Cortical muscarinic receptors in demented patients with Alzheimer's disease or Parkinson's disease.
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Alzheimer Disease↗
Biomedical subjects
P Jenner
Publications and source records attributed to P Jenner.
The D1 agonist SKF 38393 inhibits the antiparkinsonian activity of the D2 agonist LY 171555 in the MPTP-treated marmoset.
Administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to common marmosets induced persistent motor deficits. Administration of the D1 agonist SKF 38393 (2.5-20 mg/kg, i.p.) caused a dose-dependent increase of this akinesia. Administration of the D2 agonist LY 171555 (0.3 mg/kg, i.p.) reversed the motor deficits induced by MPTP treatment. Pretreatment of animals with SKF 38393 (2.5-20 mg/kg, i.p.) caused dose-dependent inhibition of the anti-parkinsonian action of LY 171555 (0.3 mg/kg i.p.). In primates SKF 38393 does not reverse motor deficits induced by MPTP and inhibits the actions of a D2-agonist.
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
The D-1 dopamine receptor partial agonist, CY 208-243, exhibits antiparkinsonian activity in the MPTP-treated marmoset.
Administration of L-DOPA plus carbidopa, or the D-2 agonist (+)-PHNO, to MPTP-treated common marmosets caused motor hyperactivity and a reversal of the parkinsonian syndrome. In contrast, administration of the putative D-1 agonist SKF 38393 was without effect on movement or motor disability. The subsequent administration of another putative selective D-1 partial agonist CY 208-243 produced a dose-related improvement in motor activity and reversal of parkinsonian motor deficits in MPTP-treated animals. The effect of CY 208-243 was inhibited by pretreatment with the D-1 antagonist SCH 23390 and, to a lesser extent, by the D-2 antagonist sulpiride. In another group of normal drug naive marmosets, the administration of CY 208-243 produced only a small increase in motor activity. Following treatment with MPTP and without other drug administration, administration of CY 208-243 produced a marked reversal of motor deficits and locomotor hyperactivity. Thus, CY 208-243, suggested to be a partial D-1 agonist exhibits antiparkinsonian activity in MPTP-treated marmosets which does not require prior or concurrent exposure to D-2 agonists.
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
Ex vivo inhibition of rat brain cytochrome P-450 activity by stiripentol.
Stiripentol is an anti-epileptic drug of novel structure with previously demonstrated strong in vitro inhibitory activity on rat cerebral cytochrome P-450 mediated naphthalene hydroxylation [6]. When administered to rats as a single i.p. dose, the drug is presently shown to have the same in vitro effect. Maximal inhibition is seen 2 hr after administration, but at this time the brain concentrations of intact drug, although peaking, appear too low (ca. 11 micrograms/g tissue) to account for the intensity of the effect seen in vitro. This suggests in vivo activation to a metabolic intermediate forming a complex with cerebral cytochrome P-450, which 2 hr after dosing is fully insensitive to stiripentol added to incubates. Restoration of enzymic activity and of sensitivity to added stiripentol occurs progressively and is practically complete 24 hr after dosing.
Animals↗
Monoamine oxidase activity and distribution in marmoset brain: implications for MPTP toxicity.
This study describes the histochemical localisation of monoamine oxidase (MAO) in marmoset brain. No MAO A staining was observed but MAO B was found in many areas, with medium intensity of staining in the substantia nigra, and high intensity staining in the striatum and nucleus accumbens, among other regions. The high activity in the nigrostriatal tract, compared with the rat, may partially explain the greater sensitivity of the marmoset to MPTP toxicity. As in the rat, high activity was present in the raphe nuclei. However, unlike the rat, no enrichment of MAO B was observed in blood vessels or ventricular linings.
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
Bladder hyperreflexia induced in marmosets by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine.
In marmosets, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) causes degeneration of the cell bodies of the substantia nigra and the animals subsequently develop parkinsonian symptoms. Cystometrograms obtained from such animals while under pentobarbitone anaesthesia, showed their bladders to be hyperreflexic when compared to those of normal animals of the same age (less than 2 years). Bladder hyperreflexia is present in many parkinsonian patients and is difficult to treat, partly because it is made worse by dopaminergic agents. This is the first demonstration of an effect of MPTP on this type of peripheral function. It suggests the suitability of MPTP-treated marmosets for studying the mechanisms by which a loss of nigrostriatal dopamine leads to bladder hyperreflexia and for devising pharmacological strategies which may be of therapeutic value in the clinic.
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
The effect of carbidopa on plasma and muscle levels of L-dopa, dopamine, and their metabolites following L-dopa administration to rats.
Administration of L-dopa (L-3,4-dihydroxyphenylalanine) (200 mg/kg p.o.) to rats produced elevated plasma and muscle concentrations of both L-dopa and 3-O-methyldopa (3-OMD). This effect was potentiated by simultaneous administration of carbidopa (25 mg/kg p.o.). Both L-dopa and 3-OMD accumulated in muscle after administration of L-dopa with or without carbidopa. Elevated dopamine levels were detected in both muscle and plasma after treatment with L-dopa alone. Concurrent administration of carbidopa only diminished dopamine levels in plasma, and the duration of raised dopamine levels in muscle was increased. Carbidopa administration had no effect on the elevated plasma concentrations of 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) caused by L-dopa administration. In muscle, carbidopa treatment tended to prolong the duration of raised metabolite levels. Muscle appears to accumulate L-dopa at a site where decarboxylation is not totally prevented by concurrent carbidopa administration, and where dopamine is not degraded as actively as in other tissues. The muscle sink for L-dopa may influence the plasma profile of the amino acid, which has implications for the therapeutic response to L-dopa in Parkinson's disease.
