Pharmacological characterization of [3H]idazoxan, [3H]RX821002 and binding to α2-adrenoceptors in rat cerebral cortical membranes

Wallace, David R.; Muskardin, Danny T.; Zahniser, Nancy R.

doi:10.1016/0014-2999(94)90058-2

Cited by 22 publications

(15 citation statements)

References 31 publications

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“…Recently, an increase in binding to α2-adrenergic sites in the parietal cortex, identified by [ 3 H]RX821002 binding, was reported in rats exposed to prenatal cocaine (Booze et al, 2006). [ 3 H]RX821002 binding has been reported to recognize the α2A and α2C subtypes of the adrenergic receptor, whereas [ 125 I]-p-iodoclonidine is more selective for the α2A form (Wallace et al, 1994). High levels of the α2A-adrenergic receptor and its mRNA are present in the LC (McCune et al, 1993;Nicholas et al, 1993;Scheinin et al, 1994;Talley et al, 1996), where it functions as an autoreceptor on NE neurons (Norenberg et al, 1997;Callado and Stamford, 1999).…”

Section: Discussionmentioning

confidence: 99%

“…The clonidine derivative, [ 125 I]-paraiodoclonidine (NEX-253; Dupont NEN, Boston, MA, 2200 Ci/mmol), was used to label the high-affinity α 2 -adrenergic receptor sites from a set of tissues, which comprised a mean of 4 slides from each rat containing LC for specific binding. Evidence indicates that this radioligand preferentially labels the high affinity state of the α2A-adrenergic receptor subtype in the LC (Baron and Siegel, 1990;Alburges et al, 1993;Wallace et al, 1994). The assay (Alburges et al, 1993) was initiated with a 20 min preincubation in 170 mM Tris-HCl buffer (pH 7.6) containing 20 mM MgCl 2 , followed by 90 min incubation at room temperature with the radioligand at twice its K D (1.1 nM) in a humidified chamber.…”

Section: Radioligand Binding and Autoradiographymentioning

confidence: 99%

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Prenatal cocaine exposure enhances responsivity of locus coeruleus norepinephrine neurons: Role of autoreceptors

et al. 2007

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Children exposed to cocaine during gestation have a higher incidence of neurobehavioral deficits. The neurochemical bases of these deficits have not been determined, but the pharmacology of cocaine and the nature of the abnormalities suggest that disruptions in catecholaminergic systems may be involved. In the current study, we used a rat model of prenatal cocaine exposure to examine the impact that this exposure has on the locus coeruleus (LC) noradrenergic system in offspring. Pregnant rats received twice-daily intravenous injections of cocaine (3 mg/kg) or saline between gestational days 10 and 20, and progeny were tested as juveniles. Exposure to a mild stressor elevated an index of norepinephrine turnover in the prefrontal cortex and also increased Fos expression in tyrosine hydroxylase-positive LC neurons in rats exposed to prenatal cocaine but not in rats exposed to prenatal saline. No change in the number of tyrosine hydroxylase-positive neurons in the LC was observed between the two prenatal treatment groups. Specific binding of [ 125 I]-para-iodoclonidine, a radioligand with specificity for high affinity α2A-adrenergic receptors, was decreased in the LC of rats exposed to prenatal cocaine compared to prenatal saline controls. As α 2 -adrenergic receptors on LC norepinephrine neurons function as autoreceptors, their down-regulation by prenatal cocaine exposure provides a plausible mechanism for the observed heightened reactivity of norepinephrine neurons in these animals. These data indicate that prenatal cocaine exposure results in lasting changes to the regulation and responsivity of rat LC norepinephrine neurons. A similar dysregulation of LC norepinephrine neurons may occur in children exposed to cocaine during gestation, and this may explain, at least partly, the increased incidence of cognitive deficits that have been observed in these subjects.

