Abstract
Electroconvulsive therapy (ECT) is one of the most effective therapies for depression and has beneficial motor effects in parkinsonian patients. However, little is known about the mechanisms of therapeutic action of ECT for either condition. The aim of this work was to explore the impact of ECT on dopaminergic function in the striatum of non-human primates. Rhesus monkeys underwent a course of six ECT treatments under a human clinical protocol. Longitudinal effects on the dopaminergic nigrostriatal system were studied over 6 weeks using the in vivo capabilities of positron emission tomography (PET). PET scans were performed prior to the onset of ECT treatments and at 24–48 h, 8–10 days, and 6 weeks after the final ECT treatment. Early increases in dopamine transporter and vesicular monoamine transporter 2 binding returned to baseline levels by 6 weeks post-ECT. Transient increases in D1 receptor binding were also observed, whereas the binding potential to D2 receptors was unaltered. The increase in dopaminergic neurotransmission suggested by our results may account in part for the therapeutic effect of ECT in mood disorders and Parkinson's disease.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
References
Andersen K, Balldin J, Gottfries CG, Granerus AK, Modigh K, Svennerholm L et al (1987). A double-blind evaluation of electroconvulsive therapy in Parkinson's disease with ‘on-off’ phenomena. Acta Neurol Scand 76: 191–199.
Antonini A, Schwarz J, Oertel WH, Beer HF, Madeja UD, Leenders KL (1994). [11C]-Raclopride and positron emission tomography in previously untreated patients with Parkinson's disease: influence of L-dopa and lisuride therapy on striatal dopamine D2-receptors. Neurology 44: 1325–1329.
Barkai AI, Durkin M, Nelson HD (1990). Localized alterations of dopamine receptor binding in rat brain by repeated electroconvulsive shock: an autoradiographic study. Brain Res 529: 208–213.
Bergstrom DA, Kellar KJ (1979). Effect of electroconvulsive shock on monoaminergic receptor binding sites in rat brain. Nature 278: 464–466.
Brown R, Jahanshahi M (1995). Depression in Parkinson's disease: a psychosocial viewpoint. Adv Neurol 65: 61–84.
Costain DW, Cowen PJ, Gelder MG, Grahame-Smith DG (1982). Electroconvulsive therapy and the brain: evidence for increased dopamine-mediated responses. Lancet 2: 400–404.
D’haenen HA, Bossuyt A (1994). Dopamine D2 receptors in depression measured with single photon emission computed tomography. Biol Psychiatry 35: 128–132.
Dewey SL, Smith GS, Logan J, Brodie JD, Fowler JS, Wolf AP (1993). Striatal binding of the PET ligand 11C-raclopride is altered by drugs that modify synaptic dopamine levels. Synapse 13: 350–356.
Ding YS, Fowler JS, Volkow ND (1995). Carbon-11-d-threo-methylphenidate: a new PET ligand for the dopamine transporter. I: studies in the baboon brain. J Nucl Med 36: 2298–2305.
Donnan GA, Kaczmarczyk SJ, Mckenzie JS, Kalnins R, Chilco PJ, Mendelsohn FA (1989). Catecholamine uptake sitesd in mouse brain: distribution determined by [3H]mazindol autoradiography. Brain Res 504: 64–71.
Doudet DJ, Dyve S, Alstrup AKO, Jakobsen S, Simonsen M, Moller A et al (2010). Noradrenaline release: potential antidepressant mechanism of brain stimulation? NeuroImage 52: S47.
Doudet DJ, Holden JE (2003). Raclopride studies of dopamine release: dependence on presynaptic integrity. Biol Psychiatry 53: 1193–1199.
Doudet DJ, Holden JE, Jivan S, McGeer EG, Wyatt RJ (2000). In vivo PET studies of the dopamine D2 receptors in rhesus monkeys with long-term MPTP-induced parkinsonism. Synapse 38: 105–113.
Doudet DJ, Jivan S, Ruth TJ, Holden JE (2002a). Density and affinity of the dopamine D2 receptors in aged symptomatic and asymptomatic MPTP-treated monkeys: PET studies with [11C]raclopride. Synapse 44: 198–202.
Doudet DJ, Jivan S, Ruth TJ, Wyatt RJ (2002b). In vivo PET studies of the dopamine D1 receptors in rhesus monkeys with long-term MPTP-induced parkinsonism. Synapse 44: 111–115.
Doudet DJ, Rosa-Neto P, Munk OL, Ruth TJ, Jivan S, Cumming P (2006). Effect of age on markers for monoaminergic neurons of normal and MPTP-lesioned rhesus monkeys: a multi-tracer PET study. NeuroImage 30: 26–35.
