Abstract
Dopamine (DA) acts through five receptor subtypes (D1–D5). We compared expression levels and distribution patterns of all DA mRNA receptors in the spinal cord of wild-type (WT) and loss of function D3 receptor knockout (D3KO) animals. D3 mRNA expression was increased in D3KO, but no D3 receptor protein was associated with cell membranes, supporting the previously reported lack of function. In contrast, mRNA expression levels and distribution patterns of D1, D2, D4, and D5 receptors were similar between WT and D3KO animals. We conclude that D3KO spinal neurons do not compensate for the loss of function of the D3 receptor with changes in the other DA receptor subtypes. This supports use of D3KO animals as a model to provide insight into D3 receptor dysfunction in the spinal cord.
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Abbreviations
- D3KO:
-
D3 receptor knockout
- DA:
-
Dopamine
- GAPDH:
-
Glyceraldehyde 3-phosphate dehydrogenase
- ISH:
-
In situ hybridization
- PBST:
-
PBS containing 0.3% Triton X-100
- PCR:
-
Polymerase chain reaction
- WT:
-
Wild-type
References
Accili D, Fishburn CS, Drago J, Steiner H, Lachowicz JE, Park BH, Gauda EB, Lee EJ, Cool MH, Sibley DR, Gerfen CR, Westphal H, Fuchs S (1996) A targeted mutation of the D3 dopamine receptor gene is associated with hyperactivity in mice. Proc Natl Acad Sci USA 93:1945–1949
Asico LD, Ladines C, Fuchs S, Accili D, Carey RM, Semeraro C, Pocchiari F, Felder RA, Eisner GM, Jose PA (1998) Disruption of the dopamine D3 receptor gene produces renin-dependent hypertension. J Clin Invest 102:493–498
Bara-Jimenez W, Aksu M, Graham B, Sato S, Hallett M (2000) Periodic limb movements in sleep: state-dependent excitability of the spinal flexor reflex. Neurology 54:1609–1616
Barriere G, Cazalets JR, Bioulac B, Tison F, Ghorayeb I (2005) The restless legs syndrome. Prog Neurobiol 77:139–165
Barriere G, Mellen N, Cazalets JR (2004) Neuromodulation of the locomotor network by dopamine in the isolated spinal cord of newborn rat. Eur J Neurosci 19:1325–1335
Branchi I, Ricceri L (2002) Transgenic and knock-out mouse pups: the growing need for behavioral analysis. Genes, brain, and behavior 1:135–141
Carp JS, Anderson RJ (1982) Dopamine receptor-mediated depression of spinal monosynaptic transmission. Brain Res 242:247–254
Centonze D, Grande C, Usiello A, Gubellini P, Erbs E, Martin AB, Pisani A, Tognazzi N, Bernardi G, Moratalla R, Borrelli E, Calabresi P (2003) Receptor subtypes involved in the presynaptic and postsynaptic actions of dopamine on striatal interneurons. J Neurosci 23:6245–6254
Clemens S, Hochman S (2004) Conversion of the modulatory actions of dopamine on spinal reflexes from depression to facilitation in D3 receptor knock-out mice. J Neurosci 24:11337–11345
Clemens S, Sawchuk MA, Hochman S (2005) Reversal of the circadian expression of tyrosine-hydroxylase but not nitric oxide synthase levels in the spinal cord of D3 receptor knockout mice. Neuroscience 133:353–357
Clemens S, Rye D, Hochman S (2006) Restless legs syndrome: revisiting the dopamine hypothesis from the spinal cord perspective. Neurology 67:125–130
Drago J, Padungchaichot P, Accili D, Fuchs S (1998) Dopamine receptors and dopamine transporter in brain function and addictive behaviors: insights from targeted mouse mutants. Dev Neurosci 20:188–203
Drago J, McColl CD, Horne MK, Finkelstein DI, Ross SA (2003) Neuronal nicotinic receptors: insights gained from gene knockout and knockin mutant mice. Cell Mol Life Sci 60:1267–1280
Gajendiran M, Seth P, Ganguly DK (1996) Involvement of the presynaptic dopamine D2 receptor in the depression of spinal reflex by apomorphine. Neuroreport 7:513–516
Gan L, Falzone TL, Zhang K, Rubinstein M, Baldessarini RJ, Tarazi FI (2004) Enhanced expression of dopamine D(1) and glutamate NMDA receptors in dopamine D(4) receptor knockout mice. J Mol Neurosci 22:167–178
Goody RJ, Oakley SM, Filliol D, Kieffer BL, Kitchen I (2002) Quantitative autoradiographic mapping of opioid receptors in the brain of delta-opioid receptor gene knockout mice. Brain Res 945:9–19
Han P, Nakanishi ST, Tran MA, Whelan PJ (2007) Dopaminergic modulation of spinal neuronal excitability. J Neurosci 27:13192–13204
Hannon JP, Petrucci C, Fehlmann D, Viollet C, Epelbaum J, Hoyer D (2002) Somatostatin sst2 receptor knock-out mice: localisation of sst1–5 receptor mRNA and binding in mouse brain by semi-quantitative RT-PCR, in situ hybridisation histochemistry and receptor autoradiography. Neuropharmacology 42:396–413
Hollon TR, Bek MJ, Lachowicz JE, Ariano MA, Mezey E, Ramachandran R, Wersinger SR, Soares-da-Silva P, Liu ZF, Grinberg A, Drago J, Young WS III, Westphal H, Jose PA, Sibley DR (2002) Mice lacking D5 dopamine receptors have increased sympathetic tone and are hypertensive. J Neurosci 22:10801–10810
