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Chronic lamotrigine does not alter the turnover of arachidonic acid within brain phospholipids of the unanesthetized rat: implications for the treatment of bipolar disorder

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Abstract

Rationale

Drugs that are effective in treating the manic phase of bipolar disorder (lithium, carbamazepine, and valproate) upon chronic administration to rats decrease the turnover of arachidonic acid in their brain phospholipids. Lamotrigine may not be effective in the manic phase, but is effective in delaying the depressive phase and for treating rapid cycling bipolar disorder. Thus, lamotrigine provides a pharmacological tool to differentiate if downregulation of arachidonic acid turnover is specific to drugs effective in the manic phase of bipolar disorder.

Materials and methods

To test this hypothesis, rats were administered lamotrigine (10 mg kg−1 day−1) or vehicle intragastrically once daily for 42 days. In the unanesthetized rat, [1-14C]arachidonic acid was infused intravenously and arterial blood plasma was sampled until the animal was killed at 5 min, and its microwaved brain was subjected to chemical and radiotracer analysis.

Results

Using equations from our fatty acid model, we found that chronic lamotrigine compared with vehicle did not alter the net incorporation rate of plasma arachidonic acid into brain phospholipids, nor did it alter the turnover of arachidonic acid within brain phospholipids.

Conclusion

Chronic lamotrigine, which is effective in the depressive phase or rapid cycling bipolar disorder does not alter brain arachidonic acid turnover in the unanesthetized rat. These results are consistent with the hypothesis that drugs effective in treating the manic phase of bipolar disorder decrease brain arachidonic acid turnover.

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Abbreviations

cPLA2 :

calcium-dependent cytosolic phospholipase A2

5-HT:

serotonin

sn:

stereospecifically numbered

References

  • Ahmad S, Fowler LJ, Whitton PS (2004) Effect of acute and chronic lamotrigine on basal and stimulated extracellular 5-hydroxytryptamine and dopamine in the hippocampus of the freely moving rat. Br J Pharmacol 142:136–142

    Article  PubMed  CAS  Google Scholar 

  • Ahmad S, Fowler LJ, Whitton PS (2005a) Effects of combined lamotrigine and valproate on basal and stimulated extracellular amino acids and monoamines in the hippocampus of freely moving rats. Naunyn Schmiedebergs Arch Pharmacol 371:1–8

    Article  PubMed  CAS  Google Scholar 

  • Ahmad S, Fowler LJ, Whitton PS (2005b) Lamotrigine, carbamazepine and phenytoin differentially alter extracellular levels of 5-hydroxytryptamine, dopamine and amino acids. Epilepsy Res 63:141–149

    Article  PubMed  CAS  Google Scholar 

  • Aveldano MI, VanRollins M, Horrocks LA (1983) Separation and quantitation of free fatty acids and fatty acid methyl esters by reverse phase high pressure liquid chromatography. J Lipid Res 24(1):83–93

    PubMed  CAS  Google Scholar 

  • Axelrod J (1990) Receptor-mediated activation of phospholipase A2 and arachidonic acid release in signal transduction. Biochem Soc Trans 18:503–507

    PubMed  CAS  Google Scholar 

  • Basselin M, Chang L, Bell JM, Rapoport SI (2005a) Chronic lithium chloride administration to unanesthetized rats attenuates brain dopamine D2-like receptor-initiated signaling via arachidonic acid. Neuropsychopharmacology 30:1064–1075

    Article  PubMed  CAS  Google Scholar 

  • Basselin M, Chang L, Seemann R, Bell JM, Rapoport SI (2005b) Chronic lithium administration to rats selectively modifies 5-HT2A/2C receptor-mediated brain signaling via arachidonic acid. Neuropsychopharmacology 30:461–472

    Article  PubMed  CAS  Google Scholar 

  • Basselin M, Chang L, Bell JM, Rapoport SI (2006) Chronic lithium chloride administration attenuates brain NMDA receptor-initiated signaling via arachidonic acid in unanesthetized rats. Neuropsychopharmacology 31:1659–1674