Dougherty DD, Bonab AA, Ottowitz WE, Livni E, Alpert NM, Rauch SL et al (2006). Decreased striatal D1 binding as measured using PET and [11C]SCH23390 in patients with major depression with anger attacks. Depress Anxiety 23: 175–177.
Douyon R, Serby M, Klutchko B, Rotrosen J (1989). ECT and Parkinson's disease revisited: a ‘naturalistic’ study. Am J Psychiat 146: 1451–1455.
Ekelund J, Slifstein M, Narendran R, Guillin O, Belani H, Guo NN et al (2007). In vivo DA D1 receptor selectivity of NNC 112 and SCH 23390. Mol Imaging Biol 9: 117–125.
Faber R, Trimble MR (1991). Electroconvulsive therapy in Parkinson's disease and other movement disorders. Mov Disord 6: 293–303.
Fink M (2001). Convulsive therapy: a review of the first 55 years. J Affect Disord 63: 1–15.
Floel A, Garraux G, Xi B, Breitenstein C, Knecht S, Herscovitch P et al (2008). Levodopa increases memory encoding and dopamine release in the striatum in the elderly. Neurobiol Aging 29: 267–279.
Fochtmann LJ (1994). Animal studies of electroconvulsive therapy: foundations for future research. Psychopharmacol Bull 30: 321–344.
Fochtmann LJ, Cruciani R, Aiso M, Potter WZ (1989). Chronic electroconvulsive shock increases D-1 receptor binding in rat substantia nigra. Eur J Pharmacol 167: 305–306.
Freis ED (1954). Mental depression in hypertensive patients treated for long periods with large doses of reserpine. N Engl J Med 251: 1006–1008.
Fukui M, Rodriguiz RM, Zhou J, Jiang SX, Phillips LE, Caron MG et al (2007). Vmat2 heterozygous mutant mice display a depressive-like phenotype. J Neurosci 27: 10520–10529.
Gordon I, Weizman R, Rehavi M (1996). Modulatory effect of agents active in the presynaptic dopaminergic system on the striatal dopamine transporter. Eur J Pharmacol 298: 27–30.
Green AR, Heal DJ, Grahame-Smith DG (1977). Further observations on the effect of repeated electroconvulsive shock on the behavioural responses of rats produced by increases in the functional activity of brain 5-hydroxytryptamine and dopamine. Psychopharmacology 52: 195–200.
Inoue O, Tsukada H, Yonezawa H, Suhara T, Langstrom B (1991). Reserpine-induced reduction of in vivo binding of SCH 23390 and N-methylspiperone and its reversal by d-amphetamine. Eur J Pharmacol 197: 143–149.
Joyce JN (1991). Differential response of striatal dopamine and muscarinic cholinergic receptor subtypes to the loss of dopamine. I. Effects of intranigral or intracerebroventricular 6-hydroxydopamine lesions of the mesostriatal dopamine system. Exp Neurol 113: 261–276.
Kennedy SH, Rizvi S (2009). Emerging drugs for major depressive disorder. Expert Opin Emerg Drugs 14: 439–453.
Kho KH, Van Vreeswijk MF, Simpson S, Zwinderman AH (2003). A meta-analysis of electroconvulsive therapy efficacy in depression. J ECT 19: 139–147.
Kobayashi K, Inoue O (1993). An increase in the in vivo binding of [3H]SCH 23390 induced by MK-801 in the mouse striatum. Neuropharmacology 32: 341–348.
Lammers CH, Diaz J, Schwartz JC, Sokoloff P (2000). Selective increase of dopamine D3 receptor gene expression as a common effect of chronic antidepressant treatments. Mol Psychiatry 5: 378–388.
Laruelle M (2000). Imaging synaptic neurotransmission with in vivo binding competition techniques: a critical review. J Cereb Blood Flow Metab 20: 423–452.
Lee CS, Samii A, Sossi V, Ruth TJ, Schulzer M, Holden JE et al (2000). In vivo positron emission tomographic evidence for compensatory changes in presynaptic dopaminergic nerve terminals in Parkinson's disease. Ann Neurol 47: 493–503.
Madhav TR, Pei Q, Grahame-Smith DG, Zetterstrom TS (2000). Repeated electroconvulsive shock promotes the sprouting of serotonergic axons in the lesioned rat hippocampus. Neuroscience 97: 677–683.
Marshall JF, Navarrette R, Joyce JN (1989). Decreased striatal D1 binding density following mesotelencephalic 6-hydroxydopamine injections: an autoradiographic analysis. Brain Res 493: 247–257.
