Comparison of the α-adrenoceptor antagonist profiles of idazoxan (RX 781094), yohimbine,rauwolscine and corynanthine

Summary In the present studies the potency and selectivity of idazoxan (RX 781094) were compared with yohimbine and its diastereoisomers rauwolscine and corynanthine in both functional studies and radioligand binding experiments. Prejunctional ₂- and postjunctional ₁-adrenoceptor antagonist potencies were assessed by determining pA₂ values against clonidine on the stimulated rat vas deferens and noradrenaline on the anococcygeus muscle, respectively. The rank order of prejunctional ₂-adrenoceptor antagonist potency was idazoxan > yohimbine > rauwolscine corynanthine. At postjunctional ₁-adrenoceptors the rank order of antagonist potency was rauwolscine > corynanthine > yohimbine > idazoxan. The selectivity values (₂/₁) for idazoxan, yohimbine, rauwolscine and corynanthine were 245, 45, 3 and 0.03 respectively. The selectivity and potency profiles established for these antagonists in functional studies were confirmed in radioligand binding studies utilising ³H-idazoxan (₂) and ³H-prazosin (₁) in rat cerebral cortex.In pithed rats intravenously administered idazoxan, yohimbine and rauwolscine fully reversed the inhibitory effects of clonidine on electrically-induced contractions of the vas deferens; idazoxan was approximately ten times more potent than both yohimbine and rauwolscine. Corynanthine was inactive. Idazoxan and yohimbine also fully antagonised the inhibitory effects of guanabenz on electrically-induced contractions of the anococcygeus muscle; idazoxan again was more than ten times more potent than yohimbine in this model. The inhibitory effects of guanabenz were less readily antagonised by rauwolscine indicating that the selectivity of this compound is less than that of yohimbine in this tissue. Corynanthine was again inactive.Studies were also undertaken in which the effects of an extended range of antagonists were examined on contractions of the anococcygeus muscle induced either by electrical stimulation or intra-arterial phenylphrine. Selective ₁-adrenoceptor antagonists produced a parallel block of the effects of stimulation and phenylephrine indicating that the postjunctional receptor in this tissue is predominantly ₁- character. In this tissue idazoxan potentiated nerve stimulation without inhibiting phenylephrine responses; of the compounds studied only idazoxan failed to influence phenylephrine responses.Under the present experimental conditions idazoxan only produced antagonist properties at -adrenoceptors and consistently displayed improved ₂-selectivity and potency with respect to yohimbine and rauwolscine.     

Anxiolytic-like effects of yohimbine in the murine plus-maze: strain independence and evidence against α2-adrenoceptor mediation

The influence of ₂-adrenoceptor antagonists in animal models of anxiety is quite inconsistent, with results spanning the full range of effect from anxiogenesis to anxiolysis. In the present study, an ethological technique was used to examine the effects of yohimbine (0.5–4.0 mg/kg) on plus-maze behaviour in DBA/2 mice. Results indicated significantanxiolytic-like effects on standard spatiotemporal measures at 2.0–4.0 mg/kg, and on risk assessment measures across the entire dose range. Full-scale follow-up studies with T1 and BALB/c strains confirmed that this action of yohimbine in the murine plus-maze is not peculiar to DBA/2 mice. The more selective ₂-adrenoceptor antagonist, idazoxan (0.63–5.0 mg/kg), exerted much weaker behavioural effects in the maze while the ₂-adrenoceptor agonist, clonidine (0.01–0.1 mg/kg), produced a profile consistent with non-specific behavioural disruption. Data are discussed in relation to the possible involvement of 5-HT_1A receptor mechanisms in the observed anxiolytic-like effects of yohimbine in the murine plus-maze.     

Analysis of the action of idazoxan calls into question the reliability of the rat isolated small mesenteric artery assay as a predictor for α1-adrenoceptor-mediated pressor activity

We have studied the effects of idazoxan in rat aorta and small mesenteric artery. In the aorta, idazoxan behaved as a partial agonist (pK_A=6.30). Prazosin produced rightward shift (pA₂=9.88) and steepening of the idazoxan curve. In contrast, idazoxan had no effect of basal tension in the mesenteric artery, but shifted the noradrenaline curve to the right in a parallel manner (pA₂=6.12). The selective al-adrenoceptor agonist, indanidine, also behaved as a partial agonist in the aorta and produced no significant contractions of the small mesenteric artery. Since idazoxan and indanidine have been reported to raise blood pressure in the pithed rat via an action at vascular ₁-adrenoceptors, these results call into question the reliability of the small mesenteric artery assay as a predictor for ₁-adrenoceptor-mediated pressor activity in vivo.     

