Abstract
Rationale
We have earlier found that 1) COMT inhibitors did not enhance amphetamine-induced dopamine efflux into striatal extracellular, that 2) they did not increase dopamine levels in striatal tissue and that 3) they did not potentiate amphetamine-induced turning behavior of hemiparkinsonian rats. Further, when COMT knockout mice were challenged with l-dopa or a dopamine transporter (DAT) inhibitor, an accumulation of dopamine occurred and the neurochemical and locomotor effects of l-dopa and GBR 12909 were modified accordingly.
Objective
Since DAT inhibitors and amphetamine apparently have different mechanisms of action, we were interested to see how COMT knockout mice would react to d-amphetamine treatment.
Methods
We measured the effects of d-amphetamine on locomotor activity and on the levels of catecholamines and their metabolites in striatal microdialysis fluid and in striatal, hypothalamic and cortical brain regions of COMT gene disrupted mice. Striatal dopamine receptor binding was also determined.
Results
After d-amphetamine administration, the DOPAC content in homozygous mice was 3-fold in the striatum, 17- to 18-fold in the cortex and 7- to 8-fold in the hypothalamus higher than in wild-type control mice, and there were no indications of genotype×sex interactions. However, the lack of COMT did not potentiate d-amphetamine-induced dopamine levels in brain tissue or in striatal extracellular fluid. d-Amphetamine-induced (10 mg/kg) hyperlocomotion was less suppressed in male COMT knockout mice than in their wild-type counterparts. Striatal dopamine D1 and D2 receptor levels in male mice were not altered by COMT gene disruption.
Conclusions
Changes in COMT activity modulates dopamine metabolism but the behavioral effects of d-amphetamine in male mice only to a small extent, and this action does not seem to depend on the actual extracellular dopamine concentration. Nor is it mediated through compensatory changes in dopamine D1 and D2 receptor levels. In dopaminergic neurons, the contribution of intracellular COMT remains secondary in conditions when dopamine is released by d-amphetamine.
Similar content being viewed by others
References
Andersen PH (1989) The dopamine inhibitor GBR 12909: selectivity and molecular mechanism of action. Eur J Pharmacol 166:493–504
Badiani A, Oates MM, Fraioli S, Browman KE, Ostrander MM, Xue C-J, Wolf M, Robinson TE (2000) Environmental modulation of the responses to amphetamine: dissociation between changes in behavior and changes in dopamine and glutamate overflow in the rat striatal complex. Psychopharmacology 151:166–174
Bossé R, Fumagalli F, Jaber M, Giros B, Gainetdinov R, Wetsel W, Missal C, Caron M (1997) Anterior pituitary hypoplasia and dwarfism in mice lacking the dopamine transporter. Neuron 19:127–138
Budygin EA, Gainetdinov RR, Kilpatrick MR, Rayevsky KS, Männistö 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
Cass WA, Zahniser NR, Flach KA, Gerhardt GA (1993) Clearance of exogenous dopamine in rat dorsal striatum and nucleus accumbens: role of metabolism and effects of locally applied uptake inhibitors. J Neurochem 61:2269–2278
Crawford CA, Drago J, Watson JB, Levine MS (1997) Effects of repeated amphetamine treatment on the locomotor activity of the dopamine D1A-deficient mouse. Neuroreport 8:2523–2527
Field KJ, White WJ, Lang CM (1993) Anaesthetic effects of chloral hydrate, pentobarbitone and urethane in adult male rats. Lab Anim 27:258–269
Floor E, Meng L (1996) Amphetamine releases dopamine from synaptic vesicles by dual mechanisms. Neurosci Lett 215:53–56
Franklin KBJ, Paxinos G (1997) The mouse brain in stereotaxic coordinates. Academic Press, San Diego
Gainetdinov RR, Wetsel WC, Jones SR, Levin ED, Jaber M, Caron MG (1999) Role of serotonin in the paradoxical calming effect of psychostimulants on hyperactivity. Science 283:397–401
Gerhardt GA, Ksir C, Pivik C, Dickinson SD, Sabeti J, Zahniser NR (1999) Methodology for coupling local application of dopamine and other chemicals with rapid in vivo electrochemical recordings in freely-moving rats. J Neurosci Meth 87:67–76
Giros B, Jaber M, Jones SR, Wightman RM, Caron MG (1996) Hyperlocomotion and indifference to cocaine and amphetamine in mice lacking the dopamine transporter. Nature 379:606–612
Gogos JA, Morgan M, Luine V, Santha M, Ogawa S, Pfaff D, Karayiorgou M (1998) Catechol-O-methyltransferase-deficient mice exhibit sexually dimorphic changes in catecholamine levels and behavior. Proc Natl Acad Sci USA 95:9991–9996
Huotari M, Gainetdinov R, Männistö PT (1999) Microdialysis studies on the action of tolcapone on pharmacologically-elevated extracellular dopamine levels in conscious rats. Pharmacol Toxicol 85:233–238
Huotari M, Gogos JA, Karayiorgou M, Koponen O, Forsberg M, Raasmaja A, Hyttinen J, Männistö PT (2002a) Brain catecholamine metabolism in catechol-O-methyltransferase (COMT)-deficient mice. Eur J Neurosci 15:246–256
Huotari M, Santha M, Lucas LR, Karayiorgou M, Gogos JA, Männistö PT (2002b) Effect of dopamine uptake inhibition on brain catecholamine levels and locomotion in catechol-O-methyltransferase (COMT) disrupted mice. J Pharmacol Exp Ther 303:1309–1316
