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Biomedical subjects

D M Jackson

Publications and source records attributed to D M Jackson.

At least 91 records · Page 5Linked to original sources
PubMed1991

Estimation of the efficacy and affinity of the beta 2-adrenoceptor agonist salmeterol in guinea-pig trachea.

1. We have attempted to estimate the affinity and efficacy of the new beta 2-adrenoceptor agonist salmeterol in the guinea-pig isolated trachea and to compare these estimates with those obtained for salbutamol. 2. The kinetics of the relaxation to salmeterol were considerably slower than those to salbutamol and the responses were poorly defined. Nevertheless, in experiments employing a cumulative curve design both salmeterol and salbutamol exhibited partial agonist behaviour. Operational model-fitting of these data indicated that the intrinsic efficacies of the two agonists were indistinguishable but that salmeterol had an affinity (pKA = 7.4) some 30 fold greater than salbutamol (pKA = 5.9). 3. Single dose experiments, using maximally effective concentrations of salmeterol or salbutamol were carried out in an attempt to quantify more reliably the relative efficacies of the two agonists. In these experiments salbutamol was found to have an efficacy (2.5) approximately 3 fold greater than that of salmeterol (0.8). 4. Full/partial agonist interaction studies were carried out to provide another estimate of the affinity of salmeterol. Isoprenaline and adrenaline were employed as full agonists in these experiments and the affinity (pKB) estimates obtained for salmeterol against these agonists were 7.3 and 7.4 respectively. These affinity estimates were similar to the pKA value (7.4) obtained by operational model-fitting. 5. Salmeterol has slightly lower efficacy (3 fold) but markedly greater affinity (30 fold) than salbutamol at beta 2-receptors. The slightly lower efficacy of salmeterol is unlikely to have clinical implications for this drug as a bronchodilator beta 2-adrenoceptor agonist in asthma.

Adrenergic beta-Agonists↗
PubMed1990

Behavioural, biochemical and electrophysiological studies on the motor depressant and stimulant effects of bromocriptine.

Bromocriptine (BRC) produced a biphasic behavioural effect in mice; an early depressant phase which lasted for about 1 h and a later stimulant phase which lasted from about 1 to 5 h. The stimulation was blocked with SCH23390. Both phases of activity were accompanied by marked striatal DA autoreceptor effects as indicated by reductions in dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) levels and by a reduction in the accumulation of DOPA (after inhibition of nigrostriatal DA nerve firing and DOPA decarboxylase). However, while the autoreceptor effects were still evident during the behavioural stimulant phase, there was a gradual rise in DOPAC and HVA from 1 to 4 h after injection, indicating a gradually increasing DA turnover. We were unable, using a variety of behavioural and biochemical paradigms, to demonstrate any change in DA autoreceptor sensitivity after one dose of BRC. In electrophysiological studies, however, it was found that prior exposure of rats to one dose of BRC rendered them subsensitive to the rate-inhibiting effects of a second dose of BRC, as measured in anaesthetized animals using extracellular single cell recordings of identified DA neurons in the substantia nigra pars compacta. It is concluded firstly, that the stimulant phase of BRC in mice occurs despite continued occupation of the DA autoreceptors by BRC because adequate endogenous DA is available to provide the required D1 receptor stimulation and secondly, that the terminal autoreceptors in the striatum (as assessed in mice using biochemical techniques) may be regulated differently to the somatodendritic autoreceptors (as assessed electrophysiologically in rats).

3,4-Dihydroxyphenylacetic Acid↗
PubMed1990

The effects of orally administered delta 9-tetrahydrocannabinol in man on mood and performance measures: a dose-response study.

A dose-response study of the effect of orally administered delta 9-tetrahydrocannabinol (THC) on human mood and skills performance was conducted. Using five dose levels of THC (0, 5, 10, 15, 20 mg) with 16 volunteers per dosage group, mood and performance measures were recorded at five testing occasions, one before and four after drug administration. The slope of the linear regression of performance on the test battery was significant for up to 200 minutes after dosage. That is to say, oral THC, at the doses used, produced significant dose-dependent impairment of performance for a period in excess of three hours. A similar time course for the effect of THC on the subjective assessment of intoxication ('stone') suggested a correlation between drug-induced impairment skills and the effects on mood.