Dose-response relationship for oral idazoxan effects in healthy human subjects: comparison with oral yohimbine

The effects of oral administration of the ₂ adrenergic receptor antagonists idazoxan (20 mg, 40 mg, 80 mg) and yohimbine (20 mg) were compared using a placebo-controlled within-subjects design. Healthy subjects completed 5 test days during which medication effects on mood and anxiety states, physiologic indices, plasma cortisol levels, and plasma levels of the norepinephrine metabolite 3-methoxy-4-hydroxyphenylethylene glycol (MHPG) were assessed. Idazoxan dose-dependently increased plasma MHPG, plasma cortisol, systolic and diastolic blood pressure, and Panic Attack Symptom Scale scores in healthy subjects. Overall, yohimbine and idazoxan produced a similar pattern of behavioral and neuroendocrine responses. Since idazoxan possesses relatively greater receptor specificity compared to yohimbine, it may be a more useful ₂ antagonist in humans.     

赛拉嗪对麻醉大鼠海马CA1区乙酰胆碱含量的影响

应用乙酰胆碱选择性微电极技术,观察到小剂量赛拉嗪(2.0和6.0mg·kg^-1)可显著增加大鼠海马CA1区ACh的含量,而大剂量赛拉嗪(10.0mg·kg^-1)及咪唑克生(0.6mg·kg^-1)则作用相反。咪唑克生虽可明显拮抗赛拉嗪的作用,但海马CA₁区ACh的含量仍显著低于正常水平。在去兰斑核的大鼠上,赛拉嗪(2.0和6.0mg·kg^-1)及咪唑克生(0.6mg·kg^-1)分别对海马CA₁区ACh的含量具有减少和增加作用,且咪唑克生拮抗赛拉嗪的作用后,海马CA₁区ACh的含量基本恢复至正常水平。结果提示,赛拉嗪对麻醉大鼠海马CA₁区ACh含量呈双相性影响,咪唑可生虽能显著拮抗赛拉嗪的作用,但海马CA₁区ACh的含量仍明显低于正常水平,可能分别与赛拉嗪和咪唑克生降低或提高中枢NE能系统的功能有关。     

Effect of isolation-rearing on noradrenaline release in rat hypothalamus and hippocampus in vitro

A fixed volume incubation method in conjunction with HPLC-ED analysis was employed to measure endogenous NA release in vitro in slices of hippocampus and hypothalamus from rats reared in either groups of five or in social isolation from weaning. NA in release supernatants from hippocampal slices was found to be increased in response to stimulation with high K⁺ (30 mM), an effect which was dependent on Ca²⁺. Basal NA release was also Ca²⁺ dependent. Isolation-rearing did not significantly alter either basal or K⁺-stimulated release. Clonidine (10 μM) caused an inhibition of basal NA release in both regions and in both rearing groups, however there was no significant effect of isolation-rearing for this response although the response tended to be greater in the hippocampus from isolates. Idazoxan (10 μM) significantly increased basal NA release in hippocampal and hypothalamic slices in both rearing groups, but this effect was significantly greater in the hippocampus from isolation-reared rats. These findings suggest there may be a region-specific change in the sensitivity of the α₂-adrenoceptor in isolates. Taken together with previous findings, there is evidence to suggest that isolation-rearing alters the sensitivity of the presynaptic terminal α₂-autoreceptor in the hippocampus.     

Idazoxan and brain α2-adrenoceptors in the rabbit

The effect of intravenous infusion of idazoxan on the depressor response to intracisternal clonidine 1 microgram/kg and on [3H]yohimbine binding in the fore- and hindbrain of the rabbit was examined. Idazoxan was infused either acutely (30 min) or chronically (5 days) at doses of 0.56 or 1.1 mg/h. Idazoxan 1.1 mg/h reduced the fall in blood pressure after clonidine. This attenuation of the depressor response was observed in the groups that were given the higher dose of idazoxan both acutely and chronically. The extent of attenuation was not modified by the duration of treatment. The low dose of idazoxan given acutely had no significant effect on the response to clonidine but the chronically infused group showed an enhanced response. A significant increase in the number of [3H]yohimbine binding sites (83%) was observed in the forebrain after 5 days infusion of 1.1 mg/h idazoxan with no change in the hindbrain. The lower dose of infusion did not cause any significant change in [3H]yohimbine binding in either brain region. Thus it appears that the susceptibility of the alpha 2-adrenoceptor binding sites to up-regulation by idazoxan may depend on the brain region observed.     

