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Dive into the research topics where Alan L. Hudson is active.

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Featured researches published by Alan L. Hudson.


European Journal of Pharmacology | 1981

Bicuculline-insensitive GABA receptors on peripheral autonomic nerve terminals.

Norman G. Bowery; Adam Doble; David Robert Hill; Alan L. Hudson; John Shaw; Michael J. Turnbull; Ruth Warrington

The action of gamma-aminobutyric acid (GABA) and related compounds on rat isolated atria and mouse and guinea pig isolated vas deferens has been studied. GABA depressed the evoked but not basal release of [3H]noradrenaline from atria (IC50 4 micro M) and reduced the twitch responses of the vas deferens (IC50 3 micro M) in a dose-dependent manner. These depressant effects were not prevented by recognized GABA antagonists such as bicuculline and picrotoxin. Numerous GABA analogues, in particular 3-aminopropanesulphonic acid, failed to mimic the action of GABA. However, beta-p-chlorophenyl GABA (baclofen) was stereospecifically active. Other related beta-substituted derivatives were also active but to a lesser degree than GABA. Pretreatment of the vas deferens with the neuronal GABA uptake inhibitors 2,4-diaminobutyric acid or cis-3-aminocyclohexanecarboxylic acid potentiated the action of GABA. These data suggest the presence of a bicuculline-insensitive GABA receptor on autonomic nerve terminals. Preliminary observations indicate a lack of chloride ion dependence in the action of GABA at this site.


British Journal of Pharmacology | 1997

Characteristics of GABAB receptor binding sites on rat whole brain synaptic membranes

Norman G. Bowery; D.R. Hill; Alan L. Hudson

1 Saturable binding of (±)‐[3H]‐baclofen and [3H]‐γ‐aminobutyric acid ([3H]‐GABA) to rat brain crude synaptic membranes has been examined by means of a centrifugation assay. 2 The binding of [3H]‐baclofen could be detected in fresh or previously frozen tissue and was dependent on the presence of physiological concentrations of Ca2+ or Mg2+ although a lower affinity Na+‐dependent component could also be observed. Both components probably reflect binding to receptor recognition sites. 3 The saturable portion of bound [3H]‐baclofen formed 20.3 ± 6.9% of total bound ligand. This could be displaced by GABA (IC50 = 0.04 μm), (–)‐baclofen (0.04 μm) and to a much lesser extent by (+)‐baclofen (33 μm). Isoguvacine, piperidine‐4‐sulphonic acid and bicuculline methobromide were inactive (up to 100 μm) and muscimol was only weakly active (IC50 = 12.3 μm). 4 Saturable binding of [3H]‐GABA increased on adding CaCl2 or MgSO4 (up to 2.5 Mm and 5.0 Mm respectively) to the Tris‐HCl incubation solution. This binding (GABAB site binding) was additional to the bicuculline‐sensitive binding of GABA (GABAA site binding) and could be completely displaced by (–)‐baclofen (IC50 = 0.13 μm). 5 Increasing the Ca2+ concentration (0 to 2.5 Mm) increased the binding capacity of the membranes without changing their affinity for the ligand. 6 The binding of [3H]‐GABA to GABAB sites could be demonstrated in fresh as well as previously frozen membranes with a doubling of the affinity being produced by freezing. Further incubation with the non‐ionic detergent Triton‐X‐100 (0.05% v/v) reduced the binding capacity by 50%. 7 The pharmacological profile of displacers of [3H]‐GABA from GABAB sites correlated well with that for [3H]‐baclofen displacement. A correlation with data previously obtained in isolated preparations of rat atria and mouse vas deferens was also apparent. 8 It is concluded that [3H]‐baclofen or [3H]‐GABA are both ligands for the same bicuculline‐insensitive, divalent cation‐dependent binding sites in the rat brain.