Jones SR, Gainetdinov RR, Jaber M, Giros B, Wightman MR, Caron MG (1998a) Profound neuronal plasticity in response to inactivation of the dopamine transporter. Proc Natl Acad Sci USA 95:4029–4034
Jones SR, Gainetdinov RR, Wightman RM, Caron MG (1998b) Mechanisms of amphetamine action revealed in mice lacking the dopamine transporter. J Neurosci 18:1979–1986
Karoum F, Chrapusta SJ, Egan MF (1994) 3-Methoxytyramine is the major metabolite of released dopamine in the rat frontal cortex: reassessment of the effects of antipsychotics on the dynamics of dopamine release and metabolism in the frontal cortex, nucleus accumbens, and striatum by a simple two-pool model. J Neurochem 63:972–979
Kopin IJ (1985) Catecholamine metabolism: basic aspects and clinical significance. Pharmacol Rev 37:333–364
Liang NY, Rutledge CO (1982a) Comparison of the release of [3H]dopamine from isolated corpus striatum by amphetamine, fenfluramine and unlabelled dopamine. Biochem Pharmacol 31:983–992
Liang NY, Rutledge CO (1982b) Evidence for carrier-mediated efflux of dopamine from corpus striatum. Biochem Pharmacol 31:2479–2484
Männistö PT, Kaakkola S (1999) Catechol-O-methyltransferase (COMT): biochemistry, molecular biology, pharmacology, and clinical efficacy of the new selective COMT inhibitors. Pharmacol Rev 51:593–628
Matsumoto M, Weickert CS, Akil M, Lipska BK, Hyde TM, Herman MM, Kleinman JE, Weinberger DR (2003) Catechol O-methyltransferase mRNA expression in human and rat brain: evidence for a role in cortical neuronal function. Neuroscience 116:127–137
Meister B, Elde R (1993) Dopamine tranporter mRNA in neurons of the rat hypothalamus. Mol Neuroendocrinol 58:388–395
Peters JL, Michael AC (2000) Changes in the kinetics of dopamine release and uptake have differential effects on the spatial distribution of extracellular dopamine concentration in rat striatum. J Neurochem 74:1563–1573
Pierce RC, Kalivas PW (1997) Repeated cocaine modifies the mechanism by which amphetamine releases dopamine. J Neurosci 17:3254–3261
Rahman S, McBride WJ (2000) Feedback control of mesolimbic somatodendritic dopamine release in rat brain. J Neurochem 74:684–692
Raiteri M, Cerrito F, Cervoni AM, Levi G (1979) Dopamine can be released by two mechanisms differentially affected by the dopamine transport inhibitor nomifensine. J Pharmacol Exp Ther 208:195–202
Sealfon SC, Olanow CW (2000) Dopamine receptors: from structure to behavior. Trends Neurosci 23:S34–S40
Seiden LS, Sabol KE, Ricaurte GA (1993) Amphetamine: effects on catecholamine systems and behavior. Annu Rev Pharmacol Toxicol 33:639–677
Sesack SR, Hawrylak VA, Matus C, Guido MA, Levey AI (1998) Dopamine axon varicosities in the prelimbic division of the rat prefrontal cortex exhibit sparse immunoreactivity for the dopamine transporter. J Neurosci 18:2697–2708
Spielewoy C, Biala G, Roubert C, Hamon M, Betancur C, Giros B (2001) Hypolocomotor effects of acute and daily d-amphetamine in mice lacking the dopamine transporter. Psychopharmacology 159:2–9
Sulzer D, Rayport S (1990) Amphetamine and other psychostimulants reduce pH gradients in midbrain dopaminergic neurons and chromaffin granules: a mechanism of action. Neuron 5:797–808
Sulzer D, Chen TK, Lau YY, Kristensen H, Rayport S, Ewing A (1995) Amphetamine redistributes dopamine from synaptic vesicles to the cytosol and promotes reverse transport. J Neurosci 15:4102–4108
Törnwall M, Männistö PT (1993) Effects of three types of catechol O-methylation inhibitors on l-3,4-dihydroxyphenylalanine-induced circling behaviour in rats. Eur J Pharmacol 250:77–84
Törnwall M, Tuomainen P, Männistö PT (1993) Modulation of rat brain endogenous dopamine metabolism by new inhibitors of catechol O-methyltransferase. Eur J Pharmacol 239:39–45
Tuomainen P, Törnwall M, Männistö PT (1996) Minor effect of tolcapone, a catechol-O-methyltransferase inhibitor, on extracellular dopamine levels modified by amphetamine or pargyline: a microdialysis study in anaesthetized rats. Pharmacol Toxicol 78:392–396
Xu C, Shen R-Y (2001) Amphetamine normalizes the electrical activity of dopamine neurons in the ventral tegmental area following prenatal ethanol exposure. J Pharmacol Exp Ther 297:746–752
Zaczek R, Culp S, De Souza EB (1991a) Interactions of [3H]amphetamine with rat brain synaptosomes. II. Active transport. J Pharmacol Exp Ther 257:830–835
Zaczek R, Culp S, Goldberg H, McCann DJ, De Souza EB (1991b) Interactions of [3H]amphetamine with rat brain synaptosomes. I. Saturable sequestration. J Pharmacol Exp Ther 257:820–829
Acknowledgements
The skilful technical assistance of Pirjo Hänninen and Kati Puputti is gratefully acknowledged. We are grateful to Dr Ewen MacDonald for linguistic advice. Support for this work was provided in part by Academy of Finland (no. 50324), The National Technology Agency (TEKES, no. 40160/99), the Whitehall Foundation (M.K.) and the Patterson Trust (M.K.).
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Huotari, M., García-Horsman, J.A., Karayiorgou, M. et al. d-Amphetamine responses in catechol-O-methyltransferase (COMT) disrupted mice. Psychopharmacology 172, 1–10 (2004). https://doi.org/10.1007/s00213-003-1627-3
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00213-003-1627-3