Effects of Dopamine and Glutamate on Synaptic Plasticity: A Computational Modeling Approach for Drug Abuse as Comorbidity in Mood Disorders

 

 Permissions and Reprints

Abstract

Major depressive disorder (MDD) affects about 16% of the general population and is a leading cause of death in the United States and around the world. Aggravating the situation is the fact that “drug use disorders” are highly comorbid in MDD patients, and vice versa. Drug use and MDD share a common component, the dopamine system, which is critical in many motivation and reward processes, as well as in the regulation of stress responses in MDD. A potentiating mechanism in drug use disorders appears to be synaptic plasticity, which is regulated by dopamine transmission. In this article, we describe a computational model of the synaptic plasticity of GABAergic medium spiny neurons in the nucleus accumbens, which is critical in the reward system. The model accounts for effects of both dopamine and glutamate transmission. Model simulations show that GABAergic medium spiny neurons tend to respond to dopamine stimuli with synaptic potentiation and to glutamate signals with synaptic depression. Concurrent dopamine and glutamate signals cause various types of synaptic plasticity, depending on input scenarios. Interestingly, the model shows that a single 0.5 mg/kg dose of amphetamine can cause synaptic potentiation for over 2 h, a phenomenon that makes synaptic plasticity of medium spiny neurons behave quasi as a bistable system. The model also identifies mechanisms that could potentially be critical to correcting modifications of synaptic plasticity caused by drugs in MDD patients. An example is the feedback loop between protein kinase A, phosphodiesterase, and the second messenger cAMP in the postsynapse. Since reward mechanisms activated by psychostimulants could be crucial in establishing addiction comorbidity in patients with MDD, this model might become an aid for identifying and targeting specific modules within the reward system and lead to a better understanding and potential treatment of comorbid drug use disorders in MDD.

