Abstract
Rationale
Available neurochemical probes that lower brain dopamine (DA) levels in man are limited by their tolerability and efficacy. For instance, the acute lowering of brain tyrosine is well tolerated, but only modestly lowers brain DA levels. Modification of tyrosine depletion to robustly lower DA levels would provide a superior research probe.
Objectives
The objective of this study was to determine whether the subthreshold stimulation of presynaptic DA receptors would potentiate tyrosine depletion-induced effects on extracellular DA levels in the medial prefrontal cortex (MPFC) and striatum of the rat.
Methods
We administered quinpirole, a predominantly DA type 2 (D2R) receptor agonist, into the MPFC and striatum by reverse dialysis. A tyrosine- and phenylalanine-free neutral amino acid mixture [NAA(−)] IP was used to lower brain tyrosine levels. DA levels in the microdialysate were measured by HPLC with electrochemical detection.
Results
Quinpirole dose-dependently lowered DA levels in MPFC as well as in the striatum. NAA(−) alone transiently lowered DA levels (80 % baseline) in the striatum, but had no effect in MPFC. The co-administration of NAA(−) and a subthreshold concentration of quinpirole (6.25 nM) lowered DA levels (50 % baseline) in both the MPFC and striatum. This effect was blocked by the mixed D2R/D3R antagonist haloperidol at IP doses that on their own did not affect DA levels (10.0 nmol/kg in the MPFC and 0.10 nmol/kg in the striatum).
Conclusions
Pharmacological stimulation of inhibitory D2R receptors during tyrosine depletion markedly lowers the extracellular DA levels in the MPFC and striatum. The data suggest that combining tyrosine depletion with a low dose of a DA agonist should robustly lower brain regional DA levels in man.
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References
Abi-Dargham A, Rodenhiser J, Printz D, Zea-Ponce Y, Gil R, Kegeles LS, Weiss R, Cooper TB, Mann JJ, Van Heertum RL, Gorman JM, Laruelle M (2000) Increased baseline occupancy of D2 receptors by dopamine in schizophrenia. Proc Natl Acad Sci U S A 97:8104–8109
Adachi Y, Uchihashi Y, Watanabe K, Satoh T (2000) Halothane anesthesia decreases the extracellular level of dopamine in rat striatum: a microdialysis study in vivo. J Anesth 14:82–90
Angrist B, Rotrosen J, Gershon S (1980) Responses to apomorphine, amphetamine, and neuroleptics in schizophrenic subjects. Psychopharmacology (Berlin) 67:31–38
Anzalone A, Lizardi-Ortiz JE, Ramos M, De MC, Hopf FW, Iaccarino C, Halbout B, Jacobsen J, Kinoshita C, Welter M, Caron MG, Bonci A, Sulzer D, Borrelli E (2012) Dual control of dopamine synthesis and release by presynaptic and postsynaptic dopamine D2 receptors. J Neurosci 32:9023–9034
Argiolas A, Fadda F, Melis MR, Serra G, Gessa GL (1979) Chronic haloperidol causes persistent increase in 3,4-dihydroxyphenylacetic acid (DOPAC) concentration in the substantia nigra but not in the ventral tegmental area. Brain Res 175:178–182
Bannon MJ, Bunney EB, Roth RH (1981a) Mesocortical dopamine neurons: rapid transmitter turnover compared to other brain catecholamine systems. Brain Res 218:376–382
Bannon MJ, Michaud RL, Roth RH (1981b) Mesocortical dopamine neurons: lack of autoreceptors modulating dopamine synthesis. Mol Pharmacol 19:270–275
Bannon MJ, Reinhard JF Jr, Bunney EB, Roth RH (1982) Unique response to antipsychotic drugs is due to absence of terminal autoreceptors in mesocortical dopamine neurones. Nature 296:444–446
Bardo MT, Bowling SL, Pierce RC (1990) Changes in locomotion and dopamine neurotransmission following amphetamine, haloperidol, and exposure to novel environmental stimuli. Psychopharmacology (Berlin) 101:338–343
Bean AJ, During MJ, Roth RH (1990) Effects of dopamine autoreceptor stimulation on the release of colocalized transmitters: in vivo release of dopamine and neurotensin from rat prefrontal cortex. Neurosci Lett 108:143–148