    Article  PubMed  CAS  Google Scholar 

  • Bazinet RP, Lee HJ, Felder CC, Porter AC, Rapoport SI, Rosenberger TA (2005a) Rapid high-energy microwave fixation is required to determine the anandamide (N-arachidonoylethanolamine) concentration of rat brain. Neurochem Res 30:597–601

    Article  PubMed  CAS  Google Scholar 

  • Bazinet RP, Rao JS, Chang L, Rapoport SI, Lee HJ (2005b) Chronic valproate does not alter the kinetics of docosahexaenoic acid within brain phospholipids of the unanesthetized rat. Psychopharmacology (Berl) 182:180–185

    Article  CAS  Google Scholar 

  • Bazinet RP, Rao JS, Chang L, Rapoport SI, Lee HJ (2006a) Chronic carbamazepine decreases the incorporation rate and turnover of arachidonic acid but not docosahexaenoic acid in brain phospholipids of the unanesthetized rat: relevance to bipolar disorder. Biol Psychiatry 59:401–407

    Article  PubMed  CAS  Google Scholar 

  • Bazinet RP, Weis MT, Rapoport SI, Rosenberger TA (2006b) Valproic acid selectively inhibits conversion of arachidonic acid to arachidonoyl-CoA by brain microsomal long-chain fatty acyl-CoA synthetases: relevance to bipolar disorder. Psychopharmacology (Berl) 184:122–129

    Article  CAS  Google Scholar 

  • Bazinet RP, Bhattacharjee AK, Lee HJ (2007) Haloperidol targets brain arachidonic acid signaling. Prog Neuropsychopharmacol Biol Psychiatry 31:314–315

    Article  PubMed  CAS  Google Scholar 

  • Bhattacharjee AK, Chang L, Lee HJ, Bazinet RP, Seemann R, Rapoport SI (2005) D2 but not D1 dopamine receptor stimulation augments brain signaling involving arachidonic acid in unanesthetized rats. Psychopharmacology (Berl) 180:735–742

    Article  CAS  Google Scholar 

  • Bhattacharjee AK, Chang L, White L, Bazinet RP, Rapoport SI (2006) d-Amphetamine stimulates D2 dopamine receptor-mediated brain signaling involving arachidonic acid in unanesthetized rats. J Cereb Blood Flow Metab 26:1378–1388

    Article  PubMed  CAS  Google Scholar 

  • Bosetti F, Rintala J, Seemann R, Rosenberger TA, Contreras MA, Rapoport SI, Chang MC (2002a) Chronic lithium downregulates cyclooxygenase-2 activity and prostaglandin E(2) concentration in rat brain. Mol Psychiatry 7:845–850

    Article  PubMed  CAS  Google Scholar 

  • Bosetti F, Seemann R, Bell JM, Zahorchak R, Friedman E, Rapoport SI, Manickam P (2002b) Analysis of gene expression with cDNA microarrays in rat brain after 7 and 42 days of oral lithium administration. Brain Res Bull 57:205–209

    Article  PubMed  CAS  Google Scholar 

  • Bosetti F, Weerasinghe GR, Rosenberger TA, Rapoport SI (2003) Valproic acid down-regulates the conversion of arachidonic acid to eicosanoids via cyclooxygenase-1 and -2 in rat brain. J Neurochem 85:690–696

    Article  PubMed  CAS  Google Scholar 

  • Bourre JM, Dumont OL, Clement ME, Durand GA (1997) Endogenous synthesis cannot compensate for absence of dietary oleic acid in rats. J Nutr 127:488–493

    PubMed  CAS  Google Scholar 

  • Bowden CL, Calabrese JR, Sachs G, Yatham LN, Asghar SA, Hompland M, Montgomery P, Earl N, Smoot TM, DeVeaugh-Geiss J (2003) A placebo-controlled 18-month trial of lamotrigine and lithium maintenance treatment in recently manic or hypomanic patients with bipolar I disorder. Arch Gen Psychiatry 60:392–400