References

• 1 APA .Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR Fourth Edition; Text Revision).. Washington, DC: Americal Psychiatric Association; 2000
  Google Scholar
• 2 Barbano PE, Spivak M, Flajolet M. et al . A mathematical tool for exploring the dynamics of biological networks.  Proc Natl Acad Sci USA. 2007;  104 19169-19174
  CrossrefPubMedGoogle Scholar
• 3 Bewernick BH, Hurlemann R, Matusch A. et al . Nucleus accumbens deep brain stimulation decreases ratings of depression and anxiety in treatment-resistant depression.  Biol Psychiatry. 2010;  67 110-116
  CrossrefPubMedGoogle Scholar
• 4 Bhalla US, Iyengar R. Emergent properties of networks of biological signaling pathways.  Science. 1999;  283 381-387
  CrossrefPubMedGoogle Scholar
• 5 Bibb JA, Snyder GL, Nishi A. et al . Phosphorylation of DARPP-32 by Cdk5 modulates dopamine signalling in neurons.  Nature. 1999;  402 669-671
  CrossrefPubMedGoogle Scholar
• 6 Calabresi P, Centonze D, Gubellini P. et al . Glutamate-triggered events inducing corticostriatal long-term depression.  J Neurosci. 1999;  19 6102-6110
  PubMedGoogle Scholar
• 7 Calabresi P, Pisani A, Mercuri NB. et al . Long-term Potentiation in the Striatum is Unmasked by Removing the Voltage-dependent Magnesium Block of NMDA Receptor Channels.  Eur J Neurosci. 1992;  4 929-935
  CrossrefPubMedGoogle Scholar
• 8 Castellani GC, Bazzani A, Cooper LN. Toward a microscopic model of bidirectional synaptic plasticity.  Proc Natl Acad Sci USA. 2009;  106 14091-14095
  CrossrefPubMedGoogle Scholar
• 9 Conner KR, Pinquart M, Holbrook AP. Meta-analysis of depression and substance use and impairment among cocaine users.  Drug Alcohol Depend. 2008;  98 13-23
  CrossrefPubMedGoogle Scholar
• 10 Dackis CA, Gold MS, Sweeney DR. The physiology of cocaine craving and ‘crashing’.  Arch Gen Psychiatry. 1987;  44 298-300
  PubMedGoogle Scholar
• 11 Desdouits F, Cheetham JJ, Huang HB. et al . Mechanism of inhibition of protein phosphatase 1 by DARPP-32: studies with recombinant DARPP-32 and synthetic peptides.  Biochem Biophys Res Commun. 1995;  206 652-658
  CrossrefPubMedGoogle Scholar
• 12 Di Chiara G, Imperato A. Drugs abused by humans preferentially increase synaptic dopamine concentrations in the mesolimbic system of freely moving rats.  Proc Natl Acad Sci USA. 1988;  85 5274-5278
  CrossrefPubMedGoogle Scholar
• 13 Drevets WC, Price JL, Furey ML. Brain structural and functional abnormalities in mood disorders: implications for neurocircuitry models of depression.  Brain Struct Funct. 2008;  213 93-118
  CrossrefPubMedGoogle Scholar
• 14 Fernandez É, Schiappa R, Girault JA. et al . DARPP-32 is a robust integrator of dopamine and glutamate signals.  PLoS Comput Biol. 2006;  2 e176
  CrossrefPubMedGoogle Scholar
• 15 Gaiarsa JL, Caillard O, Ben-Ari Y. Long-term plasticity at GABAergic and glycinergic synapses: mechanisms and functional significance.  Trends Neurosci. 2002;  25 564-570
  CrossrefPubMedGoogle Scholar
• 16 Gawin FH, Kleber HD. Abstinence symptomatology and psychiatric diagnosis in cocaine abusers. Clinical observations.  Arch Gen Psychiatry. 1986;  43 107-113
  Google Scholar
• 17 Girault JA, Hemmings Jr HC, Williams KR. et al . Phosphorylation of DARPP-32, a dopamine- and cAMP-regulated phosphoprotein, by casein kinase II.  J Biol Chem. 1989;  264 21748-21759
  PubMedGoogle Scholar
• 18 Hayer A, Bhalla US. Molecular switches at the synapse emerge from receptor and kinase traffic.  PLoS Comput Biol. 2005;  1 137-154
  PubMedGoogle Scholar
• 19 Hemmings Jr HC, Greengard P. DARPP-32, a dopamine- and adenosine 3′:5′-monophosphate-regulated phosphoprotein: regional, tissue, and phylogenetic distribution.  J Neurosci. 1986;  6 1469-1481
  PubMedGoogle Scholar
• 20 Hemmings Jr HC, Nairn AC, Greengard P. DARPP-32, a dopamine- and adenosine 3′:5′-monophosphate-regulated neuronal phosphoprotein. II. Comparison of the kinetics of phosphorylation of DARPP-32 and phosphatase inhibitor 1.  J Biol Chem. 1984;  259 14491-14497
