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D M Jackson

Publications and source records attributed to D M Jackson.

At least 55 records · Page 3Linked to original sources
PubMed1996

Partial agonist effects of BW A868C, a selective DP receptor antagonist, on Cl- secretion in dog tracheal epithelium.

We examined the interactions of prostaglandin D2, BW245C ((+/-)-5-(6-carboxyhexyl)-1-(3-cyclohexyl-3-hydroxypropyl)-hydantoin) a selective DP receptor agonist and BW A868C ((+/-)-3-benzyl-5-(6-carboxyhexyl)-1-(2-cyclohexyl-2- hydroxyethylamino)-hydantoin) a selective DP receptor antagonist on Cl- secretion using dog isolated tracheal epithelial preparations in Ussing chambers. Both prostaglandin D2 and BW245C stimulated Cl- secretion as reflected by increased short-circuit current (Isc) in the epithelial cells where the latter was more potent than the former. BW A868C produced, consistently, weak but significant partial agonism on Cl- secretion in these preparations in addition to its expected antagonism at the DP receptors. A pKB estimate of 8.16 +/- 0.06 (n = 11) for BW A868C from its antagonism to BW245C was found to be comparable with its estimates of both p[A]50 (8.19 +/- 0.14, n = 5) and pKA (8.00 +/- 0.20, n = 5). In addition, no significant effect by BW A868C up to 1 microM on Cl- secretory responses to other prostanoids, such as prostaglandin E2, prostaglandin F2 alpha and 9 alpha, 11 beta-prostaglandin F2 alpha, was detected in the system. These results are consistent with previous findings that BW A868C is a selective antagonist at the DP receptors mediating Cl- secretion by epithelial cells. To our knowledge, this is a (the first) confirmation of partial agonist properties of BW A868C in an isolated tissue system.

Animals↗
PubMed1996

Effects of BW A868C, a selective prostaglandin DP receptor antagonist, in dog isolated vascular preparations.

The effects of the selective prostaglandin DP receptor antagonist BW A868C ((+/-)-3-benzyl-5-(6-carboxyhexyl)-1-(2-cyclohexyl-2-hydroxyethylamin o)- hydantoin), 3.0 nM to 0.3 microM) were examined against prostaglandin D2 and BW245C ((+/-)-5-(6-carboxyhexyl)-1-(3-cyclohexyl-3-hydroxypropyl)-hydantoin)-in duced smooth muscle relaxation on dog isolated vascular preparations pre-contracted with a sub-maximal concentration of KCl (50 mM). In dog dorsal nasal vein BW245C was found to be more potent than prostaglandin D2 with p[A]50 estimates of 7.6 +/- 0.1 (S.E.M., n = 8) and 5.8 +/- 0.1 (n = 5), respectively. BW A868C, up to 0.3 microM, displaced the relaxant concentration-effect curves to BW245C in dog dorsal nasal vein in an apparently competitive manner with parallel rightward shifts and no significant changes in the upper asymptotes. The data were analysed by using a modified Schild equation which not only gives equal weight to all agonist concentration-effect data but also allows a direct plot in Clark plot space. A pKB estimate of 7.3 +/- 0.8 (n = 20) was obtained with a unity Schild plot slope (b = 1.0 +/- 0.1). This affinity estimate, however, is lower than the values previously reported in other studies. The affinity estimates of BW A868C against BW245C and prostaglandin D2 obtained from dog dorsal nasal vein, major palatine artery and saphenous vein were found to be consistent. The relatively low affinity estimates of BW A868C at DP receptors as observed in the present study may be due to species- or tissue-related variations or may be indicative of the possible existence of DP receptor subtypes.

Animals↗
PubMed1996

Effects of 5-HT3 receptor-selective agents on locomotor activity in rats following injection into the nucleus accumbens and the ventral tegmental area.

