Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: DrugBank:APRD00174 (Clonidine)
 2,411 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This study examined the activity of chemically diverse alpha2 adrenoceptor ligands at recombinant human (h) and native rat (r) alpha2A adrenoceptors compared with 5-HT1A receptors. First, in competition binding experiments at h alpha2A and h5-HT1A receptors expressed in CHO cells, several compounds, including the antagonists 1-(2-pyrimidinyl)piperazine (1-PP), (+/-)-idazoxan, benalfocin (SKF 86466), yohimbine and RX 821,002, displayed preference for h alpha2A versus h5-HT1A receptors of only 1.4-, 3.6-, 4-, 10- and 11-fold, respectively (based on differences in pKi values). Clonidine, brimonidine (UK 14304), the benzopyrrolidine fluparoxan and the guanidines guanfacine and guanabenz exhibited intermediate selectivity (22- to 31-fold) for h alpha2A receptors. Only the antagonist atipamezole and the agonist dexmedetomidine (DMT) displayed high preference for alpha2 adrenoceptors (1290- and 91-fold, respectively). Second, the compounds were tested for their ability to induce h5-HT1A receptor-mediated G-protein activation, as indicated by the stimulation of [35S]GTPgammaS binding. All except atipamezole and RX 821,002 exhibited agonist activity, with potencies which correlated with their affinity for h5-HT1A receptors. Relative efficacies (Emax values) were 25-35% for guanabenz, guanfacine, WB 4101 and benalfocin, 50-65% for 1-PP, (+/-)-idazoxan and clonidine, and over 70% for fluparoxan, oxymetazoline and yohimbine (relative to 5-HT = 100%). Yohimbine-induced [35S]GTPgammaS binding was inhibited by the selective 5-HT1A receptor antagonist WAY 100,635. In contrast, RX 821,002 was the only ligand which exhibited antagonist activity at h5-HT1A receptors, inhibiting 5-HT-stimulated [35S]GTPgammaS binding. Atipamezole, which exhibited negligeable affinity for 5-HT1A receptors, was inactive. Third, the affinities for r alpha2A differed considerably from the affinities for h alpha2A receptors whereas the affinities for r5-HT1A differed much less from the affinities for h5-HT1A receptors. This affected markedly the affinity ratios of certain compounds. For example, (+/-)-idazoxan was only 3.6-fold selective for h alpha2A versus h5-HT1A but 51-fold selective for r alpha2A versus r5-HT1A receptors. Conversely, yohimbine was tenfold selective for h alpha2A versus h5-HT1A adrenoceptors but 4.2-fold selective for r alpha2A versus r5-HT1A receptors. Nevertheless, both atipamezole and DMT were highly selective for both rat and human alpha2A versus rat or human 5-HT1A receptors. In conclusion, these data indicate that: (1) the agonist DMT and the antagonist atipamezole are the ligands of choice to distinguish alpha2-mediated from 5-HT1A-mediated actions, whilst several of the other compounds show only low or modest selectivity for alpha2A over 5-HT1A receptors; (2) caution should be exercised in experimental and clinical interpretation of the actions of traditionally employed alpha2 ligands, such as clonidine, yohimbine and (+/-)-idazoxan, which exhibit marked agonist activity at 5-HT1A receptors.
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PMID:Actions of alpha2 adrenoceptor ligands at alpha2A and 5-HT1A receptors: the antagonist, atipamezole, and the agonist, dexmedetomidine, are highly selective for alpha2A adrenoceptors. 975 5