    Article  PubMed  CAS  Google Scholar 

  • Calabrese JR, Bowden CL, Sachs G, Yatham LN, Behnke K, Mehtonen OP, Montgomery P, Ascher J, Paska W, Earl N, DeVeaugh-Geiss J (2003) A placebo-controlled 18-month trial of lamotrigine and lithium maintenance treatment in recently depressed patients with bipolar I disorder. J Clin Psychiatry 64:1013–1024

    Article  PubMed  CAS  Google Scholar 

  • Calabrese JR, Rapport DJ, Youngstrom EA, Jackson K, Bilali S, Findling RL (2005) New data on the use of lithium, divalproate, and lamotrigine in rapid cycling bipolar disorder. Eur Psychiatr 20:92–95

    Article  CAS  Google Scholar 

  • Chang MC, Grange E, Rabin O, Bell JM, Allen DD, Rapoport SI (1996) Lithium decreases turnover of arachidonate in several brain phospholipids. Neurosci Lett 220:171–174

    Article  PubMed  CAS  Google Scholar 

  • Chang MC, Bell JM, Purdon AD, Chikhale EG, Grange E (1999) Dynamics of docosahexaenoic acid metabolism in the central nervous system: lack of effect of chronic lithium treatment. Neurochem Res 24:399–406

    Article  PubMed  CAS  Google Scholar 

  • Chang MC, Contreras MA, Rosenberger TA, Rintala JJ, Bell JM, Rapoport SI (2001) Chronic valproate treatment decreases the in vivo turnover of arachidonic acid in brain phospholipids: a possible common effect of mood stabilizers. J Neurochem 77:796–803

    Article  PubMed  CAS  Google Scholar 

  • Cunnane SC, Ryan MA, Nadeau CR, Bazinet RP, Musa-Veloso K, McCloy U (2003) Why is carbon from some polyunsaturates extensively recycled into lipid synthesis? Lipids 38:477–484

    Article  PubMed  CAS  Google Scholar 

  • DeGeorge JJ, Noronha JG, Bell J, Robinson P, Rapoport SI (1989) Intravenous injection of [1–14C]arachidonate to examine regional brain lipid metabolism in unanesthetized rats. J Neurosci Res 24:413–23

    Article  PubMed  CAS  Google Scholar 

  • DeMar JC, Jr., Lee HJ, Ma K, Chang L, Bell JM, Rapoport SI, Bazinet RP (2006a) Brain elongation of linoleic acid is a negligible source of the arachidonate in brain phospholipids of adult rats. Biochim Biophys Acta 1761:1050–1059

    PubMed  CAS  Google Scholar 

  • DeMar JC, Jr., Ma K, Bell JM, Igarashi M, Greenstein D, Rapoport SI (2006b) One generation of n-3 polyunsaturated fatty acid deprivation increases depression and aggression test scores in rats. J Lipid Res 47:172–180

    Article  PubMed  CAS  Google Scholar 

  • Deutsch J, Grange E, Rapoport SI, Purdon AD (1994) Isolation and quantitation of long-chain acyl-coenzyme A esters in brain tissue by solid-phase extraction. Anal Biochem 220:321–323

    Article  PubMed  CAS  Google Scholar 

  • Deutsch J, Rapoport SI, Purdon AD (1997) Relation between free fatty acid and acyl-CoA concentrations in rat brain following decapitation. Neurochem Res 22:759–765

    Article  PubMed  CAS  Google Scholar 

  • Doose DR, Brodie MJ, Wilson EA, Chadwick D, Oxbury J, Berry DJ, Schwabe S, Bialer M (2003) Topiramate and lamotrigine pharmacokinetics during repetitive monotherapy and combination therapy in epilepsy patients. Epilepsia 44:917–922

    Article  PubMed  CAS  Google Scholar 

  • Fatemi SH, Rapport DJ, Calabrese JR, Thuras P (1997) Lamotrigine in rapid-cycling bipolar disorder. J Clin Psychiatry 58:522–527

    PubMed  CAS  Google Scholar 

  • Felder CC, Kanterman RY, Ma AL, Axelrod J (1990) Serotonin stimulates phospholipase A2 and the release of arachidonic acid in hippocampal neurons by a type 2 serotonin receptor that is independent of inositolphospholipid hydrolysis. Proc Natl Acad Sci USA 87:2187–2191