5-Hydroxytryptamine (5-HT) is involved in the modulation of dopaminergic activity in the mesolimbic system, but its sites of action and the receptors involved are not well understood. Locomotor activity responses in rats were monitored in Animex automated activity boxes following injection of 5-HT3 receptor-selective agents directly into two mesolimbic nuclei, the nucleus accumbens and the ventral tegmental area, via stereotactically implanted injection guide cannulae. Neither spontaneous nor dexamphetamine-stimulated locomotor activity was changed by bilateral intra-nucleus accumbens injection of the selective agonist 2-methyl-5-HT or the selective antagonists ondansetron or granisetron. In contrast, intra-ventral tegmental area injection of 2-methyl-5-HT produced significant long-lasting (approximately 240 min) increases in locomotor activity; intra-ventral tegmental area injection of ondansetron elicited an initial inhibition of spontaneous and dexamphetamine-stimulated locomotor activity (for the 0-30 min period), but granisetron had no effect. The hyperlocomotor response to intra-ventral tegmental area 2-methyl-5-HT was abolished by pretreatment with the catecholamine synthesis inhibitor alpha-methyl-p-tyrosine, or by pretreatment with ondansetron. Methiothepin pretreatment had no effect on the hyperlocomotor response to 2-methyl-5-HT, although methiothepin itself produced an initial increase in spontaneous locomotor activity (for the 60-120 min period). Intra-ventral tegmental area injection of 5-carboxamidotryptamine, alpha-methyl-5-HT or renzapride produced no changes in spontaneous locomotor activity. In some of the ventral tegmental area experiments, other behaviours were also monitored. 2-Methyl-5-HT produced forward locomotion, rearing, and increased wakefulness, but did not appreciably alter circling, grooming or sniffing. Ondansetron alone had no effect on any of these behaviours, but it opposed the 2-methyl-5-HT-induced changes. Methiothepin alone increased forward locomotion and wakefulness but did not alter the other behaviours; it had no effect on the responses to 2-methyl-5-HT. These observations show that 5-HT3 receptors may mediate increased locomotor activity by modulating firing of mesolimbic dopaminergic cell bodies in the ventral tegmental area rather than terminals in the nucleus accumbens.

Animals↗
PubMed1995

Why does clozapine stimulate the motor activity of reserpine-pretreated rats when combined with a dopamine D1 receptor agonist?

The aim of the present experiments was to investigate the locomotor stimulant effects of the atypical antipsychotic agent, clozapine, in rats depleted of their dopamine by reserpine and alpha-methyl-p-tyrosine pretreatment. Clozapine itself induced a slight but never significant stimulation of locomotor activity which was enhanced by the addition of the selective dopamine D1 receptor agonist, SKF38393 (2,3,4,5-tetrahydro-7,8-dihydroxy-1-phenyl-1H-3- benzazepine), but not by the selective dopamine D2 receptor agonist, quinpirole. The stimulation produced by clozapine plus SKF38393 was blocked by the selective dopamine D1 receptor antagonist, SCH23390 (7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5- tetrahydro-1H-3-benzapine hydrochloride), while the selective dopamine D2 receptor antagonist, haloperidol, was ineffective. A combination of SCH23390 and haloperidol blocked the clozapine plus SKF38393-induced locomotion. Unlike clozapine, neither the selective 5-HT2 receptor antagonist, ritanserin, nor the dopamine D2 receptor antagonists, haloperidol and remoxipride, caused locomotor activation when given alone or in combination with SKF38393. The indirectly acting sympathomimetic amine, d-amphetamine, was inactive in the monoamine-depleted rats, indicating that no dopamine was available for release by d-amphetamine. The muscarinic receptor antagonist, scopolamine, alone did not alter locomotion, but produced marked stimulation when combined with SKF38393 but not with quinpirole. This stimulation was not affected by haloperidol. However, the scopolamine plus SKF38393-induced stimulation was partially blocked by SCH23390 or by a combination of haloperidol and SCH23390. The data indicate that clozapine, in rats depleted of their dopamine stores, exhibits properties consistent with those of a dopamine receptor agonist.(ABSTRACT TRUNCATED AT 250 WORDS)

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1995

Time course of bromocriptine induced excitation in the rat: behavioural and biochemical studies.

