ISSN:
1432-2072
Keywords:
Adenylate cyclase
;
Apomorphine
;
Apomorphine esters
;
Dopamine
;
Mouse
;
Pharmacokinetics
;
Stereotyped behavior
Source:
Springer Online Journal Archives 1860-2000
Topics:
Medicine
Notes:
Abstract Stereotyped climbing and clinging responses of the mouse to apomorphine or its ester prodrug, O,O′-diisobutyrylapomorphine were evaluated. Acute doses of the ester up to 0.3 mmoles/kg were tolerated without apparent ill effects. Both aporphines produced dose-dependent behavioral responses that were blocked by neuroleptics. The duration of action of the ester was much greater than that of apomorphine. When maximal initial behavior during the first hour was evaluated, low equimolar doses of apomorphine and the ester were similar in potency; in contrast, the total behavioral response to larger doses of the ester was greater than to apomorphine, evidently reflecting the greater duration of action of the ester. Behavioral responses to both agents during the first hour decreased at doses above 0.1 mmoles/kg. Oxidized or O-methylated apomorphine did not antagonize the behavioral effects of apomorphine. Systemic injection of apomorphine or diisobutyrylapomorphine led to detectable levels of free apomorphine as estimated by a sensitive and selective fluorimetric assay. The time-course and magnitude of the behavioral effects of both agents corresponded closely with brain levels of apomorphine. Apomorphine and dopamine (but not diisobutyrylapomorphine) stimulated adenylate cyclase activity in mouse striatal homogenates—an effect antagonized by neuroleptic drugs but not propranolol. Apomorphine exerted a biphasic effect on the cyclase in vitro and increased cyclic AMP levels in the striatum in vivo. The prolonged activity of apomorphine esters as depot prodrug agonists of putative dopaminergic mechanisms in the brain may provide clinically desirable characteristics.
Type of Medium:
Electronic Resource
URL:
http://dx.doi.org/10.1007/BF00426693
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