Administration, Oral↗
PubMed1990

Modulation of neurogenic inflammation in rat trachea.

Antidromic stimulation of the cervical vagus nerve in anaesthetised rats resulted in plasma protein extravasation in the trachea. This response was potentiated significantly by pretreatment of the animals with an enkephalinase inhibitor, thiorphan (100 micrograms/kg). Exposure of animals to ozone (5-6 ppm) for 30 min caused a significant increase in the numbers of lung lavage epithelial cells but failed to potentiate neuronally-evoked tracheal oedema. Several compounds were investigated for anti-permeability effects on thiorphan-pretreated, nerve stimulated animals. Morphine (3 mg/kg) and salbutamol (100 micrograms/kg) were the most efficacious agents used and resulted in 66 +/- 14% and 61 +/- 9% inhibition of tracheal oedema, respectively. Sodium cromoglycate at 30 mg/kg produced a small but significant reduction in oedema (34 +/- 10%). Dexamethasone (3 mg/kg), methysergide (2 mg/kg) and theophylline (10 mg/kg) did not affect neurogenic oedema.

Albuterol↗
PubMed1990

Alpha 1 (but not alpha 2)-adrenoceptor agonists in combination with the dopamine D2 agonist quinpirole produce locomotor stimulation in dopamine-depleted mice.

Mice were premedicated with reserpine and alpha-methyl-p-tyrosine to deplete stores of dopamine (DA) (and other neurotransmitters) and to stop DA (and noradrenaline (NA] synthesis. In DA-depleted mice, the mixed alpha 1/alpha 2 agonist clonidine potentiated locomotor stimulation induced by a low dose of apomorphine as measured in automated activity cages. Clonidine and the slightly alpha 1-selective agonist ST587, but not ST91, an alpha-agonist which does not readily cross the blood brain barrier, produced marked stimulation when combined with the selective D2 agonist quinpirole. The D1 -selective agonist SKF38393 also produced marked excitation when combined with quinpirole. All the selective agonists, bar quinpirole which in some cases produced a significant locomotor stimulation, were relatively inactive when given alone. A "blind" observational analysis of the animals challenged with clonidine plus quinpirole indicated an increase in sniffing, rearing and shaking behaviour. In contrast, observation of the animals challenged with SKF38393 plus quinpirole indicated increased sniffing, rearing and biting and, in one case, increased grooming behaviour. Clonidine did not produce excitation (in automated cages) when combined with the selective D1 agonist SKF38393. The excitation produced by clonidine plus quinpirole was blocked by the selective D2 antagonist raclopride but not by the selective D1 antagonist SCH23390. The stimulation was also blocked by the alpha 1 antagonist prazosin but not by the alpha 2 antagonists idazoxan or yohimbine. Biochemical analysis in the striata of mice challenged with clonidine plus quinpirole did not provide any obvious biochemical basis for the behavioural interaction. It is concluded that alpha 1 receptor agonists in combination with D2 DA agonists can produce marked stimulation in DA depleted mice.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1989

Role of D1 and D2 dopamine receptors in mediating locomotor activity elicited from the nucleus accumbens of rats.