The aim of the present study was to further investigate the behavioural and biochemical pharmacology of the directly acting dopamine (DA) receptor agonist bromocriptine (BRC). BRC produced an initial depression of locomotion followed after about an hour by a weak but significant locomotor stimulation. The stimulation was potentiated by concomitant administration of the D1 agonist SKF38393. Ex vivo biochemical determinations indicated that reductions in dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) levels occurred in the striatum after BRC injection without a significant change in DA levels, indicating a reduced DA turnover. An increase in 5-hydroxytryptamine (5HT) and 5-hydroxyindoleacetic acid (5HIAA) levels occurred in the striatum leading to a significant increase in turnover (i.e. ratio of 5HIAA to 5HT). Noradrenaline concentrations increased in the striatum. In the cortex, sharp falls in HVA and DOPAC levels without a corresponding change in DA were observed. While there was no significant change in noradrenaline levels in this brain region, an increase in 5HIAA, but not in 5HT, levels occurred. These changes indicate an increase in 5HT turnover (ratio of 5HIAA to 5HT). In vivo dialysis indicated that extracellular levels of DA, DOPAC and HVA in the striata of freely moving rats were sharply reduced for at least 6 h after injection. In vitro binding studies showed that BRC exhibited high (Ki values in low nanomolar range) affinities for DA D2A, D2B, D3, alpha 1 and alpha 2 adrenergic receptors together with unexpectedly high affinity (about 1 nM) for 5HT1A receptors. The data indicate that the initial behavioural depression and later locomotor stimulation induced by BRC are accompanied by a sharp monophasic fall in striatal extracellular DA levels as indicated by dialysis studies. Since the behavioural stimulation was augmented by concomitant D1 receptor stimulation, the data suggest that the reduced DA turnover is influencing the amount of DA available to stimulate postsynaptic D1 receptors. However, the biochemical studies indicated that BRC has a high affinity for 5HT1A receptors and affects the turnover of 5HT in the brain. Thus, the behavioural effects of BRC may depend not only on effects on the DA system but also on 5HT systems.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1995

Prepulse inhibition of acoustic startle, a measure of sensorimotor gating: effects of antipsychotics and other agents in rats.

Schizophrenic patients are deficient in various neurologic measures reflecting information processing. One such measure in prepulse inhibition (PPI) of acoustic startle, in which schizophrenics display less inhibition than normal subjects. PPI is also diminished in rats treated with psychotomimetic drugs such as amphetamine and phencyclidine. PPI has been suggested as a model relevant for studying the pathophysiology of schizophrenia. We studied the effect of a variety of antipsychotics and putative antipsychotics and some key reference compounds on the acoustic startle response (ASR) and PPI. Some, but not all, antipsychotics tested (mainly selective dopamine D2 antagonists) enhanced PPI. Remoxipride and clozapine, both of which are antipsychotics, and the very potent and highly selective D2 antagonist, NCQ-298, did not. It is concluded that enhanced PPI in otherwise untreated rats does not reflect antipsychotic efficacy. We further noted that the effect on PPI was independent of the effect on ASR.

Acoustic Stimulation↗
PubMed1995

Eicosanoid release in allergen-induced bronchoconstriction in dogs. Its relationship to airways hyperreactivity and pulmonary inflammation.

In vitro studies have demonstrated the release of histamine, PGD2, TXB2, PGE2, PGF2 alpha, 6-keto-PGF1 alpha and the peptidoleukotrienes from sensitized lung. We have assessed the release of these mediators following antigen challenge in vivo. Antigen challenge of allergic dogs resulted in an acute bronchoconstriction and an increase in bronchial reactivity to histamine and an increase in neutrophil and eosinophil numbers recovered by bronchoalveolar lavage (BAL), 2 and 24 h later. The acute response was associated with histamine and PGD2 release but there was no increase in the levels of other eicosanoids in recovered BAL. Bronchial hyperreactivity and pulmonary inflammation, 2 and 24 h post-challenge was not associated with a concommitant (antigen specific) increase in BAL fluid eicosanoid levels. We conclude that although PGD2 is released during the acute response to antigen the subsequent changes (hyperreactivity and inflammation) are not characterised by a maintained elevation in eicosanoid levels detectable by BAL.