Jaber M, Robinson SW, Missale C, Caron MG (1996) Dopamine receptors and brain function. Neuropharmacology 35:1503–1519
Jackson DM, Westlind-Danielsson A (1994) Dopamine receptors: molecular biology, biochemistry and behavioural aspects. Pharmacol Ther 64:291–369
Joyce JN (1983) Multiple dopamine receptors and behavior. Neurosci Biobehav Rev 7:227–259
Jung MY, Skryabin BV, Arai M, Abbondanzo S, Fu D, Brosius J, Robakis NK, Polites HG, Pintar JE, Schmauss C (1999) Potentiation of the D2 mutant motor phenotype in mice lacking dopamine D2 and D3 receptors. Neuroscience 91:911–924
Karasinska JM, George SR, El-Ghundi M, Fletcher PJ, O’Dowd BF (2000) Modification of dopamine D(1) receptor knockout phenotype in mice lacking both dopamine D(1) and D(3) receptors. Eur J Pharmacol 399:171–181
Karper PE, De la Rosa H, Newman ER, Krall CM, Nazarian A, McDougall SA, Crawford CA (2002) Role of D1-like receptors in amphetamine-induced behavioral sensitization: a study using D1A receptor knockout mice. Psychopharmacology (Berl) 159:407–414
Kobayashi M, Iaccarino C, Saiardi A, Heidt V, Bozzi Y, Picetti R, Vitale C, Westphal H, Drago J, Borrelli E (2004) Simultaneous absence of dopamine D1 and D2 receptor-mediated signaling is lethal in mice. Proc Natl Acad Sci USA 101:11465–11470
Law AK, Pencea V, Buck CR, Luskin MB (1999) Neurogenesis and neuronal migration in the neonatal rat forebrain anterior subventricular zone do not require GFAP-positive astrocytes. Dev Biol 216:622–634
Leggio GM, Micale V, Drago F (2008) Increased sensitivity to antidepressants of D3 dopamine receptor-deficient mice in the forced swim test (FST). Eur Neuropsychopharmacol 18:271–277
Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods 25:402–408
McDougall SA, Reichel CM, Cyr MC, Karper PE, Nazarian A, Crawford CA (2005) Importance of D(1) receptors for associative components of amphetamine-induced behavioral sensitization and conditioned activity: a study using D(1) receptor knockout mice. Psychopharmacology (Berl) 183:20–30
Missale C, Nash SR, Robinson SW, Jaber M, Caron MG (1998) Dopamine receptors: from structure to function. Physiol Rev 78:189–225
Montplaisir J, Nicolas A, Denesle R, Gomez-Mancilla B (1999) Restless legs syndrome improved by pramipexole: a double-blind randomized trial. Neurology 52:938–943
Montplaisir J, Denesle R, Petit D (2000) Pramipexole in the treatment of restless legs syndrome: a follow-up study. Eur J Neurol 7(Suppl 1):27–31
Odin P, Mrowka M, Shing M (2002) Restless legs syndrome. Eur J Neurol 9(Suppl 3):59–67
Ondo WG, Zhao HR, Le WD (2007) Animal models of restless legs syndrome. Sleep Med 8:344–348
Park Y, Ho IK, Fan LW, Loh HH, Ko KH (2001) Region specific increase of dopamine receptor D1/D2 mRNA expression in the brain of mu-opioid receptor knockout mice. Brain Res 894:311–315
Pich EM, Epping-Jordan MP (1998) Transgenic mice in drug dependence research. Annals of medicine 30:390–396
Steiner H, Fuchs S, Accili D (1998) D3 Dopamine receptor-deficient mouse: evidence for reduced anxiety. Physiol Behav 63:137–141
Tien LT, Park Y, Fan LW, Ma T, Loh HH, Ho IK (2003) Increased dopamine D2 receptor binding and enhanced apomorphine-induced locomotor activity in mu-opioid receptor knockout mice. Brain Res Bull 61:109–115
Tran AH, Tamura R, Uwano T, Kobayashi T, Katsuki M, Ono T (2005) Dopamine D1 receptors involved in locomotor activity and accumbens neural responses to prediction of reward associated with place. Proc Natl Acad Sci USA 102:2117–2122
Zhao H, Zhu W, Pan T, Xie W, Zhang A, Ondo WG, Le W (2007) Spinal cord dopamine receptor expression and function in mice with 6-OHDA lesion of the A11 nucleus and dietary iron deprivation. J Neurosci Res 85:1065–1076
Zhu H, Clemens S, Sawchuk M, Hochman S (2007) Expression and distribution of all dopamine receptor subtypes (D1–D5) in the mouse lumbar spinal cord: a real-time polymerase chain reaction and non-autoradiographic in situ hybridization study. Neuroscience 149:885–897
Zucconi M, Ferini-Strambi L (2004) Epidemiology and clinical findings of restless legs syndrome. Sleep Med 5:293–299
Acknowledgments
Funding for this study was awarded from the National Institutes of Health, NINDS, Grant NS045248. All experimental procedures complied with the “Principles of animal care,” publication No. 86-23, revised 1985 by the NIH, and the Emory Institutional Animal Care and Use Committee. We thank Dr Dapeng Cui for assistance with real-time PCR.
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Zhu, H., Clemens, S., Sawchuk, M. et al. Unaltered D1, D2, D4, and D5 dopamine receptor mRNA expression and distribution in the spinal cord of the D3 receptor knockout mouse. J Comp Physiol A 194, 957–962 (2008). https://doi.org/10.1007/s00359-008-0368-5
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DOI: https://doi.org/10.1007/s00359-008-0368-5