    Article  PubMed  CAS  Google Scholar 

  • Folch J, Lees M, Sloane Stanley GH (1957) A simple method for the isolation and purification of total lipides from animal tissues. J Biol Chem 226:497–509

    PubMed  CAS  Google Scholar 

  • Funk CD (2001) Prostaglandins and leukotrienes: advances in eicosanoid biology. Science 294:1871–1875

    Article  PubMed  CAS  Google Scholar 

  • Ghelardoni S, Tomita YA, Bell JM, Rapoport SI, Bosetti F (2004) Chronic carbamazepine selectively downregulates cytosolic phospholipase A2 expression and cyclooxygenase activity in rat brain. Biol Psychiatry 56:248–254

    Article  PubMed  CAS  Google Scholar 

  • Ghelardoni S, Bazinet RP, Rapoport SI, Bosetti F (2005) Topiramate does not alter expression in rat brain of enzymes of arachidonic acid metabolism. Psychopharmacology (Berl) 180:523–529

    Article  CAS  Google Scholar 

  • Grange E, Deutsch J, Smith QR, Chang M, Rapoport SI, Purdon AD (1995) Specific activity of brain palmitoyl-CoA pool provides rates of incorporation of palmitate in brain phospholipids in awake rats. J Neurochem 65:2290–2298

    Article  PubMed  CAS  Google Scholar 

  • Grunze HC, Normann C, Langosch J, Schaefer M, Amann B, Sterr A, Schloesser S, Kleindienst N, Walden J (2001) Antimanic efficacy of topiramate in 11 patients in an open trial with an on–off–on design. J Clin Psychiatry 62:464–468

    Article  PubMed  CAS  Google Scholar 

  • Hassel B, Tauboll E, Gjerstad L (2001) Chronic lamotrigine treatment increases rat hippocampal GABA shunt activity and elevates cerebral taurine levels. Epilepsy Res 43:153–163

    Article  PubMed  CAS  Google Scholar 

  • Kushner SF, Khan A, Lane R, Olson WH (2006) Topiramate monotherapy in the management of acute mania: results of four double-blind placebo-controlled trials. Bipolar Disord 8:15–27

    Article  PubMed  CAS  Google Scholar 

  • Lands WEM, Crawford CG (1976) Enzymes of membrane phospholipid metabolism. In: Martonosi A (ed) The enzymes of biological membranes. Biosynthesis of cell components, vol. 2. Plenum, New York, pp 3–85

    Google Scholar 

  • Lee HJ, Ghelardoni S, Chang L, Bosetti F, Rapoport SI, Bazinet RP (2005) Topiramate does not alter the kinetics of arachidonic or docosahexaenoic acid in brain phospholipids of the unanesthetized rat. Neurochem Res 30:677–683

    Article  PubMed  CAS  Google Scholar 

  • Lee HJ, Rao JS, Ertley RN, Chang L, Rapoport SI, Bazinet RP (2007) Chronic fluoxetine increases cytosolic phospholipase A(2) activity and arachidonic acid turnover in brain phospholipids of the unanesthetized rat. Psychopharmacology (Berl) 190:103–115

    Article  CAS  Google Scholar 

  • Leverich GS, Altshuler LL, Frye MA, Suppes T, McElroy SL, Keck PE Jr, Kupka RW, Denicoff KD, Nolen WA, Grunze H, Martinez MI, Post RM (2006) Risk of switch in mood polarity to hypomania or mania in patients with bipolar depression during acute and continuation trials of venlafaxine, sertraline, and bupropion as adjuncts to mood stabilizers. Am J Psychiatry 163:232–239

    Article  PubMed  Google Scholar 

  • Makrides M, Neumann MA, Byard RW, Simmer K, Gibson RA (1994) Fatty acid composition of brain, retina, and erythrocytes in breast- and formula-fed infants. Am J Clin Nutr 60:189–194

    PubMed  CAS  Google Scholar 

  • Malik S, Arif H, Hirsch LJ (2006) Lamotrigine and its applications in the treatment of epilepsy and other neurological and psychiatric disorders. Expert Rev Neurother 6:1609–1627

