://dx.doi.org/10.2741/s518] [PMID: 29293435]
[4]
Borsook D, Linnman C, Faria V, Strassman AM, Becerra L, Elman I. Reward deficiency and anti-reward in pain chronification. Neurosci Biobehav Rev 2016; 68: 282-97.
[http://dx.doi.org/10.1016/j.neubiorev.2016.05.033] [PMID: 27246519]
[5]
Bowirrat A, Oscar-Berman M. Relationship between dopaminergic neurotransmission, alcoholism, and Reward Deficiency syndrome. American journal of medical genetics Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 2005; 132b(1): 29-37.
[http://dx.doi.org/10.1002/ajmg.b.30080]
[6]
Filippi A, Mueller T, Driever W. vglut2 and gad expression reveal distinct patterns of dual GABAergic versus glutamatergic cotransmitter phenotypes of dopaminergic and noradrenergic neurons in the zebrafish brain. J Comp Neurol 2014; 522(9): 2019-37.
[http://dx.doi.org/10.1002/cne.23524] [PMID: 24374659]
[7]
Valentino RJ, Koroshetz W, Volkow ND. Neurobiology of the Opioid Epidemic: Basic and Translational Perspectives. Biol Psychiatry 2020; 87(1): 2-3.
[http://dx.doi.org/10.1016/j.biopsych.2019.09.003] [PMID: 31806083]
[8]
Browne CJ, Godino A, Salery M, Nestler EJ. Epigenetic Mechanisms of Opioid Addiction. Biol Psychiatry 2020; 87(1): 22-33.
[http://dx.doi.org/10.1016/j.biopsych.2019.06.027] [PMID: 31477236]
[9]
Blum K, Chen AL, Chen TJ, et al. Activation instead of blocking mesolimbic dopaminergic reward circuitry is a preferred modality in the long term treatment of reward deficiency syndrome (RDS): a commentary. Theor Biol Med Model 2008; 5: 24.
[http://dx.doi.org/10.1186/1742-4682-5-24] [PMID: 19014506]
[10]
Comings DE, Blum K. Reward deficiency syndrome: genetic aspects of behavioral disorders. Prog Brain Res 2000; 126: 325-41.
[http://dx.doi.org/10.1016/S0079-6123(00)26022-6] [PMID: 11105655]
[11]
Blum K, Chen AL, Oscar-Berman M, et al. Generational association studies of dopaminergic genes in reward deficiency syndrome (RDS) subjects: selecting appropriate phenotypes for reward dependence behaviors. Int J Environ Res Public Health 2011; 8(12): 4425-59.
[http://dx.doi.org/10.3390/ijerph8124425] [PMID: 22408582]
[12]
Febo M, Blum K, Badgaiyan RD, et al. Dopamine homeostasis: brain functional connectivity in reward deficiency syndrome. Front Biosci 2017; 22: 669-91.
[http://dx.doi.org/10.2741/4509] [PMID: 27814639]
[13]
Rosell DR, Siever LJ. The neurobiology of aggression and violence. CNS Spectr 2015; 20(3): 254-79.
[http://dx.doi.org/10.1017/S109285291500019X] [PMID: 25936249]
[14]
Mahna D, Puri S, Sharma S. DNA methylation signatures: Biomarkers of drug and alcohol abuse. Mutat Res 2018; 777: 19-28.
[http://dx.doi.org/10.1016/j.mrrev.2018.06.002] [PMID: 30115428]
[15]
D’Aquila PS, Elia D, Galistu A. Role of dopamine D1-like and D2-like receptors in the activation of ingestive behaviour in thirsty rats licking for water. Psychopharmacology (Berl) 2019; 236(12): 3497-512.
[http://dx.doi.org/10.1007/s00213-019-05317-w] [PMID: 31273401]
[16]
Volkow ND, Morales M. The Brain on Drugs: From Reward to Addiction. Cell 2015; 162(4): 712-25.
[http://dx.doi.org/10.1016/j.cell.2015.07.046] [PMID: 26276628]
[17]
Yamamoto K, Fontaine R, Pasqualini C, Vernier P. Classification of Dopamine Receptor Genes in Vertebrates: Nine Subtypes in Osteichthyes. Brain Behav Evol 2015; 86(3-4): 164-75.
[http://dx.doi.org/10.1159/000441550] [PMID: 26613258]
[18]
Noble EP, Blum K, Ritchie T, Montgomery A, Sheridan PJ. Allelic association of the D2 dopamine receptor gene with receptor-binding characteristics in alcoholism. Arch Gen Psychiatry 1991; 48(7): 648-54.
[http://dx.doi.org/10.1001/archpsyc.1991.01810310066012] [PMID: 2069496]
[19]
Volkow ND, Chang L, Wang GJ, et al. Low level of brain dopamine D2 receptors in methamphetamine abusers: association with metabolism in the orbitofrontal cortex. Am J Psychiatry 2001; 158(12): 2015-21.