  PubMedGoogle Scholar
• 21 Hofmann F, Bechtel PJ, Krebs EG. Concentrations of cyclic AMP-dependent protein kinase subunits in various tissues.  J Biol Chem. 1977;  252 1441-1447
  PubMedGoogle Scholar
• 22 Hyman SE, Malenka RC. Addiction and the brain: the neurobiology of compulsion and its persistence.  Nat Rev Neurosci. 2001;  2 695-703
  CrossrefPubMedGoogle Scholar
• 23 Hyman SE, Malenka RC, Nestler EJ. Neural mechanisms of addiction: the role of reward-related learning and memory.  Annu Rev Neurosci. 2006;  29 565-598
  CrossrefPubMedGoogle Scholar
• 24 Janowsky DS, Overstreet DH. The role of acetylcholine mechanisms in mood disorders.. In:, Bloom FE,, Kupfer DJ, eds, Psychopharmacology: The fourth generation of progress. New York: Raven Press, Ltd; 1995. xlii+2002
  Google Scholar
• 25 Kauer JA. Learning mechanisms in addiction: synaptic plasticity in the ventral tegmental area as a result of exposure to drugs of abuse.  Annu Rev Physiol. 2004;  66 447-475
  CrossrefPubMedGoogle Scholar
• 26 Kessler RC, Berglund P, Demler O. et al . The epidemiology of major depressive disorder: results from the National Comorbidity Survey Replication (NCS-R).  Jama. 2003;  289 3095-3105
  CrossrefPubMedGoogle Scholar
• 27 Khantzian EJ. The self-medication hypothesis of addictive disorders: focus on heroin and cocaine dependence.  Am J Psychiatry. 1985;  142 1259-1264
  CrossrefPubMedGoogle Scholar
• 28 Kim M, Huang T, Abel T. et al . Temporal sensitivity of protein kinase a activation in late-phase long term potentiation.  PLoS Comput Biol. 2010;  6 e1000691
  CrossrefPubMedGoogle Scholar
• 29 Koob GF, Kenneth Lloyd G, Mason BJ. Development of pharmacotherapies for drug addiction: a Rosetta stone approach.  Nat Rev Drug Discov. 2009;  8 500-515
  CrossrefPubMedGoogle Scholar
• 30 Krystal JH. N-methyl-D-aspartate glutamate receptor antagonists and the promise of rapid-acting antidepressants.  Arch Gen Psychiatry. 2010;  67 1110-1111
  CrossrefPubMedGoogle Scholar
• 31 Lindskog M, Kim M, Wikstrom MA. et al . Transient calcium and dopamine increase PKA activity and DARPP-32 phosphorylation.  PLoS Comput Biol. 2006;  2 e119
  CrossrefPubMedGoogle Scholar
• 32 Luscher B, Shen Q, Sahir N. The GABAergic deficit hypothesis of major depressive disorder.  Mol Psychiatry. 2010; 
  PubMedGoogle Scholar
• 33 Maletic V, Robinson M, Oakes T. et al . Neurobiology of depression: an integrated view of key findings.  International journal of clinical practice. 2007;  61 2030-2040
  CrossrefPubMedGoogle Scholar
• 34 Markou A, Kosten TR, Koob GF. Neurobiological similarities in depression and drug dependence: a self-medication hypothesis.  Neuropsychopharmacology. 1998;  18 135-174
  CrossrefPubMedGoogle Scholar
• 35 Mayberg HS. Limbic-cortical dysregulation: a proposed model of depression.  J Neuropsychiatry Clin Neurosci. 1997;  9 471-481
  CrossrefPubMedGoogle Scholar
• 36 Mayberg HS. Defining the neural circuitry of depression: Strategies toward treatment selection based on neuroimaging phenotypes.  Psychiatric Annals. 2006;  36 259-268
  PubMedGoogle Scholar
• 37 Mayberg HS. Targeted electrode-based modulation of neural circuits for depression.  J Clin Invest. 2009;  119 717-725
  CrossrefPubMedGoogle Scholar
• 38 Monk CS, Klein RG, Telzer EH. et al . Amygdala and nucleus accumbens activation to emotional facial expressions in children and adolescents at risk for major depression.  Am J Psychiatry. 2008;  165 90-98
  PubMedGoogle Scholar
• 39 Murray CJ, Lopez AD. Global mortality, disability, and the contribution of risk factors: Global Burden of Disease Study.  Lancet. 1997;  349 1436-1442
  CrossrefPubMedGoogle Scholar
• 40 Nagase T, Murakami T, Nozaki H. et al . Tissue and subcellular distributions, and characterization of rat brain protein phosphatase 2A containing a 72-kDa delta/B” subunit.  J Biochem. 1997;  122 178-187
  CrossrefPubMedGoogle Scholar
• 41 Nakano T, Doi T, Yoshimoto J. et al . A kinetic model of dopamine- and calcium-dependent striatal synaptic plasticity.  PLoS Comput Biol. 2010;  6 e1000670