The present study examined the role of D1 and D2 receptors in mediating locomotor activity induced by dopamine (DA) agonists after injection into the nucleus accumbens (Acb). The D1 receptor agonist SKF38393 (as the racemic mixture) induced a dose-related increase in activity when injected bilaterally (1-10 micrograms/side). At a dose of 1 microgram/side, only the R-enantiomer was active. The SKF38393 (10 micrograms/side)-induced activity was antagonized by the D1 receptor antagonist SCH23390 (0.5 mg/kg i.p.), by the D2 receptor antagonist spiperone (0.1 mg/kg, i.p.), but not by the 5-HT2 antagonist ketanserin (1 mg/kg, i.p.). Another D1 agonist, CY208 243, also induced a moderate increase in activity when injected into the Acb (2 and 8 micrograms/side), but this was of much less intensity and of shorter duration than that produced by SKF38393. The D2 receptor agonist quinpirole slightly increased activity when administered into the Acb (0.3-3 micrograms/side), with the magnitude and duration of the response, however, being much less than that produced by SKF38393. The locomotor stimulant effects of SKF38393 (5 micrograms/side), CY208 243 (2 micrograms/side) and quinpirole (1 microgram/side) were blocked by the depletion of catecholamines with reserpine (5 mg/kg s.c., 24 h pretreatment) and alpha-methyl-p-tyrosine (200 mg/kg, i.p.). However, when SKF38393 and quinpirole were injected concurrently into the Acb at doses of 5 and 1 microgram/side respectively, a marked locomotor stimulation occurred in catecholamine-depleted rats. Furthermore, SKF38393 (1 microgram/side) or CY208 243 (2 micrograms/side), injected concurrently with quinpirole (0.3 microgram/side), into the Acb of rats with intact DA stores produced an at least additive effect on locomotor activity. These results suggest that both D1 and D2 receptor stimulation in the Acb is required for the expression of locomotor effects. Furthermore, D1 and D2 receptors in this nucleus appear to interact positively with each other, and may mediate the additive locomotor stimulatory effects induced by concurrent systemic administration of selective D1 and D2 agonists.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1989

Dopamine D-2 receptor agonist-induced behavioural depression: critical dependence upon postsynaptic dopamine D-1 function. A behavioural and biochemical study.

The dopamine (DA) D-2 receptor agonists quinpirole (threshold dose, 0.01 mg/kg IP), pergolide (0.025 mg/kg), B-HT 920 (0.003 mg/kg) and (-)-3-PPP (4 mg/kg) produced dose-dependent locomotor depression (immobility) in mice as assessed by a subjective scoring system, with the immobility being characterized by a frozen posture. The animals were still but had their eyes open. The immobility was accompanied by reductions in sniffing, rearing and grooming. The depression (and the associated reduction in the various behaviours) produced by quinpirole (0.1 mg/kg), pergolide (0.1 mg/kg) and B-HT 920 (0.1 mg/kg) was substantially (but not always completely) reversed by the selective D-1 receptor agonist SKF38393 (up to 12 mg/kg) and the non-selective D-1 receptor agonist CY208243 (up to 3 mg/kg). The immobility induced by (-)-3-PPP (16 mg/kg) was also reversed by CY208243 and SKF38393, but the reversal was due to an increase in grooming behaviour in mice challenged with the D-1 receptor agonists, whether or not the animals had also received (-)-3-PPP. There was no reversal of the depression of rearing or sniffing. In contrast, CY208243 and SKF38393 also antagonized the immobility induced by B-HT 920, but the reversal was accompanied by at least partial reversals of the depression of sniffing, rearing and grooming. The reversal of quinpirole-induced immobility by SKF38393 and CY208243 was antagonized by SCH23390 (0.1 mg/kg). The selective D-2 receptor antagonist raclopride (0.025 to 0.4 mg/kg) could not reverse quinpirole-induced immobility. High doses of either raclopride (0.4 mg/kg) or SCH23390 (greater than 0.1 mg/kg) significantly increased immobility. Although raclopride itself (0.2 mg/kg) produced a substantial increase in DOPAC and homovanillic acid (HVA) levels in the striatum, it did not antagonize the autoreceptor mediated effects of quinpirole (0.1 mg/kg) in reducing the striatal dihydroxyphenylacetic acid (DOPAC) to DA ratio. However, the same dose of raclopride was partly effective in reducing the effects of lower doses of quinpirole (0.01 and 0.03 mg/kg) on the striatal DOPAC to DA ratio. Raclopride (0.2 mg/kg) also partially but significantly reduced the locomotor stimulant effects of d-amphetamine in reserpinized mice. Biochemical analyses in the striata indicated that CY208243 slightly retarded DA turnover (as assessed by the DOPAC/DA ratio). SKF38393 itself also slightly reduced DA turnover. In automated activity cages, using mice depleted of DA with reserpine and alpha-methyltyrosine, all the D-2 receptor agonists tested, in combination with SKF38393, produced an increase in activity.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1989

Kinetic properties of the accumulation of 3H-raclopride in the mouse brain in vivo.