McGarvey KA, Zis AP, Brown EE, Nomikos GG, Fibiger HC (1993). ECS-induced dopamine release: effects of electrode placement, anticonvulsant treatment and stimulus intensity. Biol Psychiatry 34: 152–157.
Meyer J, Kruger S, Wilson A, Christensen BK, Goulding VS, Schaffer A et al (2001). Lower dopamine transporter binding potential in striatum during depression. NeuroReport 12: 4121–4125.
Momosaki S, Hatano K, Kawasumi Y, Kato T, Hosoi R, Kobayashi K et al (2004). Rat-PET study without anesthesia: anesthetics modify the dopamine D1 receptor binding in rat brain. Synapse 54: 207–213.
Neumeister A, Willeit M, Praschak-Rieder N, Asenbaum S, Stastny J, Hilger E et al (2001). Dopamine transporter availability in symptomatic depressed patients with seasonal affective disorder and healthy controls. Psychol Med 31: 1467–1473.
Nomikos GG, Zis AP, Damsma G, Fibiger HC (1991). Electroconvulsive shock produces large increases in interstitial concentrations of dopamine in the rat striatum: an in vivo microdialysis study. Neuropsychopharmacol 4: 65–69.
Nowak G, Zak J (1989). Repeated electroconvulsive shock (ECS) enhances striated D-1 dopamine receptor turnover in rats. Eur J Pharmacol 167: 307–308.
Nutt DJ (2006). The role of dopamine and norepinephrine in depression and antidepressant treatment. J Clin Psychiatry 67 (Suppl 6): 3–8.
Pagnin D, deQueioz V, Pini S, Cassano GB (2004). Efficacy of ECT in depression: a meta-analytic review. J ECT 20: 13–20.
Pruessner JC, Champagne F, Meaney MJ, Dagher A (2004). Dopamine release in response to a psychological stress in humans and its relationship to early life maternal care: a positron emission tomography study using [11C]raclopride. J Neurosci 24: 2825–2831.
Rami-Gonzalez L, Bernardo M, Boget T, Salamero M, Gil-Verona JA, Junque C (2001). Subtypes of memory dysfunction associated with ECT: characteristics and neurobiological bases. J ECT 17: 129–135.
Remy P, Doder M, Lees A, Turjanski N, Brooks D (2005). Depression in Parkinson's disease: loss of dopamine and noradrenaline innervation in the limbic system. Brain 128: 1314–1322.
Rosa DVF, Souza RP, Souza BR, Motta BS, Caetano F, Jornada LK et al (2007). DARPP-32 expression in rat brain after electroconvulsive stimulation. Brain Res 1179: 35–41.
Rudorfer M, Risby E, Hsiao J, Linnoila M, Potter WZ (1988). ECT alters human monoamines in a different manner from that of antidepressant drugs. Psychopharmacol Bull 24: 396–399.
Sackeim HA, Prudic J, Devanand DP, Kiersky JE, Fitzsimons L, Moody BJ et al (1993). Effects of stimulus intensity and electrode replacement on the efficacy and cognitive effects of electroconvulsive therapy. N Engl J Med 328: 839–846.
Sarchiapone M, Carli V, Camardese G, Cuomo C, Di Giuda D, Calcagni ML et al (2006). Dopamine transporter binding in depressed patients with anhedonia. Psychiatry Res 147: 243–248.
Schwartz K, Yadid G, Weizman A, Rehavi M (2003). Decreased limbic vesicular monoamine transporter 2 in a genetic rat model of depression. Brain Res 965: 174–179.
Sershen H, Wolinsky T, Douyon R, Hashim A, Wiener HL, Lajtha A et al (1991). The effects of electroconvulsive shock on dopamine-1 and dopamine-2 receptor ligand binding activity in MPTP-treated mice. J Neuropsychiatry Clin Neurosci 3: 58–63.
Shah PJ, Ogilvie AD, Goodwin GM, Ebmeier KP (1997). Clinical and psychometric correlates of dopamine D2 binding in depression. Psychol Med 27: 1247–1256.
Slaughter JR, Slaughter KA, Nichols DE, Holmes SE, Martens MP (2001). Prevalence, clinical manifestations, etiology, and treatment of depression in Parkinson's disease. J Neuropsychiatry Clin Neurosci 13: 187–196.
Smith S, Lindefors N, Hurd Y, Sharp T (1995). Electroconvulsive shock increases dopamine D1 and D2 receptor mRNA in the nucleus accumbens of the rat. Psychopharmacology (Berl) 120: 333–340.