Journal of Neurochemistry | 1984

Inhibition of GABAB Receptor Binding by Guanyl Nucleotides

D. R. Hill; N. G. Bowery; Alan L. Hudson

Abstract: GTP and GDP decreased the saturable binding of [3H]baclofen or [3H]γ‐aminobutyric acid ([3H]GABA) to GABAB but not GABAA receptors whereas GMP displayed negligible activity. This effect was specific to guanyl nucleotides and was not mimicked by high concentrations of ATP. The inhibition of ligand binding was the result of a diminished receptor affinity with no change in receptor number. The use of a complete physiological saline solution rather than Tris buffer plus Ca2+ or Mg2+ increased the potency of GTP at the GABAB receptor. The results are discussed in relation to the effects of GABA and GTP on adenylate cyclase activity in the brain.


Science | 2008

Bioactive Contaminants Leach from Disposable Laboratory Plasticware

G. Reid McDonald; Alan L. Hudson; Susan M.J. Dunn; Haitao You; Glen B. Baker; Randy M. Whittal; Jonathan W. Martin; Amitabh Jha; Dale E. Edmondson; Andrew Holt

Disposable plasticware such as test tubes, pipette tips, and multiwell assay or culture plates are used routinely in most biological research laboratories. Manufacturing of plastics requires the inclusion of numerous chemicals to enhance stability, durability, and performance. Some lubricating (slip) agents, exemplified by oleamide, also occur endogenously in humans and are biologically active, and cationic biocides are included to prevent bacterial colonization of the plastic surface. We demonstrate that these manufacturing agents leach from laboratory plasticware into a standard aqueous buffer, dimethyl sulfoxide, and methanol and can have profound effects on proteins and thus on results from bioassays of protein function. These findings have far-reaching implications for the use of disposable plasticware in biological research.


Fundamental & Clinical Pharmacology | 2004

Invited review: the evolution of antidepressant mechanisms

David A. Slattery; Alan L. Hudson; David J. Nutt

Present antidepressants are all descendents of the serendipitous findings in the 1950s that the monoamine oxidase inhibitor iproniazid and the tricyclic antidepressant imipramine were effective antidepressants. The identification of their mechanism of action, and those of reserpine and amphetamine, in the 1960s, led to the monoamine theories of depression being postulated; first, with noradrenaline then 5‐hydroxytryptamine being considered the more important amine. These monoamine theories of depression predominated both industrial and academic research for four decades. Recently, in attempts to design new drugs with faster onsets of action and more universal therapeutic action, downstream alterations common to current antidepressants are being examined as potential antidepressants. Additionally, the use of animal models has identified a number of novel targets some of which have been subjected to clinical trials in humans. However, monoamine antidepressants remain the best current medications and it may be some time before they are dislodged as the market leaders.


British Journal of Pharmacology | 1992

Characterization and autoradiographical localization of non‐adrenoceptor idazoxan binding sites in the rat brain