Although serotonin (5-HT) release from enterochromaffin (EC) cells is considered to be regulated by multiple receptor-mediated mechanisms, little is known about the signal transduction in EC cells. We investigated the effects of adrenoceptor stimulation on 5-HT release from ileal tissue and intracellular calcium dynamics of epithelial cells in isolated ileal crypts in mice. Ileal tissues placed in organ bath were perfused with a buffered solution. Released 5-HT was measured using HPLC-ECD. Ileal crypts were isolated by collagenase digestion followed by moderate pipetting. Intracellular calcium dynamics were analyzed by digital video-imaging system using fura-2. NE, but not isoprenaline (Iso), induced 5-HT release from mouse ileal tissue. NE-induced 5-HT release was antagonized by yohimbine and rauwolscine, but not by prazosin and bunazosin. NE, but not Iso, also elicited a transient elevation of intracellular calcium in some EC cells. The effect of NE (1 microM) was slightly suppressed by prazosin and bunazosin, but was remarkably suppressed by yohimbine and rauwolscine. UK 14,304 and Clonidine at 10 microM significantly induced an increase in intracellular calcium concentration. NE-induced intracellular calcium dynamics was not significantly affected by timolol, Ro20-1724, rolipram and 8-bromo-cAMP. These results suggest that NE-induced 5-HT release from ileal EC cells is mediated predominantly via alpha 2-, but not beta-adrenoceptors, by a mechanism dependent on elevation of intracellular calcium concentration.
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PMID:[Signal transduction of serotonin release from enterochromaffin cells in mouse ileal crypts]. 1019 Jan 50

Studies investigating temperament traits in humans and their biological correlates have found high levels of novelty seeking (NS) linked with dopaminergic system changes, and particularly a deficit of dopamine transporter. Harm avoidance and reward dependence, on the other hand, appeared to be associated, respectively with serotonin and noradrenaline changes. In the present study, we have investigated the dopaminergic (DA), serotonergic (5-HT), and noradrenergic (NE) functions in healthy volunteers by challenging the monoamine systems with the DA agonist bromocriptine, the 5-HT agonist D-fenfluramine, and the NE agonist clonidine, respectively. Parallel to this investigation, we examined the temperament traits of our subjects by measuring NS, harm avoidance (HA) and reward dependence (RD) using the 'Three-dimensional Personality Questionnaire' (TPQ). The aims of the study were to see whether or not the monoamine functions were correlated with temperament traits. Bromocriptine challenge induced a significant GH increase and a significant suppression of PRL. D-fenfluramine test significantly increased PRL and cortisol plasma levels and Clonidine test induced a significant rise in GH values. NS scores showed a significant direct correlation with brom-stimulated GH values (r=0.426, P<0.05) and a significant inverse correlation with brom-inhibited PRL values (r=-0.498, P<0.01). HA scores correlated significantly with D-fen-stimulated PRL and CORT AUCs, (PRL: r=0.424, P<0.05; CORT: r=0. 595, P<0.005). RD scores correlated positively with clon-stimulated GH values (r=0.55; F=8.6; P<0.01) and negatively with brom-inhibited-PRL AUCs (r=-0.439, P<0.05). Our data support Cloninger theory concerning the biological correlates of temperamental traits, and evidence the link between the neuroendocrine responses to dynamic challenges and stable temperament features.
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PMID:Neuroendocrine correlates of temperamental traits in humans. 1081 82