    Article  PubMed  CAS  Google Scholar 

  • McElroy SL, Suppes T, Keck PE, Frye MA, Denicoff KD, Altshuler LL, Brown ES, Nolen WA, Kupka RW, Rochussen J, Leverich GS, Post RM (2000) Open-label adjunctive topiramate in the treatment of bipolar disorders. Biol Psychiatry 47:1025–1033

    Article  PubMed  CAS  Google Scholar 

  • McGeer EG, Zhu SG (1990) Lamotrigine protects against kainate but not ibotenate lesions in rat striatum. Neurosci Lett 112:348–351

    Article  PubMed  CAS  Google Scholar 

  • Muller N, Schwarz MJ, Dehning S, Douhe A, Cerovecki A, Goldstein-Muller B, Spellmann I, Hetzel G, Maino K, Kleindienst N, Moller HJ, Arolt V, Riedel M (2006) The cyclooxygenase-2 inhibitor celecoxib has therapeutic effects in major depression: results of a double-blind, randomized, placebo controlled, add-on pilot study to reboxetine. Mol Psychiatry 11:680–684

    Article  PubMed  CAS  Google Scholar 

  • Muzina DJ, Elhaj O, Gajwani P, Gao K, Calabrese JR (2005) Lamotrigine and antiepileptic drugs as mood stabilizers in bipolar disorder. Acta Psychiatr Scand Suppl:21–28

  • O’Brien JS, Sampson EL (1965) Lipid composition of the normal human brain: gray matter, white matter, and myelin. J Lipid Res 6:537–544

    PubMed  CAS  Google Scholar 

  • Piomelli D, Pilon C, Giros B, Sokoloff P, Martres MP, Schwartz JC (1991) Dopamine activation of the arachidonic acid cascade as a basis for D1/D2 receptor synergism. Nature 353:164–167

    Article  PubMed  CAS  Google Scholar 

  • Post RM, Leverich GS, Nolen WA, Kupka RW, Altshuler LL, Frye MA, Suppes T, McElroy S, Keck P, Grunze H, Walden J (2003) A re-evaluation of the role of antidepressants in the treatment of bipolar depression: data from the Stanley Foundation Bipolar Network. Bipolar Disord 5:396–406

    Article  PubMed  Google Scholar 

  • Rao JS, Rapoport SI, Bosetti F (2005) Decrease in the AP-2 DNA-binding activity and in the protein expression of AP-2 alpha and AP-2 beta in frontal cortex of rats treated with lithium for 6 weeks. Neuropsychopharmacology 30:2006–2013

    Article  PubMed  CAS  Google Scholar 

  • Rao JS, Bazinet RP, Rapoport SI, Lee HJ (2007) Chronic treatment of rats with sodium valproate downregulates frontal cortex NF-kB DNA binding activity and COX-2 mRNA. Bipolar Disord (in press)

  • Rao JS, Ertley RN, Lee HJ, Rapoport SI, Bazinet RP (2006) Chronic fluoxetine upregulates activity, protein and mRNA levels of cytosolic phospholipase A2 in rat frontal cortex. Pharmacogenomics J 6:413–420

    Article  PubMed  CAS  Google Scholar 

  • Rao JS, Bazinet RP, Rapoport SI, Lee HJ (2007a) Chronic administration of carbamazepine down-regulates AP-2 DNA-binding activity and AP-2alpha protein expression in rat frontal cortex. Biol Psychiatry 61:154–61

    Article  PubMed  CAS  Google Scholar 

  • Rao JS, Ertley RN, DeMar JC, Jr., Rapoport SI, Bazinet RP, Lee HJ (2007b) Dietary n-3 PUFA deprivation alters expression of enzymes of the arachidonic and docosahexaenoic acid cascades in rat frontal cortex. Mol Psychiatry 12:151–157

    Article  PubMed  CAS  Google Scholar 

  • Rapoport SI, Bosetti F (2002) Do lithium and anticonvulsants target the brain arachidonic acid cascade in bipolar disorder? Arch Gen Psychiatry 59:592–596

