Issn Print: 0955-8810

Publication Date: 2005/09/01


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B15 AN ANIMAL MODEL FOR ASSESSING THE POTENTIAL ANTIPARKINSONIAN CHARACTERISTICS OF M4 MUSCARINIC ANTAGONISTS: EFFECTS OF THE PARTIALLY SELECTIVE M4 ANTAGONIST TROPICAMIDE

J.D. Salamone; A.J. Betz; P.J. McLaughlin; M. Burgos; K. Ishiwari; S.M. Weber; J. Felsted; C. Brown

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Excerpt

Clinical studies have demonstrated that nonselective muscarinic antagonists have antiparkinsonian and tremorolytic characteristics in humans. These drugs also produce cognitive effects such as impairments in learning, memory or stimulus processing. The muscarinic antagonists that currently are used as antiparkinsonian drugs generally do not show selectivity for distinct subtypes of muscarinic receptors. Nevertheless, neurochemical studies have demonstrated that there are at least five subtypes of muscarinic receptor (M1–M5). Although the precise nature of the neurotransmitter mechanisms related to parkinsonism remains uncertain, a number of investigators have suggested that striatal muscarinic M4 receptors are involved in motor functions related to parkinsonism. One of the tests that is used to assess the antiparkinsonian effects of drugs is tremulous jaw movements in rats. In the present studies the partially selective M4 antagonist tropicamide was assessed for suppression of the tremulous jaw movements induced by the muscarinic agonist pilocarpine and the dopamine antagonist pimozide, and also for the ability to impair visual stimulus detection. Although tropicamide was effective on all tasks, analysis of the dose–response curves indicates that tropicamide was much more potent at suppressing jaw movements (i.e. effective at doses of 0.625–1.25 mg/kg) than it was at impairing visual stimulus detection (i.e. moderately effective only at doses of 10.0–20.0 mg/kg). Preliminary evidence indicates that the nonselective antimuscarinic atropine shows a different pattern of effects. It is possible that the higher relative potency of tropicamide for suppression of jaw movements compared to the impairment of stimulus detection accuracy is related to the partial selectivity of tropicamide for M4 receptors relative to M1 receptors. Tropicamide could be useful for the treatment of parkinsonian tremor in humans. Moreover, this behavioral model could be used to assess novel muscarinic antagonists with higher M4 selectivity for their potential antiparkinsonian effects.
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