  CrossrefPubMedGoogle Scholar
• 42 Nestler EJ, Carlezon Jr WA. The mesolimbic dopamine reward circuit in depression.  Biol Psychiatry. 2006;  59 1151-1159
  CrossrefPubMedGoogle Scholar
• 43 Nishi A, Bibb JA, Snyder GL. et al . Amplification of dopaminergic signaling by a positive feedback loop.  Proc Natl Acad Sci USA. 2000;  97 12840-12845
  CrossrefPubMedGoogle Scholar
• 44 Ouimet CC, da Cruz e Silva EF, Greengard P. The alpha and gamma 1 isoforms of protein phosphatase 1 are highly and specifically concentrated in dendritic spines.  Proc Natl Acad Sci USA. 1995;  92 3396-3400
  CrossrefPubMedGoogle Scholar
• 45 Patel S, Morris SA, Adkins CE. et al . Ca2+-independent inhibition of inositol trisphosphate receptors by calmodulin: redistribution of calmodulin as a possible means of regulating Ca2+ mobilization.  Proc Natl Acad Sci USA. 1997;  94 11627-11632
  CrossrefPubMedGoogle Scholar
• 46 Pelizza L, Ferrari A. Anhedonia in schizophrenia and major depression: state or trait?.  Ann Gen Psychiatry. 2009;  8 22
  CrossrefPubMedGoogle Scholar
• 47 Price JL, Drevets WC. Neurocircuitry of mood disorders.  Neuropsychopharmacology. 2010;  35 192-216
  CrossrefPubMedGoogle Scholar
• 48 Qi Z, Miller GW, Voit EO. Computational systems analysis of dopamine metabolism.  PLoS One. 2008;  3 e2444
  CrossrefPubMedGoogle Scholar
• 49 Qi Z, Miller GW, Voit EO. A mathematical model of presynaptic dopamine homeostasis: implications for schizophrenia.  Pharmacopsychiatry. 2008;  41 (Suppl. 1) S89-S98
  Article in Thieme ConnectPubMedGoogle Scholar
• 50 Qi Z, Miller GW, Voit EO. The internal state of medium spiny neurons varies in response to different input signals.  BMC Syst Biol. 2010;  4 26
  CrossrefPubMedGoogle Scholar
• 51 Raison CL, Capuron L, Miller AH. Cytokines sing the blues: inflammation and the pathogenesis of depression.  Trends Immunol. 2006;  27 24-31
  CrossrefPubMedGoogle Scholar
• 52 Rakhilin SV, Olson PA, Nishi A. et al . A network of control mediated by regulator of calcium/calmodulin-dependent signaling.  Science. 2004;  306 698-701
  CrossrefPubMedGoogle Scholar
• 53 Rao U, Hammen CL, Poland RE. Mechanisms underlying the comorbidity between depressive and addictive disorders in adolescents: interactions between stress and HPA activity.  The American journal of psychiatry. 2009;  166 361-369
  CrossrefPubMedGoogle Scholar
• 54 Rayport SG, Kandel ER. Development of plastic mechanisms related to learning at identified chemical synaptic connections in Aplysia.  Neuroscience. 1986;  17 283-294
  CrossrefPubMedGoogle Scholar
• 55 Reynolds JN, Hyland BI, Wickens JR. A cellular mechanism of reward-related learning.  Nature. 2001;  413 67-70
  CrossrefPubMedGoogle Scholar
• 56 Reynolds JN, Wickens JR. Substantia nigra dopamine regulates synaptic plasticity and membrane potential fluctuations in the rat neostriatum, in vivo.  Neuroscience. 2000;  99 199-203
  CrossrefPubMedGoogle Scholar
• 57 Reynolds JN, Wickens JR. Dopamine-dependent plasticity of corticostriatal synapses.  Neural Netw. 2002;  15 507-521
  CrossrefPubMedGoogle Scholar
• 58 Ross HE, Glaser FB, Germanson T. The prevalence of psychiatric disorders in patients with alcohol and other drug problems.  Arch Gen Psychiatry. 1988;  45 1023-1031
  CrossrefPubMedGoogle Scholar
• 59 Ross HE, Glasser FB, Stiasny S. Sex differences in the prevalence of psychiatric disorders in patients with alcohol and drug problems.  Br J Addict. 1988;  83 1179-1192
  CrossrefPubMedGoogle Scholar
• 60 Sanacora G, Mason GF, Rothman DL. et al . Reduced cortical gamma-aminobutyric acid levels in depressed patients determined by proton magnetic resonance spectroscopy.  Arch Gen Psychiatry. 1999;  56 1043-1047
  CrossrefPubMedGoogle Scholar
• 61 Sanderson WC, Beck AT, Beck J. Syndrome comorbidity in patients with major depression or dysthymia: prevalence and temporal relationships.  Am J Psychiatry. 1990;  147 1025-1028
  PubMedGoogle Scholar
