Y-maze behavior in the mouse after morphine or an enkephalin analog

The mechanism of clonidine-induced hyperphagia and weight gain in monkeys was studied in 11 Stumptail macaques. Clonidine induced a significant increase in food intake over baseline levels and a significant weight gain after the 3-day treatment period. Both changes induced by clonidine were antagonized by the ₂-noradrenergic antagonist yohimbine, but not by prazosin, an ₂-noradrenergic antagonist. These results suggest that clonidine-induced hyperphagia and weight gain in monkeys are mediated through ₂-noradrenergic receptors.     

Changes in noradrenergic neuroendocrine responses following repeated seizures and the mechanism of action of ECT

To investigate the mechanism of action of ECT in depression, functional changes in central noradrenergic systems, resulting from a series of electroshock- or photic-induced seizures have been evaluated in baboons. The plasma growth hormone (GH) response to IV infusion of an ₂-noradrenergic agonist clonidine (0.02 mg/kg) or a ₂-adrenergic antagonist, ICI 118,551 (0.02 mg/kg) has been measured before, during and up to 15 days after the series of seizures. Electroshock (ECS) or sham ECS was given with standard clinical premedication (atropine, methohexital, suxamethonium and oxygen ventilation) seven times over 15 days. Plasma GH responses were unchanged 24 h after one or seven ECS. An enhanced GH response occurred 7 and 15 days after the seventh ECS. Sham ECS (seven times in 15 days) produced no changes in GH response to clonidine. The plasma GH response to ICI 118,551 was apparently decreased 1 and 7 days after the seventh ECS. Photic seizures were induced seven times in 15 days in baboons which were primed with a subconvulsant dose of d,l-allylglycine (180 mg/kg), but were otherwise drug-free. Plasma GH responses to clonidine were enhanced 1 and 7 days after the seventh photically induced seizure. It is concluded that in the primate there is an enhancement of a central ₂-noradrenergic response during 1–15 days after a sequence of generalised seizures. The time course of this enhancement appears to be influenced by drugs given directly before the seizures.     

Intracerebral injection of different antibodies against endogenous opioids suggest α-neoendorphin participation in control of feeding behaviour

Summary The mechanism of feeding behaviour of rats was examined. We used antibodies to different opioid peptides in order to reduce the tonic activity of various endogenous opioid peptide systems that may underly appetite. Unilateral microinjection of anti--neoendorphin antibodies into various areas of the ventromedial hypothalamus (VMH) inhibited food and water intake up to 45% in deprived animals. Injections outside this area failed to affect feeding. Administration of anti--endorphin antibodies into the VMH moderately attenuated appetite. A considerable decrease of food and water intake was observed only upon injection of this antibody into the nucleus periventricularis hypothalami, a region generally believed to be involved with feeding. A marginal reduction of appetite was observed with anti-dynorphin antibodies injected into the VMH. These data may suggest that -neoendorphin is involved in the control of food and water intake in the VMH.     

Clonidine-induced inhibition of sympathetic nerve activity: No indication for a central presynaptic or an indirect sympathomimetic mode of action

Summary The effects of clonidine on blood pressure, heart rate, contractile state of the nictitating membranes, spontaneous sympathetic nerve activity and response of sympathetic nerves to hypothalamic stimulation were compared in normal anaesthetized cats and in anaesthetized cats pretreated with reserpine and -methyl-p-tyrosine. The pretreatment lowered the noradrenaline content of various parts of the brain to less than 5 ng/g, i.e. to less than 1–3% of that of the controls. Under the conditions of this severe noradrenaline depletion, blood pressure and heart rate were low and spontaneous sympathetic nerve activity consisted of continous, high-amplitude discharges which contrasted with the low-amplitude bursts of activity—synchronous with the respiration—of the controls. In contrast to the controls, clonidine did not lower blood pressure and heart rate in the cats with noradrenaline depletion; however, the clonidine-induced contractions of the nictitating membranes were of similar magnitude and duration in both groups of animals. The efficacy of clonidine in reducing or abolishing spontaneous sympathetic nerve activity and in inhibiting the response of sympathetic nerves to hypothalamic stimulation was equal in controls and in cats with noradrenaline depletion, its potency being 3-fold higher in the former. The results indicate a direct stimulation of -adrenoceptors by clonidine both in the periphery and in the central nervous system and make it unlikely that the central effect of clonidine on blood pressure is due to a release of noradrenaline from central adrenergic neurones. It is further concluded that clonidine activates an adrenergic mechanism in the central nervous system by stimulation of postsynaptic -adrenoceptors. The inhibition of such a mechanism as a consequence of a diminished noradrenaline release due to stimulation of presynaptic -adrenoceptors—as proposed from in vitro experiments—seems to be of no importance for the central effect of clonidine on sympathetic nerve activity and blood pressure.Preliminary results have been presented at the 15th Spring Meeting of the German Pharmacological Society in Mainz (Haeusler, 1974a).     