N.J. Mallard; Alan L. Hudson; David J. Nutt

1 In rat whole brain homogenates, saturation analysis revealed that both [3H]‐idazoxan and [3H]‐RX821002, a selective α2‐adrenoceptor ligand, bound with high affinity to an apparent single population of sites. However, the Bmax for [3H]‐idazoxan was significantly (P < 0.01) greater than that for [3H]‐RX821002. 2 In competition studies, (−)‐adrenaline displaced 3 nm [3H]‐idazoxan binding with an affinity consistent with [3H]‐idazoxan labelling α2‐adrenoceptors. However, this displacement was incomplete since 23.68 ± 1.11% of specific [3H]‐idazoxan binding remained in the presence of an excess concentration (100 μm) of (−)‐adrenaline. In contrast, unlabelled idazoxan promoted a complete displacement of [3H]‐idazoxan binding with a Hill slope close to unity and an affinity comparable with its KD determined in saturation studies. 3 Displacement of [3H]‐idazoxan binding by the α2‐adrenoceptor antagonists yohimbine, RX821002 (2‐(2‐methoxy‐1,4‐benzodioxan‐2‐yl)‐2‐imidazoline) and RX811059 (2‐(2‐ethoxy‐1,4‐benzodioxan‐2‐yl)‐2‐imidazoline) was more complex, with Hill slopes considerably less than unity, and best described by a two‐site model of interaction comprising a high and low affinity component. The proportion of sites with high affinity for each antagonist was similar (60–80%). 4 The rank order of antagonist potency for the high affinity component in each displacement curve (RX821002 > RX811059 > yohimbine) is similar to that determined against the binding of [3H]‐RX821002 to rat brain, suggesting that these components reflect the inhibition of [3H]‐idazoxan binding to α2‐adrenoceptors. The remaining component in each displacement curve exhibiting low affinity towards these antagonists is attributable to the displacement of [3H]‐idazoxin from a non‐adrenoceptor idazoxan binding site (NAIBS) since a comparable amount of [3H]‐idazoxan binding was not displaced by an excess concentration of (−)‐adrenaline. 5 The displacement of [3H]‐idazoxan binding by RX801023 (6‐fluoro‐(2‐(1,4‐benzodioxan‐2‐yl)‐2‐imidazoline) was also best described by a model assuming a two site interaction with 20.07 ± 3.11% of the sites labelled displaying high affinity for RX801023. The Ki of RX801023 for the remainder of the sites labelled was similar to its Ki versus [3H]‐RX821002, indicating that this drug displays improved affinity and NAIBS/α2‐adrenoceptor selectivity compared with idazoxan. 6 In autoradiographical studies, the distribution of 5 nm [3H]‐idazoxan binding to sections of rat whole brain was consistent with that reported from previous studies and resembled the distribution of α2‐adrenoceptors. However, when sections of brain were coincubated with concentrations of α2‐adrenoceptor agonists or antagonists predicted to saturate α2‐adrenoceptors, there remained distinct areas of binding corresponding to discrete brain nuclei. This remaining binding was however displaced by unlabelled idazoxan (3 μm) or RX801023 (3 μm) indicative of the labelling of NAIBS. 7 Quantitative autoradiography of NAIBS revealed several brain nuclei which contained higher densities of these sites than α2‐adrenoceptors, notably the area postrema, interpeduncular nucleus, arcuate nucleus, ependyma and pineal gland.


Drug and Alcohol Dependence | 2001

β-carboline binding to imidazoline receptors

Stephen M. Husbands; Richard A. Glennon; Stephane Gorgerat; Rhianon Gough; Robin J. Tyacke; John Crosby; David J. Nutt; John W. Lewis; Alan L. Hudson

A series of β-carbolines were prepared and their affinities for imidazoline (I1 and I2) sites evaluated. Selected compounds were also examined at α2-adrenoceptors. Some of the β-carbolines were found to bind with high affinity to I2-sites and this affinity was dependent on both the planarity of the molecule and the presence of the aryl ring substituents. Good I1-affinity was observed with two of the compounds but none of the tested compounds bound to α2-adrenoceptors. The hallucinogenic properties of β-carbolines have been linked to activity at 5-HT receptors, in particular 5-HT2, however, it is apparent from this study that many of these compounds display substantially higher affinity for the imidazoline sites. This finding, and those showing modulation of some behavioural effects of morphine by I2-ligands, suggests that imidazoline sites may be interesting new targets in drug abuse research.