The kinetic properties of the accumulation of 3H-raclopride, a selective dopamine (DA) D-2 receptor antagonist, in mouse striatum in vivo was examined under various experimental conditions. The accumulation in striatum was saturable in contrast to that in cerebellum, which linearily increased with the dose. The specific binding of 3H-raclopride in the striatum, defined as the difference in the accumulation in striatum and cerebellum 30 min after the injection was completely inhibited by the D-2 receptor antagonists spiperone and (+)-butaclamol [but not (-)-butaclamol] and the DA receptor agonist N-n-propylnorapomorphine. The mean Bmax value of the specific binding was 40.7 +/- 2.8 pmol/g tissue and the mean apparent KD value, based on the dose injected, was 87.8 +/- 11.5 nmol/kg i.v. (18 different experiments). Pretreatment of the mice with a single injection of reserpine 4 h or 3 days beforehand reduced the apparent KD value which in part seemed to be due to the decreased concentration of synaptic DA. Similarly, gamma-butyrolactone injected immediately before raclopride reduced the apparent KD value, whereas amfonelic acid and (-)-amphetamine increased the observed KD values. These findings indicate competition between endogenous DA and raclopride for the D-2 receptors. Both reserpine and gamma-butyrolactone increased the apparent Bmax value by about 50% which indicates a receptor pool of DA for which raclopride does not compete.

4-Butyrolactone↗
PubMed1989

Kinetic properties of the in vivo accumulation of 3H-(-)-N-n-propylnorapomorphine in mouse brain.

(1) The influence of various dopamine (DA) receptor agonists and antagonists on the kinetic properties of the specific binding of 3H(-)-N-n-propylnorapomorphine (NPA) in the mouse striatum in vivo was studied. The specific binding of 3H-NPA, defined as the difference between the radioactivity in the striatum and cerebellum, was completely antagonized by the selective D-2 receptor antagonist raclopride but not by the selective D-1 antagonist SCH 23390, showing that the binding occurs exclusively to the D-2 receptors. (2) The selective D-2 receptor agonists pergolide and quinpirole inhibited the 3H-NPA binding biphasically at low doses, indicating that these DA receptor agonists have high affinities for a subfraction (10 to 30%) of the NPA binding sites. (3) Increasing the synaptic DA concentration by DA release [(+)-amphetamine] or uptake blockade (amfonelic acid and methylphenidate) inhibited the 3H-NPA binding in a competitive manner (unchanged Bmax, increased KD). Depletion of the DA in the synapses by gamma-butyrolactone or reserpine decreased the apparent KD value. (4) The possibility of estimating changes in the synaptic DA concentration from changes in the apparent KD is discussed. According to the results obtained, the normal concentration of DA in the synaptic cleft in mouse striatum in vivo is about 40 nmol/l and this concentration is increased 2 to 3 times by (+)-amphetamine and amfonelic acid in doses which evoke hyperactivity and stereotypic behaviour.

4-Butyrolactone↗
PubMed1989

Dopamine D2 agonist-induced behavioural depression is reversed by dopamine D1 agonists.

The dopamine (DA) D2 agonist bromocriptine produced dose-dependent locomotor depression in mice with intact stores of DA, as measured in automated activity cages. The DA D1 agonist CY208-243, reversed the bromocriptine-induced depression. Using direct observational analysis, another selective DA D2 agonist, quinpirole, induced dose-dependent depression and this was reversed by the D1 agonist SKF38393. The effect of SKF38393 could be blocked by prior pretreatment with SCH23390. It is concluded that DA D2 agonist-induced locomotor depression is mediated via a DA D2 autoreceptor-mediated inhibition of DA release onto postsynaptic DA receptors. This reduction in release probably deprives postsynaptic D1 and D2 receptors of endogenous DA. However, since bromocriptine (and probably quinpirole) in all likelihood occupies both pre- and postsynaptic D2 receptors immediately on injection, and since CY208-243 and SKF38393 (respectively) could reverse the depression, the depression seems to be due specifically to a deprivation of DA at postsynaptic D1 receptors.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1989

Sulphur dioxide-induced airway hyperreactivity and pulmonary inflammation in dogs.