[http://dx.doi.org/10.1176/appi.ajp.158.12.2015] [PMID: 11729018]
[20]
Volkow ND, Wang GJ, Telang F, et al. Low dopamine striatal D2 receptors are associated with prefrontal metabolism in obese subjects: possible contributing factors. Neuroimage 2008; 42(4): 1537-43.
[http://dx.doi.org/10.1016/j.neuroimage.2008.06.002] [PMID: 18598772]
[21]
Noble EP, Blum K, Khalsa ME, et al. Allelic association of the D2 dopamine receptor gene with cocaine dependence. Drug Alcohol Depend 1993; 33(3): 271-85.
[http://dx.doi.org/10.1016/0376-8716(93)90113-5] [PMID: 8261891]
[22]
Dackis CA, Gold MS. Bromocriptine as treatment of cocaine abuse. Lancet 1985; 1(8438): 1151-2.
[http://dx.doi.org/10.1016/S0140-6736(85)92448-1] [PMID: 2860349]
[23]
Muma NA, Mi Z. Serotonylation and Transamidation of Other Monoamines. ACS Chem Neurosci 2015; 6(7): 961-9.
[http://dx.doi.org/10.1021/cn500329r] [PMID: 25615632]
[24]
Lepack AE, Werner CT, Stewart AF, et al. Dopaminylation of histone H3 in ventral tegmental area regulates cocaine seeking. Science 2020; 368(6487): 197-201.
[http://dx.doi.org/10.1126/science.aaw8806] [PMID: 32273471]
[25]
Robison AJ, Nestler EJ. Transcriptional and epigenetic mechanisms of addiction. Nat Rev Neurosci 2011; 12(11): 623-37.
[http://dx.doi.org/10.1038/nrn3111] [PMID: 21989194]
[26]
Maze I, Covington HE III, Dietz DM, et al. Essential role of the histone methyltransferase G9a in cocaine-induced plasticity. Science 2010; 327(5962): 213-6.
[http://dx.doi.org/10.1126/science.1179438] [PMID: 20056891]
[27]
Jayanthi S, Gonzalez B, McCoy MT, Ladenheim B, Bisagno V, Cadet JL. Methamphetamine Induces TET1- and TET3-Dependent DNA Hydroxymethylation of Crh and Avp Genes in the Rat Nucleus Accumbens. Mol Neurobiol 2018; 55(6): 5154-66.
[http://dx.doi.org/10.1007/s12035-017-0750-9] [PMID: 28842817]
[28]
Cadet JL, Brannock C, Krasnova IN, et al. Genome-wide DNA hydroxymethylation identifies potassium channels in the nucleus accumbens as discriminators of methamphetamine addiction and abstinence. Mol Psychiatry 2017; 22(8): 1196-204.
[http://dx.doi.org/10.1038/mp.2016.48] [PMID: 27046646]
[29]
Damez-Werno DM, Sun H, Scobie KN, et al. Histone arginine methylation in cocaine action in the nucleus accumbens. Proc Natl Acad Sci USA 2016; 113(34): 9623-8.
[http://dx.doi.org/10.1073/pnas.1605045113] [PMID: 27506785]
[30]
Gary JD, Clarke S. RNA and protein interactions modulated by protein arginine methylation. Prog Nucleic Acid Res Mol Biol 1998; 61: 65-131.
[http://dx.doi.org/10.1016/S0079-6603(08)60825-9] [PMID: 9752719]
[31]
Gayatri S, Bedford MT. Readers of histone methylarginine marks. Biochim Biophys Acta 2014; 1839(8): 702-10.
[http://dx.doi.org/10.1016/j.bbagrm.2014.02.015] [PMID: 24583552]
[32]
Frankel A, Yadav N, Lee J, Branscombe TL, Clarke S, Bedford MT. The novel human protein arginine N-methyltransferase PRMT6 is a nuclear enzyme displaying unique substrate specificity. J Biol Chem 2002; 277(5): 3537-43.
[http://dx.doi.org/10.1074/jbc.M108786200] [PMID: 11724789]
[33]
Kirmizis A, Santos-Rosa H, Penkett CJ, et al. Arginine methylation at histone H3R2 controls deposition of H3K4 trimethylation. Nature 2007; 449(7164): 928-32.
[http://dx.doi.org/10.1038/nature06160] [PMID: 17898715]
[34]
Feng J, Wilkinson M, Liu X, et al. Chronic cocaine-regulated epigenomic changes in mouse nucleus accumbens. Genome Biol 2014; 15(4): R65.
[http://dx.doi.org/10.1186/gb-2014-15-4-r65] [PMID: 24758366]
[35]
Kennedy PJ, Feng J, Robison AJ, et al. Class I HDAC inhibition blocks cocaine-induced plasticity by targeted changes in histone methylation. Nat Neurosci 2013; 16(4): 434-40.