Airway Resistance↗
PubMed1995

Current usage of contrast agents, anticoagulant and antiplatelet drugs in angiography and angioplasty in the UK.

Currently, there is no consensus in the UK on what constitutes best angiographic practice. To provide a basis for discussion a questionnaire was sent to all Radiology and Cardiology departments in the UK. Information was requested on practice during diagnostic angiography and angioplasty regarding the type of contrast agent used, whether and how flush solution or contrast agents themselves were heparinised, and whether bolus doses of heparin were administered. The use of other supplementary drugs including corticosteroids was also explored. Two hundred of 353 (57%) of questionnaires were returned. Over 80% who replied used non-ionic contrast agents for all angiographic procedures. The majority of the smaller group, using ionic contrast agents for uncomplicated procedures, resorted to non-ionic contrast agents in a range of circumstances in both diagnostic angiography and angioplasty. Heparinized flush solutions were used by over 75% for both types of angiographic procedures, but employing a wide range of doses. Bolus doses of heparin were administered by over 80% performing angioplasty, again in a wide range of doses, with only (a few) cardiologists monitoring the anticoagulant effect by measuring the activated whole blood clotting time in the angiographic suite. Over 70% used aspirin or dipyridamole as supplementary agents, at the time of the angioplasty and, subsequently, continued these medications for a variable period. Corticosteroid prophylaxis for high risk patients, very variably defined, was felt necessary by 58%. A wide range of regimes of both dose and timing was noted.

Adrenal Cortex Hormones↗
PubMed1995

Effect of volatile methyl jasmonate on the oxylipin pathway in tobacco, cucumber, and arabidopsis.

The effect of atmospheric methyl jasmonate on the oxylipin pathway was investigated in leaves of tobacco (Nicotiana tabacum L.), cucumber (Cucumis sativa L.), and Arabidopsis thaliana (L.). Differential sensitivities of test plants to methyl jasmonate were observed. Thus, different concentrations of methyl jasmonate were required for induction of changes in the oxylipin pathway. Arabidopsis was the least and cucumber the most sensitive to methyl jasmonate. Methyl jasmonate induced the accumulation of lipoxygenase protein and a corresponding increase in extractable lipoxygenase activity. Atmospheric methyl jasmonate additionally induced hydroperoxide lyase activity and the enhanced production of several volatile six-carbon products. It is interesting that lipid hydroperoxidase activity, which is a measure of hydroperoxide lyase plus allene oxide synthase plus possibly other lipid hydroperoxide-metabolizing activities, was not changed by methyl jasmonate treatment. Methyl jasmonate selectively altered the activity of certain enzymes of the oxylipin pathway (lipoxygenase and hydroperoxide lyase) and increased the potential of leaves for greatly enhanced six-carbon-volatile production.

Acetates↗
PubMed1995

Does the dopamine receptor subtype selectivity of antipsychotic agents provide useful leads for the development of novel therapeutic agents?

Antipsychotic agents share the ability to antagonize dopamine (DA) receptors, and correlation studies have indicated that the clinical efficacy of neuroleptic agents may be coupled to their affinity for D2 receptors. More recently, a family of DA D2-like receptors has been identified. These receptors include the D2A, D2B, D3 and D4 receptors. On the basis of in vitro receptor-binding studies, it has been suggested that the atypical profile of clozapine might be related to a selective effect on the D4 receptor subtype. We have studied the receptor-binding profiles of a series of antipsychotic agents and evaluated some of the compounds in behavioural assays in the rat. Most of the antipsychotic agents lack selectivity for DA-receptors as well as selectivity for the various DA-receptor subtypes. Because of this lack of selectivity, it is impossible to draw firm conclusions about the role of any particular receptor in the clinical profile of the neuroleptic agents. Furthermore, the pharmacology of potential human metabolites has to be taken into account in a proper analysis of the clinical profile. Consequently, most speculations on the key-target of clinically interesting antipsychotics (including clozapine) may be of little practical value. Clinical studies with receptor (subtype)-selective agents will be more informative.