Best JA, Nijhout HF, Reed MC (2009) Homeostatic mechanisms in dopamine synthesis and release: a mathematical model. Theor Biol Med Model 6:21
Biggio G, Porceddu ML, Gessa GL (1976) Decrease of homovanillic, dihydroxyphenylacetic acid and cyclic-adenosine-3′,5′-monophosphate content in the rat caudate nucleus induced by the acute administration of an aminoacid mixture lacking tyrosine and phenylalanine. J Neurochem 26:1253–1255
Bongiovanni R, Kyser AN, Jaskiw GE (2012) Tyrosine depletion lowers in vivo DOPA synthesis in ventral hippocampus. Eur J Pharmacol 696:70–76
Bongiovanni R, Newbould E, Jaskiw GE (2008) Tyrosine depletion lowers dopamine synthesis and desipramine-induced prefrontal cortex catecholamine levels. Brain Res 1190:39–48
Bradberry CW, Karasic DH, Deutch AY, Roth RH (1989) Regionally-specific alterations in mesotelencephalic dopamine synthesis in diabetic rats: association with precursor tyrosine. J Neural Transm 78:221–229
Budygin EA, Gainetdinov RR, Kilpatrick MR, Rayevsky KS, Mannisto PT, Wightman RM (1999) Effect of tolcapone, a catechol-O-methyltransferase inhibitor, on striatal dopaminergic transmission during blockade of dopamine uptake. Eur J Pharmacol 370:125–131
Cartier EA, Parra LA, Baust TB, Quiroz M, Salazar G, Faundez V, Egana L, Torres GE (2010) A biochemical and functional protein complex involving dopamine synthesis and transport into synaptic vesicles. J Biol Chem 285:1957–1966
Cass WA, Gerhardt GA (1995) In vivo assessment of dopamine uptake in rat medial prefrontal cortex: comparison with dorsal striatum and nucleus accumbens. J Neurochem 65:201–207
Chiodo LA, Bannon MJ, Grace AA, Roth RH, Bunney BS (1984) Evidence for the absence of impulse-regulating somatodendritic and synthesis-modulating nerve terminal autoreceptors on subpopulations of mesocortical dopamine neurons. Neuroscience 12:1–16
Ciliax BJ, Heilman C, Demchyshyn LL, Pristupa ZB, Ince E, Hersch SM, Niznik HB, Levey AI (1995) The dopamine transporter: immunochemical characterization and localization in brain. J Neurosci 15:1714–1723
de La Fuente-Fernandez, Lim AS, Sossi V, Holden JE, Calne DB, Ruth TJ, Stoessl AJ (2001) Apomorphine-induced changes in synaptic dopamine levels: positron emission tomography evidence for presynaptic inhibition. J Cereb Blood Flow Metab 21:1151–1159
de Lange EC, de Boer AG, Breimer DD (2000) Methodological issues in microdialysis sampling for pharmacokinetic studies. Adv Drug Deliv Rev 45:125–148
Delanoy RL, Hunter GD, Dunn AJ (1982) Catecholamine metabolism in brain slices. Determination of relevant precursor pool and the effects of elevated K+. Biochem Pharmacol 31:3289–3296
Devoto P, Flore G, Pani L, Gessa GL (2001) Evidence for co-release of noradrenaline and dopamine from noradrenergic neurons in the cerebral cortex. Mol Psychiatry 6:657–664
Diaz J, Pilon C, Le Foll B, Gros C, Triller A, Schwartz JC, Sokoloff P (2000) Dopamine D3 receptors expressed by all mesencephalic dopamine neurons. J Neurosci 20:8677–8684
Ellis KA, Mehta MA, Naga Venkatesha Murthy PJ, McTavish SF, Nathan PJ, Grasby PM (2007) Tyrosine depletion alters cortical and limbic blood flow but does not modulate spatial working memory performance or task-related blood flow in humans. Hum Brain Mapp 28:1136–1149
Engelman K, Horwitz D, Jequier E, Sjoerdsma A (1968) Biochemical and pharmacologic effects of alpha-methyltyrosine in man. J Clin Invest 47:577–594
Fadda F, Gessa GL, Marcou M, Mosca E, Rossetti Z (1984) Evidence for dopamine autoreceptors in mesocortical dopamine neurons. Brain Res 293:67–72
Favard C, Simon A, Vigny A, Nguyen-Legros J (1990) Ultrastructural evidence for a close relationship between dopamine cell processes and blood capillary walls in Macaca monkey and rat retina. Brain Res 523:127–133
Fernstrom MH, Fernstrom JD (1995) Acute tyrosine depletion reduces tyrosine hydroxylation rate in rat central nervous system. Life Sci 57:97–102
Flietstra RJ, Levant B (1998) Comparison of D2 and D3 dopamine receptor affinity of dopaminergic compounds in rat brain. Life Sci 62:1825–1831
