Summary
The present study was aimed at clarifying to what extent the hypermotility induced by the uncompetitive N-methyl-D-aspartate (NMDA) antagonist MK-801 depends on dopamine (DA) D-1 compared to D-2 receptor tone. The D-1 receptor antagonist SCH 23390 was found to reduce locomotion to a greater extent in MK-801-treated than in vehicle-treated mice, whereas the reverse appeared to be the case for the DA D-2 receptor antagonist raclopride. In other words, MK-801-induced hyperactivity was more readily antagonized by SCH 23390 than by raclopride and, thus, DA D-1 receptors seem to be more important than D-2 receptors for MK-801-induced hyperactivity. These results are in line with our previous observation that MK-801 generally interacts synergistically with a DA D-1 but not with a D-2 receptor agonist in monoamine-depleted mice. In view of the possible role of deficient glutamatergic neurotransmission in schizophrenia, our findings underline the importance of investigating the efficacy of selective DA D-1 antagonists in this disorder.
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References
Angrist B (1987) Pharmacological models of schizophrenia. In: Henn FA, Delisi LE (eds) Handbook of schizophrenia, vol 2. Neurochemistry and neuropharmacology of schizophrenia. Elsevier, Amsterdam, pp 391–424
Bischoff S, Heinrich M, Sonntag JM, Krauss J (1986) The D1 dopamine receptor antagonist SCH 23390 also interacts potently with brain serotonin (5-HT2) receptors. Eur J Pharmacol 129: 367–370
Carlsson M, Carlsson A (1989) Dramatic synergism between MK-801 and clonidine with respect to locomotor stimulant effect in monoamine-depleted mice. J Neural Transm 77: 65–71
Carlsson M, Carlsson A (1990) Interactions between glutamatergic and monoaminergic systems within the basal ganglia-implications for schizophrenia and Parkinson's disease. Trends Neurosci 13: 272–276
Clineschmidt BV, Martin GE, Bunting PR, Papp NL (1982a) Central sympathomimetic activity of (+)-5-methyl-10, 11-dihydro-5H-dibenzo (a, d)cyclo-hepten-5, 10-imine (MK-801), a substance with potent anticonvulsant, central sympathomimetic and apparent anxiolytic properties. Drug Dev Res 2: 135–145
Clineschmidt BV, Martin GE, Bunting PR (1982 b) Anticonvulsant activity of (+)-5-methyl-10, 11-dihydro-5H-dibenzo(a, d)cyclohepten-5,10-imine (MK-801), a substance with potent anticonvulsant, central sympathomimetic and apparent anxiolytic properties. Drug Rev Res 2: 123–134
Geyer MA, Swerdlow NR, Mansbach RS, Braff DL (1990) Startle response models of sensorimotor gating and habituation deficits in schizophrenia. Brain Res Bull 25: 485–498
Girault J-A, Halpain S, Greengard P (1990) Excitatory amino acid antagonists and Parkinson's disease. Trends Pharmacol Sci 13: 325–326
Goodwin P, Starr BS, Starr MS (1992) Motor responses to dopamine D1 and D2 agonists in the reserpine-treated mouse are affected differentially by the NMDA receptor antagonist MK-801. J Neural Transm [PD-Sect] 4: 15–26
Halpain S, Girault J-A, Greengard P (1990) Activation of NMDA receptors induces dephosphorylation of DARPP-32 in rat striatal slices. Nature 343: 369–371
Hyttel J, Larsen J-J, Christensen AV, Arnt J (1985) Receptor-binding profiles of neuroleptics. In: Casey DE, Chase TN, Christensen AV, Gerlach J (eds) Dyskinesia — research and treatment. Springer, Berlin Heidelberg New York Tokyo, pp 9–18 (Psychopharmacology [Suppl 2])
Köhler C, Hall H, Ögren S-O, Gawell L (1985) Specific in vitro and in vivo binding of3H-raclopride. Biochem Pharmacol 34: 2251–2259
Liljequist S, Ossowska K, Grabowska-Andén M, Andén N-E (1991) Effect of the NMDA receptor antagonist, MK-801, on locomotor activity and on the metabolism of dopamine in various brain areas of mice. Eur J Pharmacol 195: 55–61
Martin GE, Papp NL (1984) Blockade of MK-801 induced ipsiversive turning in 6-OHDA lesioned rats by α-1-adrenoceptor antagonists. Pharmacol Biochem Behav 20: 893–897
Morelli M, Di Chiara G (1990) MK-801 potentiates dopaminergic D1 but reduces D2 responses in the 6-hydroxydopamine model of Parkinson's disease. Eur J Pharmacol 182: 611–612
Schmidt WJ (1986) Intrastriatal injection of DL-2-amino-5-phosphonovaleric acid (AP-5) induces sniffing stereotypy that is antagonized by haloperidol and clozapine. Psychopharmacology 90: 123–130
Svensson A, Carlsson M (1992) Injection of the competitive NMDA receptor antagonist AP-5 into the nucleus accumbens of monoamine-depleted mice induces pronounced locomotor stimulation. Neuropharmacology 31: 513–518
Svensson A, Carlsson A, Carlsson ML (1992) Differential locomotor interactions between dopamine D1/D2 receptor agonists and the NMDA antagonist dizocilpine in monoamine-depleted mice. J Neural Transm [Gen Sect] 90: 199–217
Tiedtke PI, Bischoff C, Schmidt WJ (1990) MK-801-induced stereotypy and its antagonism by neuroleptic drugs. J Neural Transm [GenSect] 81: 173–182
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Martin, P., Svensson, A., Carlsson, A. et al. On the roles of dopamine D-1 vs. D-2 receptors for the hyperactivity response elicited by MK-801. J. Neural Transmission 95, 113–121 (1994). https://doi.org/10.1007/BF01276430
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DOI: https://doi.org/10.1007/BF01276430