An antihypokinesic action of alpha2-adrenoceptors upon MPTP-induced behaviour deficits in mice.
The effects of co-administration of either the dopamine precursor, L-Dopa, or the directly-acting, mixed dopamine (DA) agonist, apomorphine, with the alpha-adrenoceptor agonists, clonidine and guanfacine, upon the motor activity of hypoactive L-Dopa-tolerant MPTP-treated C57 BL/6 mice were measured in four experiments. In each case, MPTP (2 x 40 mg/kg, s.c., separated by a 24-hr interval) was administered eight-to-ten weeks before behavioural testing. It was found that clonidine co-administered with L-Dopa (20 mg/kg) restored motor activity in a dose- and parameter-related manner: locomotion and total activity were restored by the 1 mg/kg dose, rearing behaviour by the 0.3 and 1 mg/kg doses. The restorative effects of clonidine (1 mg/kg), co-administered with L-Dopa, were antagonised completely by pretreatment with yohimbine (1 mg/kg), but not by prazosin (1 mg/kg). Guanfacine (1 mg/kg) co-administered with L-Dopa (20 mg/kg) restored locomotor, but not rearing, behaviour in L-Dopa-tolerant MPTP-treated mice. The antikinesic action of guanfacine was antagonised completely by yohimbine (1 mg/kg), but not prazosin (1 mg/kg). Clonidine (1 or 3 mg/kg) co-administered with apomorphine (0.1, 0.3, 1.0 or 3.0 mg/kg), directly-acting DA agonist, did not restore motor behaviour in the hypokinesic L-Dopa-tolerant MPTP-treated mice. Nor did apomorphine, by itself, affect the motor activity of these animals. Neurochemical analysis indicated marked DA, DOPAC and HVA depletions in the striatum, and to a much lesser extent in the frontal cortex, of MPTP-treated mice. The synergistic antiparkinsonian action of clonidine with L-Dopa, but not apomorphine, in hypokinetic MPTP mice for the restoration of responding to a suprathreshold dose of L-Dopa, to which "wearing-off" had been induced previously, is discussed.
Archer
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Department of Psychology, University of Göteborg, Sweden. trevor.archer@psy.gu.se
Fredriksson
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A
D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000818:Animals; D001058:Apomorphine / Q000494:pharmacology; D003000:Clonidine / Q000494:pharmacology; D004298:Dopamine / Q000172:deficiency; D018491:Dopamine Agonists / Q000494:pharmacology* / Q000627:therapeutic use; D004347:Drug Interactions / Q000502:physiology; D004359:Drug Therapy, Combination; D016316:Guanfacine / Q000494:pharmacology; D006719:Homovanillic Acid / Q000378:metabolism; D007980:Levodopa / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017072:Neostriatum / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D020734:Parkinsonian Disorders / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D011224:Prazosin / Q000494:pharmacology; D018341:Receptors, Adrenergic, alpha-2 / Q000187:drug effects* / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology; D015016:Yohimbine / Q000494:pharmacology
D018491:Dopamine Agonists; D018341:Receptors, Adrenergic, alpha-2; D015102:3,4-Dihydroxyphenylacetic Acid; D015016:Yohimbine; D016316:Guanfacine; D007980:Levodopa; D003000:Clonidine; D001058:Apomorphine; D004298:Dopamine; D006719:Homovanillic Acid; D011224:Prazosin