Freeman KA, Tallarida RJ (1994) A quantitative study of dopamine control in the rat striatum. J Pharmacol Exp Ther 268:629–638
Galloway MP, Wolf ME, Roth RH (1986) Regulation of dopamine synthesis in the medial prefrontal cortex is mediated by release modulating autoreceptors: studies in vivo. J Pharmacol Exp Ther 236:689–698
Garris PA, Wightman RM (1994) Different kinetics govern dopaminergic transmission in the amygdala, prefrontal cortex, and striatum: an in vivo voltammetric study. J Neurosci 14:442–450
Gehlert DR, Gackenheimer SL, Seeman P, Schaus J (1992) Autoradiographic localization of [3H]quinpirole binding to dopamine D2 and D3 receptors in rat brain. Eur J Pharmacol 211:189–194
Gijsman HJ, Scarna A, Harmer CJ, McTavish SB, Odontiadis J, Cowen PJ, Goodwin GM (2002) A dose-finding study on the effects of branch chain amino acids on surrogate markers of brain dopamine function. Psychopharmacology (Berlin) 160:192–197
Harmer CJ, McTavish SF, Clark L, Goodwin GM, Cowen PJ (2001) Tyrosine depletion attenuates dopamine function in healthy volunteers. Psychopharmacology (Berlin) 154:105–111
Harrison BJ, Olver JS, Norman TR, Burrows GD, Wesnes KA, Nathan PJ (2004) Selective effects of acute serotonin and catecholamine depletion on memory in healthy women. J Psychopharmacol 18:32–40
Ikeda M, Fahien LA, Udenfriend S (1966) A kinetic study of bovine adrenal tyrosine hydroxylase. J Biol Chem 241:4452–4456
Imperato A, Di Chiara G (1988) Effects of locally applied D-1 and D-2 receptor agonists and antagonists studied with brain dialysis. Eur J Pharmacol 156:385–393
Iuvone PM, Dunn AJ (1986) Tyrosine hydroxylase activation in mesocortical 3,4-dihydroxyphenylethylamine neurons following footshock. J Neurochem 47:837–844
Jaskiw GE, Bongiovanni R (2004) Brain tyrosine depletion attenuates haloperidol-induced striatal dopamine release in vivo and augments haloperidol-induced catalepsy in the rat. Psychopharmacology (Berlin) 172:100–107
Jaskiw GE, Karoum F, Freed WJ, Phillips I, Kleinman JE, Weinberger DR (1990) Effect of ibotenic acid lesions of the medial prefrontal cortex on amphetamine-induced locomotion and regional brain catecholamine concentrations in the rat. Brain Res 534:263–272
Jaskiw GE, Kirkbride B, Bongiovanni R (2006) In rats chronically treated with clozapine, tyrosine depletion attenuates the clozapine-induced in vivo increase in prefrontal cortex dopamine and norepinephrine levels. Psychopharmacology (Berlin) 185:416–422
Jaskiw GE, Kirkbride B, Newbould E, Young D, Durkalski V, Bongiovanni R (2005) Clozapine-induced dopamine release in the medial prefrontal cortex is augmented by a moderate concentration of locally administered tyrosine but attenuated by high tyrosine concentrations or by tyrosine depletion. Psychopharmacology (Berlin) 179:713–724
Jaskiw GE, Newbould E, Bongiovanni R (2008a) Gamma-butyrolactone-induced dopamine accumulation in prefrontal cortex is affected by tyrosine availability. Eur J Pharmacol 589:106–109
Jaskiw GE, Newbould E, Bongiovanni R (2008b) Tyrosine availability modulates potassium-induced striatal catecholamine efflux in vivo. Brain Res 1209:74–84
Kaenmaki M, Tammimaki A, Myohanen T, Pakarinen K, Amberg C, Karayiorgou M, Gogos JA, Mannisto PT (2010) Quantitative role of COMT in dopamine clearance in the prefrontal cortex of freely moving mice. J Neurochem 114:1745–1755
Kapatos G, Zigmond M (1977) Dopamine biosynthesis from l-tyrosine and l-phenylalanine in rat brain synaptosomes: preferential use of newly accumulated precursors. J Neurochem 28:1109–1119
Kaufman S, Kaufman EE (1985) Tyrosine Hydroxylase. In: Blakley RL, Benkovic SJ (eds) Chemistry and biochemistry of the pterins. Wiley, New York, pp 251–352
Kilts CD, Anderson CM, Ely TD, Nishita JK (1987) Absence of synthesis-modulating nerve terminal autoreceptors on mesoamygdaloid and other mesolimbic dopamine neuronal populations. J Neurosci 7:3961–3975
