Is it possible to predict the activity of a new antidepressant in animals with simple psychopharmacological tests?
Behavioural tests for predicting antidepressant activity in the animal provide a closer approximation than other tests of states of depression in man but are often long and costly to perform (except the behavioural despair test). The tests proposed here presuppose a pharmacological interaction (except the Porsolt test) but are simple enough to allow screening: included are antagonism of reserpine hypothermia, ptosis and akinesia; antagonism of effects induced by oxotremorine; antagonism of high-dose apomorphine; and potentiation of yohimbine toxicity. In combination with the study of motor activity in the mouse, these tests allow assessment of the specificity of antidepressant activity by establishing a ratio between the "antidepressant" dose and the "stimulant" or "sedative" dose. It can be predicted that a substance will be antidepressant and sedative or stimulant at the same dose if the ratio is close to 1; if the ratio is less than 1, at antidepressant doses the substance will be very sedative or stimulant according to the case. The specificity of the tests discussed can be debatable. Antagonism of reserpine-induced hypothermia indicates substances with direct or indirect beta-mimetic activity, ptosis antagonism, substances with alpha-adrenergic (not antidepressants) or serotoninergic (possibly antidepressants) activity; and akinesia antagonism, a direct or indirect dopaminergic activity (sometimes found in antidepressants) with psychostimulant activity. The oxotremorine test is related to the anticholinergic activity of substances, except in the case of hypothermia antagonism. The high-dose apomorphine test seems to be specific for substances inhibiting norepinephrine reuptake. The yohimbine test is simple to carry out, relatively inexpensive and does not fail to screen any molecule known to be effective to-date. The behavioural despair test is a good complement for screening except for drugs having a beta-agonist activity, it appears that this test is dependent on functional relationships between alpha 2 and serotonergic systems.
Department of Pharmacology, Faculty of Medicine, Nantes, France.
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Bourin
D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology; D001058:Apomorphine / Q000037:antagonists & inhibitors; D001522:Behavior, Animal / Q000187:drug effects*; D007035:Hypothermia / Q000188:drug therapy; D009043:Motor Activity / Q000187:drug effects*; D010095:Oxotremorine / Q000037:antagonists & inhibitors; D012110:Reserpine / Q000037:antagonists & inhibitors; D015016:Yohimbine / Q000494:pharmacology
D000928:Antidepressive Agents; D015016:Yohimbine; D010095:Oxotremorine; D012110:Reserpine; D001058:Apomorphine