Animals↗
PubMed1995

'Atypical' tremor.

The tremor present in a small number of patients who present with features of both Parkinson's disease (PD) and essential tremor (ET) is ill-defined. We therefore studied 8 such patients with 'atypical' tremor and compared them clinically to 11 PD and 10 ET patients in a double-blind, cross-over, placebo-controlled trial. Tremor was assessed via accelerometry and surface EMG. Tremor frequency and the acute tremorlytic response to propranolol were not useful in discriminating between groups. Over 80% of atypical and PD patients showed alternating EMG, whereas 90% of ET patients had synchronous EMG activity. Tremor amplitude improved by > 90% in 38% of atypical, 27% of PD and none of the ET patients after single-dose L-dopa/benserazide (300/75 mg), a response which was significantly different between the ET and PD groups. Failure to differentiate electrophysiologically and pharmacologically between the atypical and other groups probably relates to clinical heterogeneity in the atypical group.

Benserazide↗
PubMed1995

Case report: diffuse fatty infiltration of the renal parenchyma secondary to bilateral angiomyolipomas--features on ultrasound and computed tomography.

A case is described where ultrasound demonstrated diffusely increased echogenicity in massively enlarged kidneys. Computed tomography confirmed fatty replacement of the renal parenchyma, allowing a confident diagnosis of multiple bilateral angiomyolipomas in a clinical setting of tuberous sclerosis. This is the first ultrasound demonstration of such diffusely echogenic kidneys in angiomyolipoma.

Adult↗
PubMed1995

State legislative strategies to improve the supply and distribution of generalist physicians, 1985 to 1992.

State laws enacted between 1985 and 1992 were reviewed to examine state involvement in influencing the supply and distribution of generalist physicians. Forty-seven states enacted 238 relevant laws during this period. In 1991 and 1992, 36 states enacted 98 laws, as compared with 1985 and 1986, when 8 states enacted 12 laws. Legislation addressed planning and oversight; financial incentives to institutions, students, and residents; and strategies to enhance the practice environment. A new strategy is to link funding to measureable outcomes, such as the career choices of a state medical school's graduates. Few states devoted resources to evaluate their efforts.

Education, Medical↗
PubMed1994

The atypical antipsychotic, remoxipride, blocks phencyclidine-induced disruption of prepulse inhibition in the rat.

The effect of various typical (haloperidol) and atypical (clozapine, raclopride, remoxipride) antipsychotics on phencyclidine (PCP)-induced disruption of sensorimotor gating was tested in rats using an acoustic startle paradigm. Clozapine (4-40 mumol/kg), haloperidol (1-5 mumol/kg) and raclopride (1-12 mumol/kg) failed to reverse PCP-induced disruption of prepulse inhibition (PPI) of the acoustic startle response. In contrast, remoxipride (12-60 mumol/kg) caused a dose-dependent block of this effect. PCP-induced disruption of PPI is a widely accepted animal model of a corresponding behavioural deficit observed in schizophrenia although little evidence has been presented that it is in fact sensitive to antipsychotic agents. The present results indicate that remoxipride behaves in a unique way in this model compared to clozapine, haloperidol and raclopride.

Acoustic Stimulation↗
PubMed1994

Development of tolerance to 8-OH-DPAT induced blockade of acquisition of a passive avoidance response.