Sossi V, Holden JE, Topping GJ, Camborde ML, Kornelsen RA, McCormick SE et al (2007). In vivo measurement of density and affinity of the monoamine vesicular transporter in a unilateral 6-hydroxydopamine rat model of PD. J Cereb Blood Flow Metab 27: 1407–1415.
Strome EM, Clark C, Zis AP, Doudet DJ (2005). Electroconvulsive shock decreases binding to 5HT2 receptors in non-human primates: an in vivo PET study with [18]-setoperone. Biol Psychiatry 57: 1004–1010.
Strome EM, Zis AP, Doudet DJ (2007). Electroconvulsive shock enhances striatal D1 and D3 receptor binding and improves motor performance in 6-OHDA lesioned rats. J Psychiatry Neurosci 32: 193–202.
Tandberg E, Larsen JP, Aarsland D, Cummings JL (1996). The occurrence of depression in Parkinson's disease. A community-based study. Arch Neurol 53: 175–179.
Tong J, Wilson A, Boileau I, Houle S, Kish SJ (2008). Dopamine modulating drugs influence striatal (+)-[11C]DTBZ binding in rats: VMAT2 binding is sensitive to changes in vesicular dopamine concentration. Synapse 62: 873–876.
UK ECT Review Group (2003). Efficacy and safety of electroconvulsive therapy in depressive disorders: a systemic review and meta-analysis. Lancet 361: 799–808.
West CHK, Weiss JM (2010). Effects of chronic antidepressant drug administration and electroconvulsive shock on activity of dopaminergic neurons in ventral tegmentum. Int J Neuropsychopharmacol 19: 1–10.
Willner P, Hale AS, Argyropoulos S (2005). Dopaminergic mechanism of antidepressant action in depressed patients. J Affect Disorders 86: 37–45.
Yatham LN, Liddle PF, Lam RW, Zis AP, Stoessl AJ, Sossi V et al (2010). Effect of electroconvulsive therapy on brain 5-HT2 receptors in major depression. Br J Psychiatry 196: 474–479.
Zis AP, Nomikos GG, Brown EE, Damsma G, Fibiger HC (1992). Neurochemical effects of electrically and chemically induced seizures: an in vivo microdialysis study in the rat hippocampus. Neuropsychopharmacol 7: 189–195.
Zis AP, Nomikos GG, Damsma G, Fibiger HC (1991). In vivo neurochemical effects of electroconvulsive shock studied by microdialysis in the rat striatum. Psychopharmacology 103: 343–350.
Zis AP, Yatham LN, Lam RW, Clark CM, Srisurapanont M, McGarvey KA (1996). Effect of stimulus intensity on prolactin and cortisol release induced by unilateral electroconvulsive therapy. Neuropsychopharmacol 15: 263–270.
Zucker M, Weizman A, Rehavi M (2005). Repeated swim stress leads to down-regulation of vesicular monoamine transporter 2 in rat brain nucleus accumbens and striatum. Eur Neuropsychopharmacol 15: 199–201.
Acknowledgements
We are grateful to the staff of the UBC Animal Resource Unit for providing animal care. We thank Jessica Grant (animal health technician) for her care of the animals during the PET studies and maintenance of their well-being during the entire study. We also thank the members of the UBC/TRIUMF PET group, in particular Dr T Ruth (head, PET group), Carolyn English (PET technologist), and Salma Jivan (radiochemist). The Parkinson Society Canada and the Danish Medical Research Council funded postdoctoral salary for AML. Funding for the studies was provided by CIHR MOP 74746.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no conflict of interest.
PowerPoint slides
Rights and permissions
About this article
Cite this article
Landau, A., Chakravarty, M., Clark, C. et al. Electroconvulsive Therapy Alters Dopamine Signaling in the Striatum of Non-human Primates. Neuropsychopharmacol 36, 511–518 (2011). https://doi.org/10.1038/npp.2010.182
Received:
Revised:
Accepted:
Published:
Issue date:
DOI: https://doi.org/10.1038/npp.2010.182
Keywords
This article is cited by
-
A longitudinal study of the association between basal ganglia volumes and psychomotor symptoms in subjects with late life depression undergoing ECT
Translational Psychiatry (2021)
-
Antidepressant treatment effects on dopamine transporter availability in patients with major depression: a prospective 123I-FP-CIT SPECT imaging genetic study
Journal of Neural Transmission (2018)
-
Retinal dysfunction of contrast processing in major depression also apparent in cortical activity
European Archives of Psychiatry and Clinical Neuroscience (2015)