European Journal of Pharmacology | 1998

Characterisation and localisation of [3H]2-(2-benzofuranyl)-2-imidazoline binding in rat brain: a selective ligand for imidazoline I2 receptors

Lisa A. Lione; David J. Nutt; Alan L. Hudson

In rat whole brain homogenates, saturation binding analysis revealed that both [3H]2-BFI (2-(2-benzofuranyl)-2-imidazoline) and [3H]idazoxan (in the presence of 5 microM rauwolscine) bound with high affinity to an apparent single population of sites. However, the Kd for [3H]2-BFI (1.74+/-0.14 nM) was significantly (P < 0.01) less than that for [3H]idazoxan (10.4+/-2.68 nM). In competition studies idazoxan, 2-BFI, BU224 (2-(4,5-dihydroimidaz-2-yl)-quinoline), amiloride and guanabenz displayed high affinity (Ki values = 7.32, 1.71, 2.08, 21.80 and 14.90 nM, respectively) for 70-80% of sites, and low microM affinity for the remaining 20-30% of sites labelled by [3H]2-BFI. In contrast, several alpha2-adrenoceptor, imidazoline I1 receptor and histamine receptor ligands exhibited only micromolar affinity for the [3H]2-BFI labelled site. Quantitative receptor autoradiography revealed high binding by [3H]2-BFI to discrete brain nuclei, notably the area postrema, interpeduncular nucleus, arcuate nucleus, mammillary peduncle, ependyma and pineal gland. These data indicate that [3H]2-BFI recognises imidazoline I2 receptors in rat brain with higher affinity and selectivity than [3H]idazoxan and thus represents a superior radioligand to [3H]idazoxan for the study of imidazoline I2 receptors.


Annals of the New York Academy of Sciences | 1999

Novel Selective Compounds for the Investigation of Imidazoline Receptorsa

Alan L. Hudson; R. Gough; Robin J. Tyacke; Lisa A. Lione; M. D. Lalies; John W. Lewis; Stephen M. Husbands; P. Knight; F. Murray; Peter H. Hutson; David J. Nutt

ABSTRACT: Over several years our group has sought to synthesize and identify selective ligands for imidazoline (I) receptors, in particular the I2 binding site. As a consequence, [3H]2‐(2‐benzofuranyl)‐2‐imidazoline (2BFI) has proved extremely useful for binding and autoradiographic studies. More recently we have synthesized a BU series of compounds and examined these for their affinities for both I1 and I2 binding sites. BU224 (2‐(4,5‐dihydroimidaz‐2‐yl)‐quinoline) shows high affinity for I2 receptors with a Ki of 2.1 nM. BU226 (2‐(4,5‐dihydroimidaz‐2‐yl)‐isoquinoline) demonstrated slightly higher affinity (Ki 1.4 nM) for I2 receptors, but overall BU224 displayed greater selectivity for I2 over I1 receptors (832‐fold) than BU226 (380‐fold). Both compounds showed low (μM) affinity for α2‐adrenoceptors. Given BU224s ability to cross the blood brain barrier, we predict that its in vivo effects are likely to be mediated via I2 receptors. Brain dialysis revealed BU224 to dose dependently (0–20 mg/kg ip) elevate basal noradrenaline in rat frontal cortex and basal dopamine in striatum. In a rat model of opiate withdrawal, behavioral studies showed that BU224 (10 mg/kg, sc) was able to reduce acute weight loss and diarrhea, but not the number of wet dog shakes associated with the withdrawal syndrome.


Journal of Psychopharmacology | 1997

Noradrenergic mechanisms in the prefrontal cortex

David J. Nutt; M. D. Lalies; Lisa A. Lione; Alan L. Hudson

There is growing evidence that noradrenergic inputs to the prefrontal cortex (PFC) play an important role in regulating its function. This paper reviews the pharmacological control of noradrenaline (NA) release in this region, with particular reference to our studies using brain microdialysis, and also describes how NA levels are modulated by antidepressant and antipsychotic drugs. The suggestion that atypical antipsychotics such as clozapine and risperidone may produce clinical benefits by their ability to increase NA release is discussed. Finally, a new class of drugs, which show selectivity for imidazoline receptors is described. These compounds are shown to similarly increase extracellular NA in the PFC. Their potential utility as clinical treatments is discussed.

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Maria Gdaniec

Adam Mickiewicz University in Poznań

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