Role of alpha1- and alpha2-adrenoceptors in the regulation of locomotion and spatial behavior in the active place avoidance task: a dose-response study

Studies on the neurotransmitter substrate of locomotion and place navigation occupy a central position in behavioral neuroscience. Active allothetic place avoidance (AAPA) is a task, in which animals are trained to avoid a room frame defined stable sector on a continuously rotating arena. The aim of the present study was to test the effect of the blockage of alpha1- and alpha2-adrenoceptors, using specific antagonists prazosin and idazoxan, on the locomotor activity and spatial behavior in the AAPA task. Both prazosin and idazoxan at the highest doses (4 and 6 mg/kg, respectively) were found to decrease the locomotor activity in the AAPA and they also impaired navigational performance. The results suggest that antagonizing alpha-adrenoceptors with systemically administered drugs affects locomotor activity together with avoidance behavior and does not cause a purely cognitive deficit in the AAPA task.     

Extracellular brain cortical levels of noradrenaline in ischemia:

Summary Using microdialysis, extracellular noradrenaline (NA) levels in the rat cerebral cortex were studied under isoflurane/N₂O anaesthesia before, during and for 6 hours following 10 min of forebrain ischemia in a 2-vessel occlusion model. A microdialysis probe was introduced into the parietal cortex and dorsal hippocampus in anaesthetized rats and continuously perfused with Krebs-Ringerbicarbonate buffer with or without the NA uptake inhibitor desipramine (DMI, 5 M). Twenty min fractions were collected and the extracellular NA levels were measured in the dialysates using HPLC with electrochemical detection. The basal NA concentration in the dialysate was 10.5±1.8 (mean±SEM) pg/20 min fraction and increased to 39.3±4.8 pg/20 min fraction after local administration of DMI. During ischemia, NA increased to 38 times the basal level without DMI, and 6 times with DMI included during two hours' perfusion prior to ischemia. After recirculation NA levels returned to, or even transiently decreased below, preischemic values. With DMI present in the dialysis buffer, administration of idazoxan immediately following ischemia delayed the return to preischemic NA levels in the recirculation phase. In the absence of DMI, no effect of idazoxan on postischemic levels of NA was found. Local administration of DMI increases basal extracellular NA levels and reduces the ischemia-induced NA release. The latter effect may be a due to inhibition of the NA uptake system working in a reversed mode, or as a result of decreased synthesis of NA due to activation of presynaptic ₂-receptors by the increased synaptic NA levels. Postischemic treatment with the ₂-adrenoceptor antagonist idazoxan in combination with DMI prolongs the period of elevated extracellular NA levels, which may be of importance for the protective properties of idazoxan against ischemic cell injury.Abbreviations DMI desmethyl-imipramine, desipramine - DOPA 3,4-dihydroxyphenylalanine - LC locus coeruleus - MABP mean arterial blood pressure - NA noradrenaline, norepinephrine     

The involvement of α2-adrenoceptors in the anticonvulsive effect of swim stress in mice

RATIONALE: Various studies have shown that stressful manipulations in rats and mice lower the convulsant potency of GABA-related, but also some GABA-unrelated convulsants. The mechanism of this anticonvulsive effect of stress is still unknown. OBJECTIVES: We tested the possible involvement of alpha2-adrenoceptors in the previously observed anticonvulsive effect of swim stress. METHODS: The mice were, prior to exposure to swim stress and the IV infusion of picrotoxin, pre-treated with clonidine (an alpha2-adrenoceptor agonist), yohimbine (a non-selective alpha2-adrenoceptor antagonist), idazoxan (a selective alpha2-adrenoceptor antagonist), or niguldipine (an alpha1-adrenoceptor antagonist), and the latency to the onset of two convulsant signs was registered. RESULTS: In control unstressed animals clonidine (0.1 and 1 mg/kg IP), yohimbine (2 mg/kg IP) and idazoxan (1 mg/kg IP) failed to affect the doses of picrotoxin needed to produce convulsant signs, while niguldipine (5 mg/kg IP) prolonged the latency, i.e. it enhanced the doses of picrotoxin producing running/bouncing clonus and tonic hindlimb extension. In swim stressed mice clonidine enhanced, while idazoxan decreased doses of picrotoxin needed to produce two convulsive signs. Yohimbine decreased the dose of convulsant needed to produce tonic hindlimb extension, while niguldipine enhanced doses of picrotoxin needed to produce both symptoms. CONCLUSIONS: The results demonstrate the alpha2-adrenoceptor agonist-induced potentiation and alpha2-adrenoceptor antagonist-induced diminution of the anticonvulsive effect of stress. Additionally, they show the anticonvulsive effect of niguldipine in unstressed and stressed animals. Hence, the results suggest that alpha2-adrenoceptors are involved in the anticonvulsive effect of swim stress in mice.