R.J. Boakes

Antagonism of 5-hydroxytryptamine by LSD 25 in the central nervous system: A possible neuronal basis for the actions of LSD 25

1 5‐Hydroxytryptamine (5‐HT), acetylcholine (ACh), noradrenaline (NA), glutamate, d,l‐homocysteic acid (DLH), glycine and γ‐aminobutyric acid (GABA) were applied to single neurones in the brain stem of decerebrate cats by microiontophoresis. The abilities of d‐lysergic acid diethylamide tartrate (LSD 25), methysergide maleate (UML 491) and 2‐bromo‐lysergic acid diethylamide (BOL 148) to antagonize the actions of these compounds were studied. 2 LSD 25 antagonized 5‐HT excitation of single neurones when applied iontophoretically or administered intravenously. LSD 25 also antagonized glutamate excitation of neurones which could be excited by 5‐HT. Inhibitory effects of 5‐HT, the action of glutamate on neurones which could be inhibited by 5‐HT and the actions of all the other compounds tested were unaffected by LSD 25. 3 Iontophoretically applied UML 491 was also a specific antagonist to 5‐HT and glutamate excitation but was less potent than LSD 25, and BOL 148 rarely exhibited antagonism. 4 It is suggested that antagonism to 5‐HT and glutamate excitation of brain stem neurones may be the basis of the psychotomimetic action of LSD 25. It is also suggested that there may be similarities in the mechanisms by which 5‐HT and glutamate produce excitation where they act on the same neurone.

A neuronal basis for the alerting action of (+)‐amphetamine

1 (+)‐Amphetamine mimicked the excitatory and inhibitory actions of (—)‐noradrenaline on single neurones in the brain stem of acute halothane‐anaesthetized rats when these compounds were applied by iontophoresis. (+)‐Amphetamine had no actions on neurones unaffected by (—)‐noradrenaline. 2 These mimicking actions of (+)‐amphetamine could not be observed 20 h after treatment of the animals with reserpine 5 mg/kg. 3 The enzyme inhibitors α‐methyl‐p‐tyrosine and FLA 63 also greatly reduced the number of (—)‐noradrenaline‐mimicking responses to (+)‐amphetamine. 4 In animals pretreated with α‐methyl‐p‐tyrosine, but not in those pretreated with FLA 63, excitatory actions of (+)‐amphetamine on neurones excited by (—)‐noradrenaline could be elicited 45–90 min after systemic injection of l‐DOPA. 5 These results indicate that (+)‐amphetamine can release noradrenaline from presynaptic sites in the brain stem, which may be a basis for its alerting actions.

Actions of noradrenaline, other sympathomimetic amines and antagonists on neurones in the brain stem of the cat

1 The effects of (–)‐noradrenaline ((–)‐NA) and related compounds on brain stem neurones in decerebrate unanaesthetized cats have been investigated using the technique of iontophoretic application from micropipettes. 2 Four types of response to (–)‐NA have been described. These were short lasting inhibition, long lasting inhibition, excitation, and a biphasic response consisting of short lasting inhibition followed by excitation. A variable amount of desensitization of the excitatory response, but not of inhibitory responses, was observed. 3 Experiments in which small currents were used to pass (–)‐NA from pipettes with smaller tips did not lead to any appreciable change in the proportions of neurones excited or inhibited. 4 A variety of sympathomimetic agonists was tested. Short lasting inhibition was less sensitive than excitation to changes in molecular structure. Long lasting inhibition was more sensitive to molecular change and was not mimicked by some of the agonists which mimicked short lasting inhibition. 5 Although agonists without one ring hydroxyl had weaker effects than those with both, compounds in which both ring hydroxyl groups were absent (β‐hydroxyphenylethylamine, ephedrine and amphetamine) mimicked excitation strongly. It is possible that the compounds without both ring hydroxyl groups had some effect other than simple agonistic activity. 6 A dissociation was observed between responses to dopamine and (–)‐NA. p‐Tyramine mimicked dopamine, rather than (–)‐NA. 7 Neither the α‐agonist, phenylephrine nor the β‐agonist, isoprenaline mimicked neuronal responses to (–)‐NA. The α‐antagonists phentolamine and phenoxybenzamine and the β‐antagonists dichloroisoprenaline, propranolol and d(–)‐INPEA and combinations of propranolol with phentolamine or phenoxybenzamine were ineffective in blocking either excitation or inhibition. Thus, the central receptors appear to be different from peripheral α‐ and β‐receptors. 8 The most effective antagonist of excitation was (–)‐α‐methylnoradrenaline. Metaraminol and dihydroergotamine also had some antagonistic activity. None of the compounds tested blocked inhibition. The effects of (–)‐α‐methylnoradrenaline have been discussed in relation to the hypotensive action of α‐methyldopa.

Abnormal behavioural changes associated with vasopressin-induced barrel rotations

Arginine-8-vasopressin (AVP) was injected into the cerebral ventricles of rats in order to characterize the dose-response relations of the convulsant actions of AVP and to obtain a detailed description of other acute behavioural effects. The incidence of barrel rotations, a violent and apparently uncontrolled motor activity during which rats rotate about their long axis, was found to be dose dependent, with a threshold of between 1 and 10 ng per rat. Other behavioural effects of AVP including immobility, titubation, ataxia, backward walking, and inhibition of exploratory activities and of grooming were seen at doses as low as 100 pg. These behavioural effects occurred within 9 min after injection, and thus have the same time course as barrel rotations. These acute actions of AVP may be significant in interpreting the effects of AVP on cognitive processes and memory and should also be taken into consideration in the clinical use of AVP as an anti-amnestic.

INTERACTIONS OF (+)‐AMPHETAMINE AND CHLORPROMAZINE ON NEURONES IN THE LOWER BRAIN STEM OF THE RAT

1 The ability of chlorpromazine to antagonize the effects of iontophoretic application of (+)‐amphetamine to single neurones in the medulla and lower pons of anaesthetized rats has been studied. 2 Chlorpromazine, administered systemically or iontophoretically, consistently and specifically antagonized the excitatory actions of (+)‐amphetamine, but not those of noradrenaline on the same neurone. 3 It is concluded that chlorpromazine reduces the effect of (+)‐amphetamine by a presynaptic mechanism. 4 (+)‐Amphetamine did not mimic the prolonged inhibitory response of some neurones to noradrenaline but often excited these neurones and chlorpromazine blocked these excitatory responses to (+)‐amphetamine.