The alpha(2)-adrenoceptor (AR) agonist, S18616 ((S)-spiro[(1-oxa-2-amino-3-azacyclopent-2-ene)-4,2'-(8'-chloro-1' , 2',3',4'-tetrahydronaphthalene)] accompanying article), suppressed electrical activity of adrenergic neurons in the locus ceruleus, an action reversed by the alpha(2)-AR antagonist, idazoxan, which itself enhanced their firing rate. Electrical activity of serotonergic neurons in the dorsal raphe nucleus was similarly suppressed, an action likewise blocked by idazoxan, which did not, itself, influence firing. In freely moving rats, S18616 decreased extracellular levels of norepinephrine (NE), serotonin (5-HT), and dopamine (DA) in frontal cortex and hippocampus. The selective alpha(2)- versus alpha(1)-AR antagonists, atipamezole and BRL-44408 (a preferential alpha(2A)-AR antagonist), elevated levels of NE and DA but not 5-HT. In their presence, the influence of S18616 on frontocortical levels of NE, DA, and 5-HT was blocked. In contrast, prazosin, a selective alpha(1)- versus alpha(2)-AR antagonist (which also preferentially blocks alpha(2B/2C)-ARs) dose dependently decreased levels of 5-HT, but not NE and DA, and failed to modify the actions of S18616. Ultrasonic vocalizations elicited by rats in an aversive environment were inhibited by S18616, which also suppressed aggressive and marble-burying behaviors in mice. Furthermore, S18616 (biphasically) enhanced punished responses in the Vogel conflict test and active social interaction tests in rats. At higher doses, S18616 displayed sedative/hypnotic properties. Both anxiolytic and motor actions of S18616 were inhibited by atipamezole and BRL-44408 but not prazosin. Dexmedetomidine mimicked the actions of S18616 at higher doses except for more potent sedative/hypnotic properties. Clonidine also mimicked S18616, but only at markedly higher doses. In conclusion, via activation of alpha(2)-ARs, S18616 potently inhibits corticolimbic adrenergic, serotonergic, and (frontocortical) dopaminergic transmission in parallel with the expression of its anxiolytic and sedative properties.
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PMID:S18616, a highly potent spiroimidazoline agonist at alpha(2)-adrenoceptors: II. Influence on monoaminergic transmission, motor function, and anxiety in comparison with dexmedetomidine and clonidine. 1108 58

1. This study investigated the effect of acute (2 days) and chronic (14 days) treatment with a selective inhibitor of noradrenaline uptake, reboxetine (10 mg kg(-1) day(-1)) by osmotic pumps, on extracellular noradrenaline and the sensitivity of alpha(2)-adrenoceptors in the prefrontal cortex of rats. 2. The effect of continuous infusion of reboxetine for 14 days on cortical extracellular noradrenaline was significantly higher (599% of vehicle levels) than after 2 days (263% of vehicle levels). 3. Brain concentrations of reboxetine after 2 and 14 days of infusion were 37.9+/-17.8 and 37.1+/-7.7 ng g(-1), respectively. 4. Reboxetine infused for 2 and 14 days significantly increased extracellular dopamine in the prefrontal cortex, to a similar extent (257 and 342% of vehicle levels, respectively), whereas extracellular 5-HT was not modified by either treatment. 5. Clonidine (10 and 30 microg kg(-1) i.p.) reduced cortical extracellular noradrenaline similarly in animals treated with reboxetine or vehicle for 2 days whereas the effects in rats infused with reboxetine for 14 days were markedly less than in vehicle-treated animals. 6. Clonidine (0.05 and 0.2 microM), infused through the dialysis probe into the prefrontal cortex, reduced cortical extracellular noradrenaline much less in rats treated with reboxetine for 14 days than in vehicle-treated animals. 7. Reboxetine's effect on extracellular noradrenaline in the prefrontal cortex was greater after chronic treatment and could be associated with desensitization of terminal alpha(2)-adrenoceptors that normally serve to inhibit noradrenaline release.
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PMID:Chronic treatment with reboxetine by osmotic pumps facilitates its effect on extracellular noradrenaline and may desensitize alpha(2)-adrenoceptors in the prefrontal cortex. 1115 76