Kuczenski RT, Mandell AJ (1972) Regulatory properties of soluble and particulate rat brain tyrosine hydroxylase. J Biol Chem 247:3114–3122
Kurata K, Shibata R (1990) Biphasic effect of locally applied apomorphine and 2,3,4,5-tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine on the release of striatal dopamine investigated by means of brain dialysis. Neurosci Lett 117:264–268
Levant B, Grigoriadis DE, De Souza EB (1995) Relative affinities of dopaminergic drugs at dopamine D2 and D3 receptors. Eur J Pharmacol 278:243–247
Levesque D, Diaz J, Pilon C, Martres MP, Giros B, Souil E, Schott D, Morgat JL, Schwartz JC, Sokoloff P (1992) Identification, characterization, and localization of the dopamine D3 receptor in rat brain using 7-[3H]hydroxy-N,N-di-n-propyl-2-aminotetralin. Proc Natl Acad Sci U S A 89:8155–8159
LeWitt PA, Ondo WG, Van LB, Bottini PB (2009) Open-label study assessment of safety and adverse effects of subcutaneous apomorphine injections in treating “off” episodes in advanced Parkinson disease. Clin Neuropharmacol 32:89–93
Lythe KE, Anderson IM, Deakin JF, Elliott R, Strickland PL (2005) Lack of behavioural effects after acute tyrosine depletion in healthy volunteers. J Psychopharmacol 19:5–11
Mao A, Freeman KA, Tallarida RJ (1996) Transient loss of dopamine autoreceptor control in the presence of highly potent dopamine agonists. Life Sci 59:L317–L324
Masana M, Bortolozzi A, Artigas F (2011) Selective enhancement of mesocortical dopaminergic transmission by noradrenergic drugs: therapeutic opportunities in schizophrenia. Int J Neuropsychopharmacol 14:53–68
McTavish SF, Cowen PJ, Sharp T (1999a) Effect of a tyrosine-free amino acid mixture on regional brain catecholamine synthesis and release. Psychopharmacology (Berlin) 141:182–188
McTavish SF, McPherson MH, Harmer CJ, Clark L, Sharp T, Goodwin GM, Cowen PJ (2001) Antidopaminergic effects of dietary tyrosine depletion in healthy subjects and patients with manic illness. Br J Psychiatry 179:356–360
McTavish SF, McPherson MH, Sharp T, Cowen PJ (1999b) Attenuation of some subjective effects of amphetamine following tyrosine depletion. J Psychopharmacol 13:144–147
Mehta MA, Gumaste D, Montgomery AJ, McTavish SF, Grasby PM (2005) The effects of acute tyrosine and phenylalanine depletion on spatial working memory and planning in healthy volunteers are predicted by changes in striatal dopamine levels. Psychopharmacology (Berlin) 180:654–663
Meller E, Bohmaker K, Namba Y, Friedhoff AJ, Goldstein M (1987) Relationship between receptor occupancy and response at striatal dopamine autoreceptors. Mol Pharmacol 31:592–598
Menniti FS, Diliberto EJ Jr (1989) Newly synthesized dopamine as the precursor for norepinephrine synthesis in bovine adrenomedullary chromaffin cells. J Neurochem 53:890–897
Miller HL, Delgado PL, Salomon RM, Berman R, Krystal JH, Heninger GR, Charney DS (1996) Clinical and biochemical effects of catecholamine depletion on antidepressant-induced remission of depression. Arch Gen Psychiatry 53:117–128
Montgomery AJ, McTavish SF, Cowen PJ, Grasby PM (2003) Reduction of brain dopamine concentration with dietary tyrosine plus phenylalanine depletion: an [11C]raclopride PET study. Am J Psychiatry 160:1887–1889
Neff NH, Wemlinger TA, Duchemin AM, Hadjiconstantinou M (2006) Clozapine modulates aromatic l-amino acid decarboxylase activity in mouse striatum. J Pharmacol Exp Ther 317:480–487
Nord M, Farde L (2011) Antipsychotic occupancy of dopamine receptors in schizophrenia. CNS Neurosci Ther 17:97–103
Palmour RM, Ervin FR, Baker GB, Young SN (1998) An amino acid mixture deficient in phenylalanine and tyrosine reduces cerebrospinal fluid catecholamine metabolites and alcohol consumption in vervet monkeys. Psychopharmacology (Berlin) 136:1–7
Pothos E, Desmond M, Sulzer D (1996) L-3,4-dihydroxyphenylalanine increases the quantal size of exocytotic dopamine release in vitro. J Neurochem 66:629–636
