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The relationship between sedation and pinna reflex inhibition has been measured for a range of centrally acting drugs. Ability to abolish the pinna reflex was not related to sedative activity as assessed by a behavioural method. Thus, at equisedative doses, diazepam, haloperidol, mianserin, prazosin and indoramin failed to abolish the pinna reflex while phenobarbitone and chlorpromazine caused partial- and clonidine complete-inhibition. At the ED50 for pinna reflex inhibition, guanabenz and guanfacine were significantly less sedative than clonidine. Mepyramine, yohimbine, RS-21361, idazoxan and phenylephrine produced little or no sedation and did not inhibit the reflex. When these agents (except for guanabenz and guanfacine) were tested for their ability to prevent clonidine-induced pinna reflex inhibition, all except the drugs with alpha 2-adrenoceptor antagonist activity were inactive. The potency order of the active agents was idazoxan greater than yohimbine greater than RS-21361 = mianserin. Antagonism of clonidine-induced pinna reflex inhibition may therefore prove to be a useful quantitative model for assessing the central potency of alpha 2-adrenoceptor antagonists.

In the mouse, central noradrenaline receptor stimulation by clonidine, or intracerebroventricular injection of noradrenaline or alpha-methylnoradrenaline, caused marked enhancement of the locomotor stimulant effects of dexamphetamine in doses that were without effect when given alone. A minimally locomotor-stimulant dose of apomorphine reduced the effect of dexamphetamine. Pimozide and phenoxybenzamine each virtually abolished locomotor stimulation after dexamphetamine, while FLA63 caused significant reduction. Phenoxybenzamine also abolished the enhancement by clonidine. The intensity of the dexamphetamine effect was dose-related, while in the case of apomorphine the duration rather than the intensity was related to the dose administered. Clonidine potentiated apomorphine locomotor stimulation; following this drug combination, the nature of the movements more closely resembled those seen after dexamphetamine. The results suggest the involvement of both noradrenaline and dopamine in the dexamphetamine response.

Effects of agents with selectivity for the alpha1- or alpha2-adrenoceptor have been investigated on the head twitches induced by 5-HT injected into the cerebral ventricles in the mouse. Alpha-adrenoceptor agonists inhibited head-twitching with a rank order of potency: guanabenz, clonidine, phenylephrine, methoxamine. The antagonists yohimbine and piperoxane, potentiated the head-twitch frequency. These results suggest that there may be an involvement of an alpha2-adrenoceptor. Small doses of phenylephrine (s.c.) potentiated the head-twitch. Methoxamine, injected intracerebroventricularly potentiated the head-twitch only when alpha2-adrenoceptors were blocked by a small dose of yohimbine. Prazosin and thymoxamine inhibited the head-twitch, suggesting that alpha1-adrenoceptors also modulate this phenomenon. Yohimbine and phenylephrine increased the incidence of spontaneous head-twitches. A tonic noradrenergic input may be necessary for the occurrence of the head-twitch induced by 5-HT.

The kynurenine pathway metabolites kynurenine, 3-hydroxykynurenine and xanthurenic acid have been tested against 5-hydroxytryptamine (5-HT) and 5-hydroxytryptophan (5-HTP)-induced head twitches in the mouse in a dose-range of 0.5--5.0 mg/kg. Kynurenine and 3-hydroxykynurenine were highly active. Low doses caused marked potentiation of the twitch response to both 5-HT and 5-HTP with increased toxicity of 5-HT. High doses caused antagonism of both responses. Xanthurenic acid was inactive over the same dose range. The effects of kynurenine could not be duplicated in the guinea-pig ileum. The relevance of these results to the involvement of kynurenine pathway metabolites in depressive illness is discussed.

The effects on 18 items of dexamphetamine-induced behaviour of increasing the ratio of dopaminergic to noradrenergic activity have been investigated in mice. The dopamine-beta-oxidase inhibitor bis-(4-methyl-1-homopiperazinyl-thiocarbonyl)-disulfide (Fla 63) produced varying degrees of reduction in the intensity of all items except raised body position, which was enhanced. Apomorphine alone induced compulsive gnawing and increased locomotor activity but produced long-lasting suppression of these and certain other items induced by dexamphetamine. Vocalisation, touch and startle responses and stereotyped sniffing were, however, unaffected while compulsive grooming and elevated body position were enhanced. The results are discussed in the context of the relative contribution of noradrenergic and dopaminergic mechanisms to the behavioural effects of dexamphetamine.

1. At an ambient temperature of 20 degrees C, intraventricular injection of noradrenaline in the mouse resulted in hypothermia accompanied by a fall in metabolic rate and by cutaneous vasodilatation. Subcutaneous injection of noradrenaline resulted in hyperthermia with raised metabolic rate and cutaneous vasodilatation.2. The hypothermia and fall in oxygen consumption rate following intraventricular noradrenaline were prevented by pre-treatment with subcutaneous propranolol, while the cutaneous vasodilatation was un-affected. However, the effects of subcutaneously injected noradrenaline were completely abolished by subcutaneous propranolol. Intraventricular propranolol did not modify the hypothermic effect of intraventricular noradrenaline.3. The direction of the effect on body temperature of intraventricular noradrenaline was dependent upon ambient temperature; hypothermia occurring at low (15 degrees C) and hyperthermia at high (36 degrees C) ambient temperatures. However, when the possibility of any peripheral action of noradrenaline escaping into the systemic circulation was prevented by prior subcutaneous injection of propranolol, significant hypothermia could be detected at temperatures as high as 32 degrees C.4. The possibility that the effects of intraventricular noradrenaline could be due to complete abolition of central temperature regulation was further excluded by the occurrence of thermal salivation in all animals during experiments performed at 36 degrees C.5. It is suggested that, in the mouse, the hypothermic actions of intraventricular noradrenaline are due to a central effect, while its hyperthermic effects at high ambient temperature are due to escape of noradrenaline into the peripheral circulation. The hypothermia could be the result of selective activation of central heat loss mechanisms.6. Intraventricular noradrenaline was without effect on brain plasma-space although exposure to 100% oxygen caused a detectable fall.