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 a-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.

BEHAVIOURAL CHANGES INDUCED BY N,N‐DIMETHYLTRYPTAMINE IN RODENTS

“…While methysergide and methergoline effectively blocked the behavioural changes, cyproheptadine, cinanserin and the peripheral 5-HT antagonist, xylamidine tosylate, were without activity (Clineschmidt, McGuffin & Pflueger, 1977 (Deakin & Green, 1978). The differing anatomical basis for the behavioural components may explain the differential effects of various 5-HT antagonists.…”

“…The differing anatomical basis for the behavioural components may explain the differential effects of various 5-HT antagonists. Thus, Deakin & Green (1978) have proposed that the ability of methergoline and methysergide to block some components of the behavioural syndrome while enhancing hyperactivity may be because these drugs do not block supra-spinal 5-HT receptors. Indeed, electrophysiological experiments indicate that many 5-HT responses are unaffected by methergoline or methysergide (Haigler & Aghajanian, 1977).…”

“…& Domino, 1974;Domino, 1975 and references therein). The DMT-induced syndrome does contain many of the behavioural components seen following the administration of other presumed 5-HT agonists, L-tryptophan, tryptamine, a-methyltryptamine, 5-methoxy-N,N-dimethyltryptamine, p-chloro-amphetamine or quipazine all in the presence of a MAOI (Grahame- Smith, 1971;Foldes & Costa, 1973;Jacobs, 1974Jacobs, , 1976Crow & Deakin, 1977;Deakin & Green, 1978;Sloviter, Drust & Connor, 1978;Marsden, 1978).…”

The Influence of L‐tryptophan and Monoamine Oxidase Inhibitors on Catecholamine Metabolism in Rat Brain

“…Deakin & Green (1978) also demonstrated the inhibition of part of the syndrome by the 5-HT antagonists methergoline and methysergide. In addition they found that propranolol, when given before tryptophan and tranylcypromine, blocked all components of the syndrome.…”

“…Deakin & Green (1978) made specific chemical lesions of the 5-HT neurones in the spinal cord, and administered a 5-HT receptor agonist when sufficient time had elapsed for supersensitivity of the receptors to develop. Because headweaving, forepaw treading and limb abduction were increased in these animals they concluded that these facets of the syndrome were spinal while hyperactivity and hyper-reactivity were central in origin.…”