Rodenhuis N, Dijkstra D, de BP, Vermeulen ES, Timmerman W, Wikstrom HV (2000) Dopamine D(2) activity of R-(−)-apomorphine and selected analogs: a microdialysis study. Eur J Pharmacol 387:39–45
Roth RH (1984) CNS dopamine autoreceptors: distribution, pharmacology, and function. Ann N Y Acad Sci 430:27–53
Santiago M, Machado A, Cano J (1993a) Effects of age and dopamine agonists and antagonists on striatal dopamine release in the rat: an in vivo microdialysis study. Mech Ageing Dev 67:261–267
Santiago M, Machado A, Cano J (1993b) Regulation of prefrontal cortical dopamine release by dopamine receptor agonists and antagonists. Eur J Pharmacol 239:83–91
Sarre S, Ebinger G, Michotte Y (1996) Levodopa biotransformation in hemi-Parkinson rats: effect of dopamine receptor agonists and antagonists. Eur J Pharmacol 296:247–260
Stanwood GD, Artymyshyn RP, Kung MP, Kung HF, Lucki I, McGonigle P (2000) Quantitative autoradiographic mapping of rat brain dopamine D3 binding with [(125)I]7-OH-PIPAT: evidence for the presence of D3 receptors on dopaminergic and nondopaminergic cell bodies and terminals. J Pharmacol Exp Ther 295:1223–1231
Starke K, Gothert M, Kilbinger H (1989) Modulation of neurotransmitter release by presynaptic autoreceptors. Physiol Rev 69:864–989
Tam SY, Elsworth JD, Bradberry CW, Roth RH (1990) Mesocortical dopamine neurons: high basal firing rate frequency predicts tyrosine dependence of dopamine synthesis. J Neural Transm 81:97–110
Tanaka T, Vincent SR, Nomikos GG, Fibiger HC (1992) Effect of quinine on autoreceptor-regulated dopamine release in the rat striatum. J Neurochem 59:1640–1645
Tyler CB, Galloway MP (1992) Acute administration of amphetamine: differential regulation of dopamine synthesis in dopamine projection fields. J Pharmacol Exp Ther 261:567–573
Wang J, Lou H, Pedersen CJ, Smith AD, Perez RG (2009) 14-3-3zeta contributes to tyrosine hydroxylase activity in MN9D cells: localization of dopamine regulatory proteins to mitochondria. J Biol Chem 284:14011–14019
Waymire JC, Haycock JW (2002) Lack of regulation of aromatic l-amino acid decarboxylase in intact bovine chromaffin cells. J Neurochem 81:589–593
Westerink BH, De Vries JB (2001) A method to evaluate the diffusion rate of drugs from a microdialysis probe through brain tissue. J Neurosci Methods 109:53–58
Westerink BH, Kawahara Y, De Boer P, Geels C, De Vries JB, Wikstrom HV, Van Kalkeren A, Van Vliet B, Kruse CG, Long SK (2001) Antipsychotic drugs classified by their effects on the release of dopamine and noradrenaline in the prefrontal cortex and striatum. Eur J Pharmacol 412:127–138
Wolf ME, Roth RH (1990) Autoreceptor regulation of dopamine synthesis. Ann N Y Acad Sci 604:323–343, 323–343
Wu Q, Reith ME, Walker QD, Kuhn CM, Carroll FI, Garris PA (2002) Concurrent autoreceptor-mediated control of dopamine release and uptake during neurotransmission: an in vivo voltammetric study. J Neurosci 22:6272–6281
Wurtman RJ, Larin F, Mostafapour S, Fernstrom JD (1974) Brain catechol synthesis: control by brain tyrosine concentration. Science 185:183–184
You ZB, Herrera-Marschitz M, Nylander I, Goiny M, O’Connor WT, Ungerstedt U, Terenius L (1994) The striatonigral dynorphin pathway of the rat studied with in vivo microdialysis—II. Effects of dopamine D1 and D2 receptor agonists. Neuroscience 63:427–434
Zhang H, Sulzer D (2012) Regulation of striatal dopamine release by presynaptic auto- and heteroreceptors. Basal Ganglia 2:5–13
Acknowledgments
This work was funded by MERIT award 1 I01 BX000381-01 from the Medical Research Service of the Department of Veterans Affairs. There are no conflicts of interest.
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Brodnik, Z., Double, M. & Jaskiw, G.E. Presynaptic regulation of extracellular dopamine levels in the medial prefrontal cortex and striatum during tyrosine depletion. Psychopharmacology 227, 363–371 (2013). https://doi.org/10.1007/s00213-013-2977-0
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DOI: https://doi.org/10.1007/s00213-013-2977-0