Anaesthetised Beagle dogs were exposed to sulphur-dioxide (SO2) for 2 h and the pulmonary effects studied up to 24 h using bronchoalveolar lavage (BAL) and lung mechanics measurements. SO2-induced hyperreactivity to histamine was associated with epithelial cell shedding, an increase in airway permeability to plasma proteins and an increase in BAL PGE2 content. Leukotrienes were not recovered in BAL. Ibuprofen reduced hyperreactivity at 24 h post SO2 but not immediately after SO2 and had no effect on BAL cells at anytime. These results suggest that 2 phases of hyperreactivity exist--an immediate effect which may involve epithelial cell loss and a later phase which may be inflammatory.

Animals↗
PubMed1989

The effects on central dopamine function of chronic L-dopa (methyl ester hydrochloride) treatment of mice.

Mice were treated for 28 days with drinking water containing L-DOPA methyl ester hydrochloride (DME) plus carbidopa, carbidopa alone, or with the vehicle. All mice were then given the vehicle for 1 day and behavioural and biochemical assessments made on the 29th day. On average, mice consumed between 181 and 302 mg/kg of DME (expressed as the base) each day. In behavioural experiments DME- and carbidopa-treated mice were subsensitive to the locomotor stimulating effects of apomorphine, after their pretreatment with reserpine plus alpha-methyl-p-tyrosine to remove endogenous stores of dopamine and to stop its synthesis. Even mice pretreated for only one day with chronic DME or carbidopa displayed some subsensitivity to apomorphine challenge, but the effect was more marked the longer the chronic treatment. Other mice were chronically treated for 28 days with alpha-methylDOPA or vehicle, and these mice when challenged with apomorphine after dopamine depletion (as described above), were also markedly subsensitive to the locomotor activating effects of apomorphine. There were no changes in sensitivity of drug-treated mice to the hypothermic effects of apomorphine, to the stereotypy-inducing effects of apomorphine or d-amphetamine, or to the locomotor activating effects of L-DOPA itself or to bromocriptine. There were, however, some changes in the basal grooming behaviour of both DME- and carbidopa-treated mice, and in their response to SKF38393 challenge. Striatal binding studies with [3H]-spiperone and [3H]-SCH23390 indicated that there were no marked changes in Kd or Bmax of either D-1 or D-2 receptors.(ABSTRACT TRUNCATED AT 250 WORDS)

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1989

Nedocromil sodium and sensory nerves in the dog lung.

The effect of nedocromil sodium on the main sensory nerve types in the dog lung has been studied. Nedocromil sodium (0.1, 1.0 and 10 mg/kg i.v.) did not stimulate or inhibit the discharge pattern of pulmonary stretch receptors, rapidly adapting irritant receptors or pulmonary C-fibre endings. Nedocromil sodium 5 micrograms/kg given into the aortic arch did, however, stimulate bronchial C-fibre endings. These endings were also stimulated when the drug was given by aerosol. The possibility that nedocromil sodium suppresses cough in the dog by stimulation of bronchial C-fibre endings is discussed.

Animals↗
PubMed1989

The involvement of dopamine D1 and D2 receptors in the locomotor stimulation produced by (+)-amphetamine in naive and dopamine-depleted mice.