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Section: Discussionmentioning

confidence: 99%

Section: Radioligand Binding and Autoradiographymentioning

confidence: 99%

Prenatal cocaine exposure enhances responsivity of locus coeruleus norepinephrine neurons: Role of autoreceptors

et al. 2007

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“…Clonidine is an agonist at I1Rs in addition to a2Rs (Bricca et al, 1993;De Vos et al, 1994;Ernsberger et al, 1993Ernsberger et al, , 1987Michel et al, 1989;Wallace et al, 1994). To determine if the above actions were because of actions at a2ARs, we studied the effect of UK14304, a specific a2-adrenoreceptor agonist with an I1 binding site/a2 binding site affinity ratio o0.01 (Andorn et al, 1988;Bricca et al, 1993;Buccafusco et al, 1995;Urban et al, 1995).…”

Section: Costimulation Of A2-adrenergic Receptors and I1rs Is Requirementioning

confidence: 99%

Prolonged Activation of Mesolimbic Dopaminergic Neurons by Morphine Withdrawal Following Clonidine: Participation of Imidazoline and Norepinephrine Receptors

Georges

Aston‐Jones

2003

Neuropsychopharmacol

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The a2 adrenoceptor (a2R) agonist clonidine is used as a treatment for heroin addiction. Substantial evidence indicates that dopaminergic and noradrenergic systems have key roles in opiate dependence and withdrawal but the possible interactions between these two pathways remain unclear. The objective of this study was to establish the effects of clonidine pretreatment on ventral tegmental area dopaminergic (VTA DA) neuronal activity during morphine withdrawal. Responses of VTA DA neurons to withdrawal precipitated by naltrexone were characterized in anesthetized rats using extracellular recordings. As expected, withdrawal produced a marked inhibition of VTA DA neuronal activity. However, pretreatment with clonidine prevented this inhibition induced by withdrawal, and instead produced a long-lasting activation of firing rate (+50%) and burst firing (+19%). In contrast, pretreatment with a more selective a2R agonist, UK14304, did not prevent the inhibition of VTA DA neuron activity during withdrawal. We tested whether the high affinity of clonidine for imidazoline-1 receptors (I1Rs) was responsible for the difference between these two a2R agonists. In morphine-dependent rats pretreated with rilmenidine (mixed a2R/I1R agonist), precipitation of withdrawal elicited a 22% increase of VTA DA impulse activity. The action of clonidine on I1Rs was studied by coadministering clonidine with RX821002, a specific a2R antagonist. Pretreatment with RX821002 plus clonidine prevented the inhibition of VTA DA activity during withdrawal but failed to produce excitation. These results indicate that the pharmacological effects of clonidine on VTA DA neurons during morphine withdrawal is related to actions on I1Rs as well as a2Rs.

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“…In the central nervous system, α 2A adrenoceptors are more widely distributed than α 2B and α 2C adrenoceptors, being detected in cortex, septum, dorsal horn and the endopiriform nucleus (Uhlén and Wikberg 1997). Further, the density of α 2A adrenoceptors markedly exceeds that of the other subtypes, constituting the totality of α 2 adrenoceptors in hypothalamus, and 90% of adrenoceptors in frontal cortex (Ordway et al 1993;Sastre and García-Sevilla 1994;Wallace et al 1994).…”

mentioning

confidence: 99%

“…Chemical O'Rourke et al 1994;Renouard et al 1994;Sastre and García-Sevilla 1994;Wallace et al 1994;Hieble and Ruffolo 1996). In view of these issues, the present study undertook, first, a comparative in vitro study of the ligand binding affinity for recombinant h5-HT 1A and hα 2A receptors of some recent and/or clinically tested selective ligands including the agonists brominidine (UK 14304) and dexmedetomidine (DMT), and the antagonists fluparoxan and atipamezole.…”

mentioning

confidence: 99%

Actions of α2 adrenoceptor ligands at α2A and 5-HT1A receptors: the antagonist, atipamezole, and the agonist, dexmedetomidine, are highly selective for α2A adrenoceptors

Newman‐Tancredi

Nicolas

Audinot

et al. 1998

Naunyn-Schmiedeberg's Arch Pharmacol

113

101

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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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Pharmacological characterization of [3H]idazoxan, [3H]RX821002 and binding to α2-adrenoceptors in rat cerebral cortical membranes

Cited by 22 publications

References 31 publications

Prenatal cocaine exposure enhances responsivity of locus coeruleus norepinephrine neurons: Role of autoreceptors

Prenatal cocaine exposure enhances responsivity of locus coeruleus norepinephrine neurons: Role of autoreceptors

Prolonged Activation of Mesolimbic Dopaminergic Neurons by Morphine Withdrawal Following Clonidine: Participation of Imidazoline and Norepinephrine Receptors

Actions of α2 adrenoceptor ligands at α2A and 5-HT1A receptors: the antagonist, atipamezole, and the agonist, dexmedetomidine, are highly selective for α2A adrenoceptors

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