Cardiovascular effects of alpha-adrenergic drugs: Differences between clonidine and guanabenz

Summary Guanabenz induced a pressor effect in pithed rats through postsynaptic ₂-adrenoceptors whereas clonidine activated both vascular ₁ and ₂-adrenoceptors. Previous treatment with prazosin, and ₁-antagonist, or depletion of the noradrenergic stores by reserpine produced supersensitivity to the pressor response to clondine only, probably through postsynaptic ₁-adrenoceptors.The hypotension and bradycardia developed in normotensive rats after intravenous guanabenz administration were abolished by prazosin, whereas the central effects of clonidine were antagonized by both prazosin and yohimbine.Selective destruction of central noradrenergic neurons by [N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine] (DSP 4) or reserpine plus blockade of catecholamine synthesis by -methyl-p-tyrosine abolished the hypotension and bradycardia produced by guanabenz but merely reduced the bradycardia from clonidine.The present results suggest that, in rats, guanabenz is a selective stimulant of central -autoadrenoceptors antagonized by prazosin whereas at a vascular level guanabenz preferentially activates -adrenoceptors antagonized by yohimbine. The differences observed between the mechanisms by which guanabenz and clonidine produce their central cardiovascular responses might be attributed to their acting on different nuclei.     

Depression of exploratory activity by clonidine in rats as a model for the detection of relative pre- and postsynaptic central noradrenergic receptor selectivity of α-adrenolytic drugs

Summary The effects of various -adrenoceptorblocking drugs on the depression of exploratory activity (ambulation and rearing) induced by 0.1 mg/kg i.p. clonidine were investigated in the rat. In parallel experiments, the effects of the same drugs on pre- and postsynaptic -receptors were determined in vitro (field-stimulated cortex slices and isolated vas deferens of the rat, respectively). Tolazoline, esproquine, yohimbine and piperoxan distinctly antagonized the inhibition of exploration produced by clonidine. All these drugs were found to possess relatively higher selectivity for the presynaptic -receptors, as judged by the ratios of the concentrations inducing a 50% increase in field-stimulated ³H-noradrenaline-overflow and the concentrations required to shift the EC₅₀ for the antagonism of noradrenaline-induced contractions of the vas deferens to the right by a factor of 2 (pA₂, ratio <1): In contrast, phentolamine and phenoxybenzamine which showed preferential postsynaptic -receptor blocking activity (ratio>1), potentiated rather than antagonized the effects of clonidine. Mianserin, although preferentially blocking the postsynaptic receptors, had no effect on clonidine-induced hypoactivity up to the high dose of 100 mg/kg i.p., probably because of its additional NA-uptake-inhibiting properties. The antagonism of clonidine by the selective presynaptic -receptor blockers was observed within a limited dose-range. Increasing the doses above an optimal level, which varied from one compound to another, resulted in a decrease in the effect. It is suggested that this phenomenon reflects the counter-balancing postsynaptic -adrenoceptor blockade occuring at higher concentrations of these drugs. In general, the results show a fairly good correlation between antagonism of clonidine in vivo and preferential blockade of presynaptic -receptors in vitro. Clonidine-induced suppression of exploration therefore seems to be a valuable model for the investigation of drug interactions with -adrenergic receptors in the central nervous system.These results were presented in part at the Spring Meeting of German Pharmacological Society, Mainz, 16–18 March, 1977     

Effects of α2-receptors

Summary Clonidine has a dual action on naloxone-precipitated morphine withdrawal symptoms in rats: a suppressive action on body shakes and body weight loss and a potentiating action on jumping and aggression.It has been suggested that this potentiating, excitatory action is mediated by ₁-receptors. More specific ₂-agonists therefore should have a less excitatory effect on the latter symptoms. This hypothesis has been studied in rats dependent on morphine. Withdrawal was precipitated using naloxone. Prior to naloxone the ₂-agonists clonidine, guanfacine, azepexole, BHT-920, UK 14304 or the centrally acting ₁-agonist ST 587 were administered. All ₂-agonists but not the ₁-agonist potentiated the jumping and decreased body shakes and body weight loss.The effects of clonidine and azepexole were characterized pharmacologically using the -antagonists yohimbine and prazosin. Jumping potentiated by clonidine was antagonized by yohimbine whereas prazosin had no effect. Azepexole induced jumping was decreased by yohimbine both with respect to incidence and frequency, whereas prazosin only lowered the frequency. The suppressive actions of clonidine and azepexole on body shakes were reversed by yohimbine and not by prazosin. The data indicate that the potentiation of jumping by ₂-agonists as well as the suppression of body shakes in morphine withdrawal behaviour is mediated by ₂-receptors.     

