Effect of chronic clonidine treatment on the turnover of noradrenaline and dopamine in various regions of the rat brain

Summary The turnover of noradrenaline (NA) and dopamine (DA) was estimated in various rat brain regions by measuring the depletion of the amines after inhibition of their biosynthesis by -methyltyrosine. Acute treatment with clonidine (0.1 mg/kg) reduced NA turnover in the brain stem, hypothalamus and rest of the brain but had no effect on DA turnover in the corpus striatum and rest of the brain. After chronic clonidine treatment (0.1 mg/kg, twice daily for 15 days), NA turnover was not affected by an additional injection of clonidine in the brain stem or in the hypothalamus but was still markedly reduced in the rest of the brain. In addition, DA turnover was reduced in the corpus striatum and rest of the brain, an effect which was also observed after a single injection of a high dose of clonidine (1 mg/kg). These findings suggest that a chronic administration of clonidine may cause regionally differential changes in the sensitivity of central NA receptors.     

Effects of various catecholamine receptor antagonists, muscle relaxation and physical hindrance on shuttlebox self-stimulation

Certain drugs, particularly clozapine and clonidine, have been reported to increase selectively the latency to initiate brain stimulation (the ON latency) in a shuttlebox test of self-stimulation, suggesting a preferential attenuation of the "reward" component. The pharmacological selectivity of this reported effect was systematically evaluated. At doses that blocked bar-pressing self-stimulation, metoclopramide (3 mg/kg), prazosin (3 mg/kg) clonidine (0.1mg/kg), clozapine (3 mg/kg)and haloperidol (0.3 mg/kg), all elevated the ON latency to a greater extent than the OFF latency. Methocarbamol (200 mg/kg), and a muscle relaxant, also elevated the ON latency preferentially but the magnitude of this preferential effect was smaller than that produced by the other drugs. A hurdle in the center of the shuttlebox increased the ON and OFF latencies nonselectively. The shuttlebox procedure does not clearly discriminate among various substances that interfere with noradrenergic or dopaminergic neurotransmission, but the common profile produced by the these substances is distinguishable to some degree from simple motor disruption.     

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.     

Clonidine induced hyperphagia and weight gain in monkeys

The effect of the -noradrenergic receptor agonist, clonidine, on food intake and weight was examined in ten adult Stumptail macaque monkeys. An intramuscular injection of 0.1 mg/kg of clonidine HCl for seven consecutive days significantly increased food intake from baseline levels throughout treatment. All but two monkeys gained weight during clonidine treatment with seven animals gaining from 5–15% of their original body weight by the end of 1 week.To whom offprint requests should be sent     

Lipophilicity and brain disposition of clonidine and structurally related imidazolidines

Summary The apparent partition coefficients (P) of clonidine and 27 of its structurally related imidazolidines were determined in the octanol/buffer (pH=7.4) system as a measure of lipophilic behaviour. Lipophilicity of the imidazolidines is limited to the free bases and the principle of additivity is valid for this series of structurally similar compounds.Brain concentrations of clonidine and a number of its derivatives, achieved at the moment of maximal decrease in blood pressure, were determined following intravenous administration to anaesthetized rats. These brain concentrations represent the maximally attainable values. The ratio of log brain concentration/ dose administered intravenously, log (C_brain/C_i.v.), was employed as a measure of the penetration ability of the imidazolidines into the brain. The octanol/buffer (pH=7.4) system proved a satisfactory reference model in order to describe the transport process of the present imidazolidines from the blood to the brain. The penetration ability of these compounds into the brain could be expressed mathematically by a highly significant, parabolic relationship in log P. Ideal lipophilic character for optimal brain concentrations is connected with a log P value of 2.16.     

Clonidine-induced locomotor hyperactivity in rats

Summary The -adrenergic agonist, clonidine, causes sedation in normal rats. The present study demonstrates that clonidine evokes strong locomotor stimulation in rats pretreated with 6-hydroxydopamine plus reserpine. Similar, but less intensive hyperactivity is observed in rats given clonidine after combined pretreatment with 6-hydroxydopamine plus p-chlorophenylalanine plus -methyl-p-tyrosine, or with reserpine plus low doses of yohimbine. The -adrenolytic drugs, phenoxybenzamine, phentolamine and aceperone, as well as high doses of yohimbine, antagonise the clonidine-induced locomotor stimulation; in contrast, the dopamine receptor blocking agents, pimozide and spiroperidol, exert no antagonistic effect. The results indicate that in the brain of normal animals, clonidine predominantly activates presynaptic -adrenoceptors on noradrenergic neurones and thereby induces sedation. After destruction of the noradrenergic fibres by 6-hydroxydopamine plus reserpine, activation of postsynaptic -adrenoceptors prevails so that hyperactivity results.This study was supported by Polish Academy of Sciences (10.4). Preliminary accounts were presented at the Pharmacology Meeting, Hannover, September 14–17, 1976 and at the 1 st Joint Symposium of Hungarian and Polish Pharmacological Societies, Zakopane, October, 13–15, 1976     

Clonidine antinociceptive activity: Effects of drugs influencing central monoaminergic and cholinergic mechanisms in the rat