We examined the effects of manipulating 5-HT1A receptors on the performance of a passive avoidance task in rats. Firstly, we studied the effect of racemic 8-OH-DPAT and compared it to the pure enantiomers (subcutaneous injection, s.c.). Secondly, we investigated the effect (s.c.) of the selective 5-HT1A receptor antagonist (S)-UH-301 [(S)-5-fluoro-8-hydroxy-2-(dipropylamino)tetralin] both alone and on 8-OH-DPAT-induced disruption of acquisition. Thirdly, we examined whether tolerance occurs to the effects of 8-OH-DPAT on passive avoidance acquisition. Finally, we examined the effects (s.c.) of the selective NMDA receptor antagonist dizocilpine, (+)-MK-801[(5R,10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo(a,d)cyclohe pten-5, 10-imine], on this tolerance development. Different doses of racemic 8-OH-DPAT were injected 10 min before rats were exposed to the acquisition phase of a step through passive avoidance response. When tested for retention 24 h later, 8-OH-DPAT-pretreated rats failed to exhibit any avoidance. R(+) and S(-)-8-OH-DPAT were also active with the R(+)-isomer being more active than the S(-)-isomer. The 5-HT1A antagonist (S)-UH-301 [(S)-5-fluoro-8-hydroxy-2-(dipropylamino)tetralin] was without effect on avoidance performance but antagonized the effect of 8-OH-DPAT. In a further experiment, rats were pretreated with racemic 8-OH-DPAT (0.3 mg/kg). Twenty four hours later, they received a challenge dose of 8-OH-DPAT and exposed to the acquisition phase of the avoidance response. When tested 24 hr later for retention, 8-OH-DPAT challenged rats failed to show any indication of an avoidance response.(ABSTRACT TRUNCATED AT 250 WORDS)

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1994

Contrasting effects of dopaminergic blockade on MDMA and d-amphetamine conditioned taste aversions.

A series of experiments examined the role of dopamine in the conditioned taste aversion (CTA) produced by 3,4-methylenedioxymethamphetamine (MDMA) and d-amphetamine in rats. The CTA induced by MDMA (1.0 mg/kg) was unaffected by the D1 dopamine receptor antagonist SCH23390 (0.3 or 0.6 mg/kg), the D2 receptor antagonist raclopride (0.3 or 0.6 mg/kg), SCH23390 and raclopride combined (both 0.3 or 0.6 mg/kg), or the D1/D2 receptor antagonist haloperidol (0.4 mg/kg). In contrast, the CTA produced by d-amphetamine (0.5 mg/kg) was attenuated by SCH23390 and raclopride combined (both 0.3 mg/kg) as well as haloperidol (0.4 mg/kg), but not by SCH23390 (0.3 or 0.6 mg/kg) or raclopride (0.3 or 0.6 mg/kg) alone. These results suggest that dopamine plays different roles in MDMA and amphetamine CTAs, and that the D1 and D2 receptors independently mediate the aversive effect of amphetamine in CTA.

3,4-Methylenedioxyamphetamine↗
PubMed1994

Reward summation and the effects of dopamine D1 and D2 agonists and antagonists on fixed-interval responding for brain stimulation.

The effects of dopamine D1 and D2 agonists and antagonists on fixed-interval (FI) self-stimulation were investigated using a reward-summation model, trading off frequency with train duration. The D1 antagonist SCH 23390 (0.005-0.02 mg/kg) decreased FI self-stimulation and the inhibition was reversed by increasing stimulation frequency. Moreover, amphetamine (0.5 mg/kg) reversed the inhibition by a low dose of SCH 23390 (0.005 mg/kg) but not after a higher dose inhibition could not be dissociated from a performance deficit. There was no significant interaction between low doses of spiperone and SCH 23390 when coadministered that could not be predicted from their effects when given individually. Self-stimulation was inhibited by the D1 agonist SKF 38393 (5 mg/kg). When coadministered with amphetamine, SKF 38393 partially blocked amphetamine's facilitation. The D2 agonist bromocriptine (10 mg/kg) produced an extraordinary enhancement of performance that was also evident after a lower dose (5 mg/kg) when it was combined with amphetamine. This enhancement of performance showed little extinction when stimulation was no longer available, suggesting it was a novel form of stereotypy. These results support the concept that D1 dopamine receptors play a critical role in modulating the reinforcing consequences of lateral hypothalamic stimulation. The involvement of D2 receptors on reinforcement processes remains contentious due to their effects on performance and insensitivity of responding to coincide with changes in reinforcement magnitude.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