The effects on central dopamine function of chronic L-dopa (methyl ester hydrochloride) treatment of mice.
Mice were treated for 28 days with drinking water containing L-DOPA methyl ester hydrochloride (DME) plus carbidopa, carbidopa alone, or with the vehicle. All mice were then given the vehicle for 1 day and behavioural and biochemical assessments made on the 29th day. On average, mice consumed between 181 and 302 mg/kg of DME (expressed as the base) each day. In behavioural experiments DME- and carbidopa-treated mice were subsensitive to the locomotor stimulating effects of apomorphine, after their pretreatment with reserpine plus alpha-methyl-p-tyrosine to remove endogenous stores of dopamine and to stop its synthesis. Even mice pretreated for only one day with chronic DME or carbidopa displayed some subsensitivity to apomorphine challenge, but the effect was more marked the longer the chronic treatment. Other mice were chronically treated for 28 days with alpha-methylDOPA or vehicle, and these mice when challenged with apomorphine after dopamine depletion (as described above), were also markedly subsensitive to the locomotor activating effects of apomorphine. There were no changes in sensitivity of drug-treated mice to the hypothermic effects of apomorphine, to the stereotypy-inducing effects of apomorphine or d-amphetamine, or to the locomotor activating effects of L-DOPA itself or to bromocriptine. There were, however, some changes in the basal grooming behaviour of both DME- and carbidopa-treated mice, and in their response to SKF38393 challenge. Striatal binding studies with [3H]-spiperone and [3H]-SCH23390 indicated that there were no marked changes in Kd or Bmax of either D-1 or D-2 receptors.(ABSTRACT TRUNCATED AT 250 WORDS)
Tabar
J
J
Department of Pharmacology, University of Sydney, New South Wales, Australia.
Hashizume
M
M
Cook
C J
CJ
Beart
P M
PM
Jackson
D M
DM
D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; D000818:Animals; D001058:Apomorphine / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects*; D001552:Benzazepines / Q000494:pharmacology; D001831:Body Temperature / Q000187:drug effects; D001971:Bromocriptine / Q000494:pharmacology; D003913:Dextroamphetamine / Q000494:pharmacology; D004298:Dopamine / Q000502:physiology*; D007980:Levodopa / Q000031:analogs & derivatives* / Q000494:pharmacology; D051379:Mice; D008815:Mice, Inbred Strains; D009043:Motor Activity / Q000187:drug effects; D011954:Receptors, Dopamine / Q000187:drug effects; D013239:Stereotyped Behavior / Q000187:drug effects
D001552:Benzazepines; D011954:Receptors, Dopamine; D001971:Bromocriptine; D007980:Levodopa; D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; C035420:levodopa methyl ester; D001058:Apomorphine; D003913:Dextroamphetamine; D004298:Dopamine