    Article  PubMed  CAS  Google Scholar 

  • Rapoport SI, Chang MC, Spector AA (2001) Delivery and turnover of plasma-derived essential PUFAs in mammalian brain. J Lipid Res 42:678–685

    PubMed  CAS  Google Scholar 

  • Rintala J, Seemann R, Chandrasekaran K, Rosenberger TA, Chang L, Contreras MA, Rapoport SI, Chang MC (1999) 85 kDa cytosolic phospholipase A2 is a target for chronic lithium in rat brain. Neuroreport 10:3887–3890

    Article  PubMed  CAS  Google Scholar 

  • Robinson PJ, Noronha J, DeGeorge JJ, Freed LM, Nariai T, Rapoport SI (1992) A quantitative method for measuring regional in vivo fatty-acid incorporation into and turnover within brain phospholipids: review and critical analysis. Brain Res Brain Res Rev 17:187–214

    Article  PubMed  CAS  Google Scholar 

  • Serhan CN, Oliw E (2001) Unorthodox routes to prostanoid formation: new twists in cyclooxygenase-initiated pathways. J Clin Invest 107:1481–1489

    Article  PubMed  CAS  Google Scholar 

  • Shimizu T, Wolfe LS (1990) Arachidonic acid cascade and signal transduction. J Neurochem 55:1–15

    Article  PubMed  CAS  Google Scholar 

  • Skipski VP, Good JJ, Barclay M, Reggio RB (1968) Quantitative analysis of simple lipid classes by thin-layer chromatography. Biochim Biophys Acta 152:10–19

    PubMed  CAS  Google Scholar 

  • Washizaki K, Smith QR, Rapoport SI, Purdon AD (1994) Brain arachidonic acid incorporation and precursor pool specific activity during intravenous infusion of unesterified [3H]arachidonate in the anesthetized rat. J Neurochem 63:727–736

    Article  PubMed  CAS  Google Scholar 

  • Weisler RH, Kalali AH, Ketter TA (2004) A multicenter, randomized, double-blind, placebo-controlled trial of extended-release carbamazepine capsules as monotherapy for bipolar disorder patients with manic or mixed episodes. J Clin Psychiatry 65:478–484

    Article  PubMed  CAS  Google Scholar 

  • Weisler RH, Cutler AJ, Ballenger JC, Post RM, Ketter TA (2006) The use of antiepileptic drugs in bipolar disorders: a review based on evidence from controlled trials. CNS Spectr 11:788–799

    PubMed  Google Scholar 

  • Yatham LN, Kennedy SH, O’Donovan C, Parikh SV, Macqueen G, McIntyre RS, Sharma V, Beaulieu S (2006) Canadian Network for Mood and Anxiety Treatments (CANMAT) guidelines for the management of patients with bipolar disorder: update 2007. Bipolar Disord 8:721–739

    Article  PubMed  CAS  Google Scholar 

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Acknowledgment

We would like to thank Dr. Bjornar Hassel for his valuable comments on the study design. This work was entirely supported by the Intramural Research Program of the National Institute on Aging, National Institutes of Health.

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Authors and Affiliations

  1. Brain Physiology and Metabolism Section, National Institute on Aging, National Institutes of Health, Bethesda, MD, 20892, USA

    Ho-Joo Lee, Jagadeesh S. Rao, Lisa Chang, Stanley I. Rapoport & Richard P. Bazinet

  2. Department of Nutritional Sciences, Faculty of Medicine, University of Toronto, FitzGerald Building, 150 College St., Room 306, Toronto, ON, M5S 3E2, Canada

    Richard P. Bazinet

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  1. Ho-Joo Lee
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  2. Jagadeesh S. Rao
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  3. Lisa Chang
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  4. Stanley I. Rapoport
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  5. Richard P. Bazinet
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Correspondence to Richard P. Bazinet.

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Lee, HJ., Rao, J.S., Chang, L. et al. Chronic lamotrigine does not alter the turnover of arachidonic acid within brain phospholipids of the unanesthetized rat: implications for the treatment of bipolar disorder. Psychopharmacology 193, 467–474 (2007). https://doi.org/10.1007/s00213-007-0803-2

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