The purpose of this study was to analyse adrenergic and serotonergic interactions in the anxiolytic effects of several 5-HT(1A) agonists including ipsapirone, buspirone, indorenate and 8-OH-DPAT. To this end, the effects of different doses of the adrenergic compounds clonidine (0.015-0.0625mg/kg), yohimbine (0.125-0.5mg/kg), prazosin (0.5-2.0mg/kg), pindolol (1.55-6.2mg/kg) and practolol (0.25-1.0mg/kg) on defensive burying behaviour were established. Clonidine (0.015-0.0625mg/kg), prazosin (1.0 and 2.0mg/kg), pindolol (1.55 and 6.2mg/kg) and all 5-HT(1A) agonists reduced burying behaviour by themselves. In contrast, yohimbine (0.250 and 0.5mg/kg) increased, while practolol did not modify, this behaviour. Additionally, the actions of yohimbine (0.125mg/kg), prazosin (0.5mg/kg), pindolol (3.1mg/kg) and practolol (0.5mg/kg) on the effects of ipsapirone (5.0mg/kg), buspirone (5.0mg/kg), indorenate (5.0mg/kg) and 8-OH-DPAT (0.25mg/kg) were examined. Prazosin enhanced the effects of ipsapirone, indorenate and buspirone, while yohimbine antagonized the actions of indorenate and 8-OH-DPAT. Pindolol enhanced the effects of indorenate while practolol antagonized the actions of ipsapirone, buspirone and 8-OH-DPAT. Only buspirone (5.0mg/kg) affected motor coordination, an effect that was not counteracted by the antagonists. Based on these data an interaction between 5-HT(1A) agonists and the noradrenergic system in the regulation of anxiety is proposed.
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PMID:Noradrenaline-serotonin interactions in the anxiolytic effects of 5-HT(1A) agonists. 1122 50

The modulatory effects of the biogenic amines octopamine and serotonin on pheromonal receptor neurons of Mamestra brassicae were investigated. The responses to sex pheromone components of two cells types (A and B) in single male long sensilla trichodea were monitored. Cell types A and B do not respond to the same compound. The response of type A to a pulse of the major sex pheromone component increased 5 min after octopamine injection. Responses of type B to other odorants increased after 30 min. In the absence of any pheromone stimulation the background firing activity of type A increased following octopamine injection. This background activity was used to evaluate the kinetics of octopamine and other biogenic amine effects on olfactory receptor neurons. Octopamine increased this background activity in a concentration- and time-dependent manner. Clonidine, an octopamine agonist, was shown to be more powerful in increasing the background activity of olfactory receptor neurons. The effects of octopamine and clonidine were hypothesized to arise from specific receptor activation as chlorpromazine (an octopamine antagonist) was shown to block the effect of octopamine. Serotonin, a known neuromodulator in most animal species, induced a reversible inhibition of spike firing. Altogether, these results indicate that biogenic amines can modulate the sensitivity of olfactory receptor neurons of moths either directly or by an action on adaptation.
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PMID:Biogenic amines modulate olfactory receptor neurons firing activity in Mamestra brassicae. 1147 31

Effects of milnacipran (MIL), a serotonin and noradrenaline reuptake inhibitor (SNRI), on synaptic transmission were examined in the rat locus coeruleus (LC). Bath-application of MIL produced a hyperpolarization associated with a decrease in input resistance of LC neurons. The MIL-induced hyperpolarization reversed polarity near the equilibrium potential of K+. The MIL-induced hyperpolarization was blocked by yohimbine (1 microM). Clonidine, but not serotonin (5-hydroxytryptamine; 5-HT), produced a hyperpolarizing potential in LC neurons. The MIL-induced hyperpolarization reversed polarity at -114 +/- 3 mV (n=4). MIL (0.1-10 microM) depressed the amplitude of the excitatory postsynaptic potential (EPSP), while it enhanced the amplitude and duration of the inhibitory postsynaptic potential (IPSP). These results suggest that MIL hyperpolarizes LC neurons and enhances the IPSP by increasing endogenous noradrenaline (NA) concentration at synapses in LC neurons.
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PMID:Effects of milnacipran on the inhibitory postsynaptic potential in neurons of the rat locus coeruleus. 1568 25

Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder that can present with a wide array of symptoms that make treatment difficult. Current therapies are directed at relieving symptoms of abdominal pain or discomfort, bloating, constipation, and diarrhea. Pharmacologic agents used to treat IBS-associated pain include myorelaxants, peppermint oil, and peripherally acting opiates. Dicyclomine and hyoscyamine, the two myorelaxants available in the United States, have not been proven effective in reducing abdominal pain in patients with IBS. The efficacy of peppermint oil is debated, but methodological problems with existing studies preclude definitive judgment. Loperamide is ineffective for relief of abdominal pain. For IBS patients with excessive abdominal bloating, a small number of studies suggest that bacterial eradication with gut-directed antibiotics and bacterial reconstitution with nonpathogenic probiotics may reduce flatulence. For constipation-predominant (C-IBS) symptoms, current treatment options include fiber supplementation, polyethylene glycol, and tegaserod. Soluble fibers (ispaghula, calcium polycarbophil, psyllium) are more effective than insoluble fibers (wheat bran, corn fiber) in alleviating global symptoms and relieving constipation, although fiber in general has marginal benefit in treatment of overall IBS symptoms. Polyethylene glycol increases bowel frequency in chronic constipation, but its overall efficacy against IBS is unclear. Tegaserod, a 5-HT(4) agonist, demonstrates superiority over placebo in improving bowel frequency and stool consistency and alleviating abdominal pain and bloating in women with C-IBS. Overall global symptoms are modestly improved with tegaserod when compared with placebo. Additional agents under investigation for C-IBS include the ClC(2) chloride channel opener lubiprostone, mu-opioid receptor antagonist alvimopan, and 5-HT(4) agonist renzapride. For diarrhea-predominant (D-IBS) symptoms, available therapies include loperamide, alosetron, and clonidine. Alosetron, a 5-HT(3) antagonist, is superior to placebo for reducing bowel frequency, improving stool consistency, and relieving abdominal pain in women with D-IBS. However, alosetron is available under a restricted license because of concerns for ischemic colitis and severe constipation necessitating colectomy. Clonidine may be helpful in alleviating global symptoms for D-IBS patients.
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PMID:Current gut-directed therapies for irritable bowel syndrome. 1683 50

Cocaine-induced increases in dopamine (DA) contribute importantly to cocaine effects on behavior but, the role of concomitant increases in norepinephrine (NE) and serotonin (5-HT) is less well understood. In order to selectively block the increases in NE and 5-HT evoked by cocaine, autoreceptor preferring low doses (0.01, 0.025 and 0.05 mg/kg) of the a2 agonist, Clonidine or the 5-HT1A agonist, 8-OHDPAT were given as pretreatments 20 min prior to saline or cocaine (10.0 mg/kg) in separate groups of rats (N=10). With pharmacological stimulation of NE and 5-HT autoreceptors, release of these neurotransmitters would be suppressed and, therefore, less available for re-uptake blockade by cocaine. With increasing dose levels, Clonidine had marked inhibitory effects on spontaneous and cocaine-induced locomotion, grooming and rearing. 8-OHDPAT pretreatment also suppressed spontaneous locomotion, grooming and rearing; but, in contrast, did not reduce the cocaine locomotor stimulant effects. 8-OHDPAT, however, did suppress central zone entry and rearing in cocaine treated rats. Using ex vivo methods, we found that 8-OHDPAT selectively reduced 5-HT metabolism in the medial frontal cortex (MFC) and subcortical limbic brain. Clonidine selectively reduced NE metabolism in the MFC, but decreased both DA and 5-HT metabolism in the subcortical limbic brain without affecting NE metabolism. This diverse and broad spectrum of Clonidine effects upon neurotransmitters and behavior is striking and points-up the important, complex and integrative role of NE in brain function. While both Clonidine and 8-OHDPAT can substantially attenuate a number of cocaine behavioral effects, these inhibitory effects appear to be secondary to reductions in the behavioral baseline rather than reversals of cocaine effects.
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PMID:Effects on spontaneous and cocaine-induced behavior of pharmacological inhibition of noradrenergic and serotonergic systems. 1815 56


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