Summary Clonidine is able to increase the threshold for vocalisation during stimulation and the threshold for vocalisation after withdrawal of stimulus (vocalisation afterdischarge). These effects of clonidine were investigated after treatment of rats with drugs influencing central monoaminergic and cholinergic mechanisms.Chlorpromazine, atropine and p-chlorophenyl-alanine increased the activity of clonidine at both thresholds while phenoxybenzamine and reserpine pretreatment increased the activity at the threshold for vocalisation only.Yohimbine decreased clonidine activity at both thresholds while 5-HTP and -methyl-p-tyrosine decreased the effects at the threshold for vocalisation afterdischarge. Naloxone did not change the activity of clonidine at either pain response studied.It is concluded from the present findings that influence from several neuronal systems modulate the antinociceptive action of clonidine.The inhibition of the medullary nociceptive response after clonidine might be connected to a decreased activity of noradrenergic neurons. Endogenous noradrenaline seems to be of minor importance in mediating this effect. It is moreover shown that decreased cholinergic receptor activity enhances clonidine antinociceptive action on both medullary and diencephalic-rhinencephalic pain responses. The possible involvement of serotonin in these functional responses after clonidine is also discussed.Data from this investigation was presented at the International Narcotic Research Club Conference, Airlie, Va. 1975.     

Studies on the possible contribution of a peripheral presynaptic action of clonidine and dopamine to their vascular effects under in vivo conditions

Summary The functional consequences of drug-induced stimulation under in vivo conditions of -adrenoceptors and dopamine receptors at vascular adrenergic nerve endings (presynaptic receptors) was studied in the autoperfused hindquarters or hindlegs of cats anaesthetized with urethane. The changes in perfusion pressure in response to electrical stimulation of the lumbar sympathetic chain were taken as a measure of noradrenaline release from the vascular adrenergic nerves. Presynaptic inhibitory -adrenoceptors and dopamine receptors were activated by clonidine and dopamine, respectively. According to in vitro experiments these two drugs are more potent stimulants of peripheral presynaptic than postsynaptic receptors. The lowest frequency of stimulation of the lumbar sympathetic chain which yielded a reproducible pressor response was 4 Hz for the autoperfused hindquarters and 1 Hz for the hindlegs. Clonidine was tested over a wide dose range (1–100 g/kg i.v.). A reduction of the stimulation-induced pressor response in the autoperfused hindquarters or hindlegs was observed only after the rather high dose of 100 g/kg of clonidine. The inhibition was marked at low frequencies of stimulation (1–4 Hz) and weak or absent at high frequencies (16 and 32 Hz). The dose of clonidine (100 g/kg) which proved to be effective at presynaptic receptors produced a transient increase in blood pressure and in perfusion pressure of the hindquarters and hindlegs and virtually abolished spontaneous sympathetic nervous activity. In spinal cats, the clonidine-induced increases in blood pressure and perfusion pressure were very pronounced and of rather long duration. Thus, under in vivo conditions clonidine showed no selectivity for presynaptic -adrenoceptors in a blood-perfused vascular bed, and its presynaptic action was negligible as compared to its powerful central sympatho-inhibitory effect.Dopamine was constantly infused into the autoperfused hindquarters or hindlegs at increasing rates until a vasoconstriction due to stimulation of vascular (postsynaptic) -adrenoceptors occurred. The monoamine did not inhibit the stimulation-induced increases in perfusion pressure of the autoperfused hindquarters or hindlegs and, thus, an effect on presynaptic receptors was not found. The results underscore the importance of in vivo experiments for assessing the therapeutic significance of drug-induced stimulation of presynaptic receptors.Part of the results has been presented at the 16th Spring Meeting of the German Pharmacological Society in Mainz (Haeusler, 1975)     

可乐定对原代培养大鼠皮质神经元氧糖剥夺损伤的保护作用

目的：研究可乐定对原代培养大鼠皮质神经元氧糖剥夺( OGD)损伤的保护作用。方法取培养8 d的皮质神经元,分为正常对照组、模型对照组、可乐定(1.0,3.0,10.0μmol·L-1)预处理组。神经元氧糖剥脱损伤模型通过化学性缺氧、孵育液缺糖的方法建立。神经元损伤程度采用噻唑蓝( MTT)染色法和检测乳酸脱氢酶( LDH)的释放量来进行评价,观察预给予可乐定(1.0,3.0,10.0μmol·L-1)对神经元损伤的保护作用。结果显微镜下,正常对照组细胞密集,胞体饱满,边缘光滑,有较强折光性;神经元存活率(100.00±32.12)％,LDH释放比率(100.00±37.51)％。模型对照组细胞核固缩,细胞膜不完整,折光性差,MTT染色吸光度值明显降低,神经元存活率(53.61±7.62)％,LDH释放量显著增加,释放率为(166.07±9.65)％。可乐定(1.0,3.0,10μmol·L-1)预处理可明显逆转ODG损伤所致细胞形态的改变,剂量依耐性升高MTT染色吸光度值,神经元存活率分别为(67.53±10.54)％,(71.50±9.79)％和(87.48±5.29)％,同时可明显降低LDH的释放量,释放率分别为(136.45±25.72)％,(130.92±24.94)％和(121.63±32.68)％。结论可乐定对原代培养大鼠皮质神经元ODG损伤具有良好的保护作用。     

可乐定对豚鼠腹腔神经节突触前神经末梢乙酰胆硷量子释放的影响

应用细胞内生物电记录技术,观察到可乐定使离体豚鼠腹腔神经节突触前神经末梢自发的微小兴奋性突触后电位(mEPSP)频率减少,使刺激突触前神经引起的乙酰胆硷(Ach)量子释放的失败机率增加,平均量子含量减少,但对平均量子大小无影响,表明可乐定能减少突触前神经末梢Ach的量子性释放,但对Ach在囊泡中的平均含量无影响。本工作提示可乐定对交感神经节突触传递的阻断作用与可乐定减少突触前神经末梢Ach量子释放有关。