[http://dx.doi.org/10.1038/nn.3354] [PMID: 23475113]
[36]
Adermark L, Clarke RB, Ericson M, Söderpalm B. Subregion-Specific Modulation of Excitatory Input and Dopaminergic Output in the Striatum by Tonically Activated Glycine and GABA(A) Receptors. Front Syst Neurosci 2011; 5: 85.
[http://dx.doi.org/10.3389/fnsys.2011.00085] [PMID: 22028683]
[37]
Trulson ME, Joe JC, Babb S, Raese JD. Chronic cocaine administration depletes tyrosine hydroxylase immunoreactivity in the meso-limbic dopamine system in rat brain: quantitative light microscopic studies. Brain Res Bull 1987; 19(1): 39-45.
[http://dx.doi.org/10.1016/0361-9230(87)90163-8] [PMID: 2888517]
[38]
Ferguson SM, Eskenazi D, Ishikawa M, et al. Transient neuronal inhibition reveals opposing roles of indirect and direct pathways in sensitization. Nat Neurosci 2011; 14(1): 22-4.
[http://dx.doi.org/10.1038/nn.2703] [PMID: 21131952]
[39]
Feltmann K, Borroto-Escuela DO, Rüegg J, et al. Effects of Long-Term Alcohol Drinking on the Dopamine D2 Receptor: Gene Expression and Heteroreceptor Complexes in the Striatum in Rats. Alcohol Clin Exp Res 2018; 42(2): 338-51.
[http://dx.doi.org/10.1111/acer.13568] [PMID: 29205397]
[40]
Fried L, Modestino EJ, Siwicki D, Lott L, Thanos PK, Baron D, et al. Hypodopaminergia and “Precision Behavioral Management” (PBM): It is a Generational Family Affair. Curr Pharm Biotechnol 2019.
[http://dx.doi.org/10.2174/1389201021666191210112108] [PMID: 31820688]
[41]
Dahlgren A, Wargelius HL, Berglund KJ, et al. Do alcohol-dependent individuals with DRD2 A1 allele have an increased risk of relapse? A pilot study. Alcohol Alcohol 2011; 46(5): 509-13.
[http://dx.doi.org/10.1093/alcalc/agr045] [PMID: 21613303]
[42]
Heinsbroek JA, Neuhofer DN, Griffin WC III, et al. Loss of Plasticity in the D2-Accumbens Pallidal Pathway Promotes Cocaine Seeking. J Neurosci 2017; 37(4): 757-67.
[http://dx.doi.org/10.1523/JNEUROSCI.2659-16.2016] [PMID: 28123013]
[43]
Blum K, Noble EP, Sheridan PJ, et al. Allelic association of human dopamine D2 receptor gene in alcoholism. JAMA 1990; 263(15): 2055-60.
[http://dx.doi.org/10.1001/jama.1990.03440150063027] [PMID: 1969501]
[44]
Volkow ND, Wang GJ, Newcorn JH, et al. Motivation deficit in ADHD is associated with dysfunction of the dopamine reward pathway. Mol Psychiatry 2011; 16(11): 1147-54.
[http://dx.doi.org/10.1038/mp.2010.97] [PMID: 20856250]
[45]
Blum K, Gondré-Lewis MC, Baron D, et al. Introducing Precision Addiction Management of Reward Deficiency Syndrome, the Construct That Underpins All Addictive Behaviors. Front Psychiatry 2018; 9: 548.
[http://dx.doi.org/10.3389/fpsyt.2018.00548] [PMID: 30542299]
[46]
Solanki N, Abijo T, Galvao C, Darius P, Blum K, Gondré-Lewis MC. Administration of a putative pro-dopamine regulator, a neuronutrient, mitigates alcohol intake in alcohol-preferring rats. Behav Brain Res 2020; 385: 112563.
[http://dx.doi.org/10.1016/j.bbr.2020.112563] [PMID: 32070691]
[47]
Clark KH, Wiley CA, Bradberry CW. Psychostimulant abuse and neuroinflammation: emerging evidence of their interconnection. Neurotox Res 2013; 23(2): 174-88.
[http://dx.doi.org/10.1007/s12640-012-9334-7] [PMID: 22714667]
[48]
Beardsley PM, Hauser KF. Glial modulators as potential treatments of psychostimulant abuse. Adv Pharmacol 2014; 69: 1-69.
[http://dx.doi.org/10.1016/B978-0-12-420118-7.00001-9] [PMID: 24484974]
[49]
Pierce RC, Bari AA. The role of neurotrophic factors in psychostimulant-induced behavioral and neuronal plasticity. Rev Neurosci 2001; 12(2): 95-110.
[http://dx.doi.org/10.1515/REVNEURO.2001.12.2.95] [PMID: 11392459]

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