β‐ADRENOCEPTOR ANTAGONISTS INHIBIT THE BEHAVIOURAL RESPONSES OF RATS TO INCREASED BRAIN 5‐HYDROXYTRYPTAMINE

Abstract

1 The effect of various β-adrenoceptor blocking agents on the 5-hydroxytryptamine (5-HT)-induced hyperactivity response produced in rats by administration of tranylcypromine (10 mg/kg i.p.) followed by L-tryptophan (50 mg/kg i.p.) has been investigated. 2 (±)-Alprenolol, (±)-timolol, (+)-sotalol, (±)-pindolol (all at 40 mg/kg) all inhibited the hyperactivity response to some degree when given 45 min before the tranylcypromine, as did (±)-oxprenolol when given after the L-tryptophan. 3 β-Adrenoceptor antagonists that are not found in the brain in appreciable amount after peripheral injection, (+)-atenolol, (±)-practolol, (+)-labetalol and (+)-acebutalol, did not inhibit the 5-HT-mediated behaviour. 4 Neither the β-selective drug (±)-metoprolol, nor the β₂-selective drug (±)-butoxamine inhibited the behavioural response. 5 The drugs that blocked the 5-HT-mediated behaviour did not alter brain 5-HT concentrations, synthesis rate or the accumulation of 5-HT following tranylcypromine/L-tryptophan. However, they did inhibit the hyperactivity produced by the suggested 5-HT agonist, 5-methoxy N,N-dimethyltrypt-amine, indicating that the β-adrenoceptor blocking drugs were inhibiting the post-synaptic 5-HT-mediated response. 6 Circling produced by methamphetamine (3 mg/kg) in unilateral nigro-striatal lesioned rats was not altered by alprenolol, sotalol, pindolol or metaprolol, indicating that these drugs do not alter dopamine-mediated behaviour. 7 It is concluded that non-selective (fi_x and p₂) adrenoceptor antagonists which have a high brain/ blood ratio following their peripheral injection, block 5-HT-mediated behavioural responses in the rat.