The interaction between (+)-amphetamine and dopamine (DA) D1 and D2 receptors was investigated. In naïve mice, i.e., mice with intact stores of DA, both the selective D1 antagonist SCH23390 and the selective D2 antagonist spiperone blocked the locomoter stimulation produced by (+)-amphetamine. The selective D1 agonist SKF38393 (6 mg/kg intraperitoneally) did not produce a consistent dose-dependent effect on the response to (+)-amphetamine in naïve mice. In mice depleted of DA with reserpine 24 hr before a challenge with (+)-amphetamine, neither SCH23390 nor spiperone were completely effective in blocking (+)-amphetamine. A combination of spiperone plus SCH23390 was, however, more effective than either drug alone, although significant activity remained even after the combination. In mice pretreated with reserpine and various doses of alpha methyl-p-tyrosine (alpha MPT, intraperitoneally), the degree of stimulation produced by (+)-amphetamine was dependent on the amount and frequency of alpha MPT dosage - the higher and more frequent the dose, the more effective the blockade. In these animals, both SKF38393 and the selective D2 agonist quinpirole potentiated the stimulation induced by (+)-amphetamine when the dose of alpha MPT was not maximal. However, in those animals pretreated with reserpine plus two doses each of 400 mg/kg alpha MPT, neither SKF38393 nor quinpirole were effective in potentiating (+)-amphetamine. Nevertheless, when SKF38393 and quinpirole were administered simultaneously to these mice, marked locomotor stimulation occurred implying that the pretreatment itself had not rendered the mice incapable of locomotion.(ABSTRACT TRUNCATED AT 250 WORDS)

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1989

Effect of nedocromil sodium on SO2-induced airway hyperresponsiveness and citric acid-induced cough in dogs.

In anaesthetized dogs exposed to SO2, nedocromil sodium prevented the increase in bronchial responsiveness to histamine challenge and suppressed the cellular changes taking place in the lung. In conscious dogs challenged with citric acid, by inhalation, nedocromil sodium prolonged the time to onset of coughing and had an inhibitory effect on the total number of coughs in each episode. Nedocromil sodium has been observed to stimulate bronchial C fibers, and it is suggested that this activity may relate to the antitussive effect of the compound.

Animals↗
PubMed1988

The motor effects of bromocriptine--a review.

For many years, bromocriptine has proven to be a useful treatment for some of the disabling motor effects seen in Parkinson's disease. As such, it has been the only commonly used directly acting D2 agonist available. But its mechanism of action has been obscure because many animal models indicated an absolute requirement for the presence of endogenous DA for bromocriptine to have any efficacy, despite its undoubted occupation of the D2 receptor with high affinity. Several scattered reports indicated, however, that bromocriptine could potentiate the effects of a number of other dopamine agonists (such as apomorphine and L-dopa) in a variety of pharmacological models and in the clinic. With the availability of SKF38393 and SCH23390, it soon became clear that bromocriptine, while a selective D2 agonist, depended in an absolute sense on the integrity of the D1 receptors. Thus, if SKF38393 was administered together with bromocriptine to rodents depleted of dopamine, marked locomotor excitation was produced, despite either drug alone being inactive. The present review explores the literature on the motor effects of bromocriptine and endeavours to integrate its behavioural, biochemical and electrophysiological effects into a coherent whole. It closes with a consideration of several remaining unsolved problems associated with the pharmacology of bromocriptine and suggests some future studies.

Animals↗
PubMed1988

Further studies on the interaction between bromocriptine and SKF38393 in reserpine and alpha methyl-para-tyrosine-treated mice.

In a previous report, we showed that the relatively selective dopamine (DA) D-2 agonist bromocriptine (BRC), when combined with the selective D-1 agonist SKF38393, produced in DA-depleted mice a marked locomotor stimulation, despite BRC and SKF38393 being inactive by themselves (Jackson and Hashizume 1986). The present series of experiments was designed to further explore this interaction. In all experiments, mice were pretreated with reserpine and/or alpha methyl-p-tyrosine (AMPT). In mice pretreated with reserpine, AMPT or reserpine plus AMPT, BRC plus SKF38393 produced marked excitation whether the BRC was given 3 or 1 h prior to the SKF38393 challenge. However, while there was no absolute requirement that BRC be given a certain time before SKF38393, this factor was of some importance, with the onset of locomotor stimulation produced by the combination being much more rapid if the BRC was given 3 h rather than 1 h before the SKF38393. Interestingly, the degree of locomotor stimulation produced by the combination was always greatest in the animals premedicated with reserpine alone. If AMPT was also used (with or without reserpine), the stimulation produced by the combination was reduced, which may have resulted in part from a non-specific depressant effect of the AMPT. From these results, it seems as though endogenous DA is not required for BRC to work, provided that D-1 receptors are stimulated.(ABSTRACT TRUNCATED AT 250 WORDS)

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