Acute effects of two tetrahydrocannabinols (Δ9-THC and Δ8-THC) on water intake in water deprived rats: Implications for behavioral studies on marijuana compounds

Water intake was studied in water deprived albino rats at various time intervals after injections of two tetrahydrocannabinols ( ⁹-THC and ⁸-THC) and solvents. The dose levels used were: 1.25, 2.5, and 5.0 mg/kg of ⁹-THC and 2.5, 5.0, and 10.0 mg/kg of ⁸-THC. The results show a clear, dose dependent inhibitory effect on water intake as compared to the controls.Reduced intake of food was seen at 1 day post injection. This effect was, however, significant only for the groups treated with 5.0 and 10.0 mg/kg of ⁸-THC. A decreased body weight was also recorded after the drug treatment, especially with ⁸-THC. With respect to cannabis-induced vocalization the data suggest an increased possibility of its appearance with increasing dosages of THC.     

Effects of clonidine and some α-adrenergic antagonists alone and in combination on schedule-controlled behavior in pigeons and mice

Schedule-controlled responding was maintained under multiple fixed-interval, fixed-ratio schedules in pigeons and single fixed-ratio schedules in mice. In pigeons, clonidine, an ₂-receptor agonist, produced dose-related decreases in responding under both fixed-interval and fixedratio schedules; fixed-interval responding was decreased at a lower dose than fixed-ratio responding. Low to intermediate doses of yohimbine, an ₂-receptor antagonist, increased responding under the fixed-interval schedule without appreciably affecting responding under the fixed-ratio schedule; higher doses decreased responding under both schedules. In mice, both clonidine and yohimbine produced dose-related decreases in responding under fixed-ratio schedules. Decreases in response rates produced by clonidine were antagonized by low to intermediate doses of yohimbine. Decreases in response rates under fixed-ratio schedules produced by yohimbine were antagonized only slightly, if at all, by clonidine. Under the fixed-interval schedule, clonidine potentiated the response-rate increasing effects of intermediate doses of yohimbine and slightly antagonized the rate-decreasing effects. Although some effects of clonidine were antagonized by yohimbine, at no dose combination did performances completely resemble control performances. Prazosin, an ₁-receptor antagonist, was ineffective both when administered alone and as an antagonist of the effects of clonidine. The behavioral effects of clonidine appeared to be mediated by ₂ rather than ₁ receptors. Additionally, yohimbine appears to have significant behavioral effects other than ₂-antagonist actions.     

Absence of an effect of mianserin on the actions of clonidine or methyldopa in hypertensive patients

Summary The concurrent administration of tricyclic antidepressants has been shown in man to result in a clinically significant impairment of the antihypertensive effect of clonidine. This interaction is thought to be related to competition for central ₂ receptors where clonidine acts as an agonist and the tricyclics act as antagonists. Although it seems to cause less cardiovascular effects than tricyclic antidepressants, the tetracyclic antidepressant, mianserin also has been reported to be an receptor antagonist and may, therefore, also interfere with the antihypertensive activity of centrally-acting drugs. This study investigates the effects of acute and chronic mianserin administration in patients with essential hypertension established on long term treatment with either clonidine or methyldopa. The first dose of mianserin was not associated with an increase in blood pressure and during a further two weeks of mianserin therapy there were no significant alterations in blood pressure, supine or erect. Similarly, mianserin did not alter heart rate either after acute or after chronic administration. Mianserin itself had a sedative effect but there was no interference with the sedation attributable to clonidine or methyldopa. Mianserin caused no reduction in salivary flow and did not influence the reduced saliva production caused by clonidine. Both clonidine and methyldopa are associated with a reduction in sympathetic outflow but there was no evidence in this study of any further change in plasma noradrenaline or 24 h urinary catecholamine excretion. This study demonstrates that if mianserin is given acutely or chronically, it does not interfere with the effects of the centrally acting antihypertensive drugs, clonidine and methyldopa. Mianserin may therefore be a suitable antidepressant for patients receiving these antihypertensive agents if drug treatment for depression is indicated.