Some biochemical and behavioural correlates of a possible animal model of human hyperkinetic syndromes

Unanesthetized cats, with and without chlorpromazine pretreatment, were infused i.v. with 250 μCi of [³H]tyrosine at the rate of 125 μCi/h. The caudate nucleus of animals pretreated with chlorpromazine was then perfused with Locke's solution using a push-pull cannula. Basic and acidic [³H]catechols in either the perfusate or whole-caudate homogenates were determined by differential elution from alumina columns and liquid scintillation. Chlorpromazine pretreatment, 10 mg/kg i.p., increased the incorporation of [³H] label into the basic catechol pool of the caudate but did not affect the incorporation of [³H] into the acidic catechol pool. The release of basic and acidic catechols, from the caudate, during the first 60 min perfusion period was extremely small. Atropine, but not dexamphetamine nor d-tubocurarine, 1 mg/ml added to the perfusion fluid, significantly increased the release of basic [³H]catechols. Local stimulation during perfusion with either Locke's solution, dexamphetamine or atropine, did not increase the amounts of either basic or acidic [³H]catechols in the perfusate. With the addition fo d-tubocurarine, stimulation produced on the average a 6-fold increase in the amount of [³H]catechols without a significant increase in acidic catechols. The application of d-tubocurarine, 2.4-10 μg, unilaterally, in the nucleus caudatus putamen of rats produced choreiform activity characterized by involuntary movements of the contralateral forelimb, contralateral rotation of the head, facial grimacing and teeth chattering. These effects were blocked by intraperitoneal doses of either haloperidol or chlorpromazine, and intrastriatal injections of neostigmine. It is suggested that the choreiform activity in the rat could be due to an inappropriate increased release of catecholamines in the striatum as evidenced by the increased release of basic [³H]catechols from the caudate nucleus of the cat. The limited pharmacological and biochemical data in human hyperkinetic syndromes correlate quite well with data derived from this investigation and suggest that the d-tubocurarine-induced choreiform activity in the rat may represent at least the beginning of a workable animal model of human hyperkinetic disorders.