• 62 Shi SH, Hayashi Y, Petralia RS. et al . Rapid spine delivery and redistribution of AMPA receptors after synaptic NMDA receptor activation.  Science. 1999;  284 1811-1816
  CrossrefPubMedGoogle Scholar
• 63 Sim AT, Ratcliffe E, Mumby MC. et al . Differential activities of protein phosphatase types 1 and 2A in cytosolic and particulate fractions from rat forebrain.  J Neurochem. 1994;  62 1552-1559
  PubMedGoogle Scholar
• 64 Snyder GL, Allen PB, Fienberg AA. et al . Regulation of phosphorylation of the GluR1 AMPA receptor in the neostriatum by dopamine and psychostimulants in vivo.  J Neurosci. 2000;  20 4480-4488
  PubMedGoogle Scholar
• 65 Stahl SM. Stahl's Essential Psychopharmacology: Neuroscientific Basis and Practical Applications.. 3rdedition ed: Cambridge University Press; 2008: 1132
  Google Scholar
• 66 Sulzer D, Sonders MS, Poulsen NW. et al . Mechanisms of neurotransmitter release by amphetamines: a review.  Prog Neurobiol. 2005;  75 406-433
  CrossrefPubMedGoogle Scholar
• 67 Takahashi S, Ohshima T, Cho A. et al . Increased activity of cyclin-dependent kinase 5 leads to attenuation of cocaine-mediated dopamine signaling.  Proc Natl Acad Sci USA. 2005;  102 1737-1742
  CrossrefPubMedGoogle Scholar
• 68 Tang K, Low MJ, Grandy DK. et al . Dopamine-dependent synaptic plasticity in striatum during in vivo development.  Proc Natl Acad Sci USA. 2001;  98 1255-1260
  CrossrefPubMedGoogle Scholar
• 69 Tisch S, Silberstein P, Limousin-Dowsey P. et al . The basal ganglia: anatomy, physiology, and pharmacology.  Psychiatr Clin North Am. 2004;  27 757-799
  CrossrefPubMedGoogle Scholar
• 70 Usui H, Inoue R, Tanabe O. et al . Activation of protein phosphatase 2A by cAMP-dependent protein kinase-catalyzed phosphorylation of the 74-kDa B” (delta) regulatory subunit in vitro and identification of the phosphorylation sites.  FEBS Lett. 1998;  430 312-316
  CrossrefPubMedGoogle Scholar
• 71 Voit EO. Computational analysis of biochemical systems: a practical guide for biochemists and molecular biologists.. Cambridge, UK: Cambridge University Press; 2000. xii, 531 p.
  Google Scholar
• 72 Voit EO, Qi Z, Miller GW. Steps of modeling complex biological systems.  Pharmacopsychiatry. 2008;  41 (Suppl. 1) S78-S84
  Article in Thieme ConnectPubMedGoogle Scholar
• 73 Weiss RD, Mirin SM, Griffin ML. Methodological considerations in the diagnosis of coexisting psychiatric disorders in substance abusers.  Br J Addict. 1992;  87 179-187
  CrossrefPubMedGoogle Scholar
• 74 Wickens JR, Begg AJ, Arbuthnott GW. Dopamine reverses the depression of rat corticostriatal synapses which normally follows high-frequency stimulation of cortex in vitro.  Neuroscience. 1996;  70 1-5
  CrossrefPubMedGoogle Scholar
• 75 Willner P. Dopamine and depression: a review of recent evidence. I. Empirical studies.  Brain Res. 1983;  287 211-224
  PubMedGoogle Scholar
• 76 Willner P. Dopamine and depression: a review of recent evidence. II. Theoretical approaches.  Brain Res. 1983;  287 225-236
  PubMedGoogle Scholar
• 77 Willner P. Dopamine and depression: a review of recent evidence. III. The effects of antidepressant treatments.  Brain Res. 1983;  287 237-246
  PubMedGoogle Scholar
• 78 Zetterstrom T, Sharp T, Ungerstedt U. Further evaluation of the mechanism by which amphetamine reduces striatal dopamine metabolism: a brain dialysis study.  Eur J Pharmacol. 1986;  132 1-9
  CrossrefPubMedGoogle Scholar

Appendix

Reactions, kinetics, and initial conditions in the mathematical model of signal transduction and trafficking of AMPA receptors

All reactions are represented in the form of an enzymatic reaction or a simple binding reaction, with K_f denoting the rate constant for the forward process, K_b denoting the rate constant for the backward process, and K_c denoting the rate constant for the catalytic step in a Michaelis-Menten kinetics.

Correspondence

E. O. VoitPhD 

313 Ferst Drive

Department of Biomedical

Engineering

GA 30332-0535 Atlanta

USA

Phone: +1/404/385 5057

Fax: +1/404/894 4243

Email: eberhard.voit@bme.gatech.edu