The effects of putative 5-hydroxytryptamine antagonists on the behaviour produced by administration of tranylcypromine and L-tryptophan or tranylcypromine and L-DOPA to rats

Abstract

1 The putative 5-hydroxytryptamine (5-HT) receptor blocking drugs methysergide (10 mg/kg) and methergoline (5 mg/kg) were found to abolish some components of the hyperactivity syndrome, including head weaving and forepaw treading, which follow administration to rats of tranylcypromine (20 mg/kg) and L-tryptophan (100 mg/kg). Hyperactivity and hyper-reactivity were potentiated with a resultant increase in automated locomotor activity counts. In contrast (-)-propranolol (20 mg/kg) inhibited all features of the syndrome. The same results were obtained with these drugs when the behaviour was elicited by p-chloroamphetamine (10 mg/kg) or by tranylcypromine and tryptamine (10 mg/kg). 2 Methysergide and methergoline had similar effects on the syndrome produced by tranylcypromine and L-DOPA (50 mg/kg) whereas propranolol was without effect. 3 None of the putative 5-HT receptor antagonists affected brain 5-HT turnover as assessed by rate of accumulation of 5-HT following monoamine oxidase inhibition with tranylcypromine. 4 Microinjections of 5,7-dihydroxytryptamine into the spinal cord resulted in a 70% fall in cord 5-HT concentrations without an effect on brain 5-HT concentrations. The behavioural response to the putative 5-HT receptor agonist, 5-methoxy N,N-dimethyltryptamine (2 mg/kg), was potentiated in these animals suggesting that 5-HT receptors become supersensitive on denervation, and that some components of the behavioural syndrome are mediated by spinal cord 5-HT receptors. 5 Pretreatment with alpha-methyl p-tyrosine (2 X 200 mg/kg) delayed the onset of all components of the behaviour elicited by tranylcypromine/L-tryptophan by 60 min, indicating an involvement of catecholamines in the syndrome. 6 p-Chloroamphetamine-induced 5-HT depletion had no effect on any component of the tranylcypromine-L-DOPA behaviour.