3,4-Dihydroxyphenylacetic Acid↗
Receptor changes during chronic dopaminergic stimulation.
The underlying cause of the long term complications of L-DOPA or dopamine agonist therapy in Parkinson's disease remains unknown. Previous studies of repeated administration of L-DOPA or bromocriptine to rodents have shown increases, decreases or no change in brain dopaminergic activity. For this reason we have re-examined the effects of chronic L-DOPA or dopamine agonist administration on brain dopamine receptor function in rats. Repeated intraperitoneal administration of L-DOPA to rats for 21 days followed by 3 days drug withdrawal caused an enhancement of apomorphine-induced stereotypy but no apparent alteration in striatal dopamine receptor numbers or affinity (as judged by 3H-spiperone; 3H-NPA and 3H-piflutixol binding). Chronic oral administration of L-DOPA plus carbidopa to rats for one year was without effect on apomorphine-induced stereotypy or striatal D-2 dopamine receptors. Similarly, no effects were observed on striatal dopamine function following one year's administration of bromocriptine. Pergolide produced an enhancement of apomorphine-induced stereotypy but a decrease in D-2 receptor density as judged by 3H-spiperone binding. In rats with a unilateral 6-OHDA lesion of the medial forebrain bundle the oral administration of L-DOPA plus carbidopa for 4 weeks, followed by 4 days withdrawal, enhanced the rate of apomorphine-induced contraversive rotation. It appears difficult, at least in rats, to manipulate striatal dopamine receptors with L-DOPA or dopamine agonist drugs. An enhancement of motor behaviour can occur in the presence of no change or a decrease in dopamine receptor numbers identified by in vitro ligand binding to tissue homogenates.
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
The pharmacological characterisation of pilocarpine-induced purposeless chewing behaviour in the rat.
Purposeless chewing in rats was induced by the acute administration of the cholinergic agonist pilocarpine or by physostigmine. Pilocarpine-induced chewing was antagonised by the centrally acting anticholinergic drugs scopolamine, benzhexol and secoverine, but not by the peripherally acting anticholinergic drug methylscopolamine. Both benzhexol and secoverine caused dose-dependent inhibition of pilocarpine-induced chewing. The D-2 antagonist sulpiride and the D-1 antagonist SCH 23390 did not inhibit pilocarpine-induced chewing. The non-selective neuroleptics pimozide, trifluoperazine and thioridazine also were inactive. In contrast, clozapine caused a dose-related inhibition of pilocarpine-induced chewing. The alpha-1 antagonist prazosin, the alpha-2 antagonist idazoxan, the beta-antagonists propranolol and metoprolol and the H-1 antagonist mepyramine did not reduce pilocarpine-induced chewing. Purposeless chewing behaviour induced by pilocarpine was reduced in a dose-related manner by the administration of the 5-HT antagonists methiothepin and mianserin, but not by spiperone or ketanserin. These data confirm that pilocarpine-induced chewing behaviour in the rat is a model of central cholinergic activity, but suggest that a serotonergic component may be involved in the mediation of this behaviour.
Adrenergic alpha-Antagonists↗
High affinity binding of [3H] (-)-nicotine to rat brain membranes and its inhibition by analogues of nicotine.
Analysis of the characteristics of cerebral binding of [3H] (-)-nicotine revealed a single population of sites with high affinity (KD = 6.0 +/- 0.6 nM). The regional distribution of the binding of [3H] (-)-nicotine was heterogeneous with the largest concentration of binding sites being in the thalamus, cortex and striatum, and a low level of binding activity in the cerebellum and hypothalamus. Competition studies showed that several metabolites and congeners of nicotine potently competed with [3H] (-)-nicotine and their in vitro activity was correlated with behavioural activity, as estimated from previously published data for rats trained to discriminate central effects of nicotine. Conversely, nicotine antagonists, with the exception of dihydro-beta-erythroidine, were weak or inactive in this binding assay. It is concluded that the binding site for [3H] (-)-nicotine investigated probably mediates at least one of the behavioural effects of nicotine, the nicotine discrimative stimulus.
Animals↗
The effect of long-term treatment with amine-depleting drugs or chlorpromazine on alpha-adrenoreceptors and 5-HT2 receptors in the brain of the rat.
The effect of chlorpromazine, oxypertine, tetrabenazine or reserpine on alpha-adrenoreceptors and 5-HT2 receptors in the brain of the rat was studied both in vitro and after the administration to animals for up to 12 months. In vitro, chlorpromazine and oxypertine potently displaced the specific binding of [3H]WB 4101 to alpha 1 adrenoreceptors in the cortex and of [3H]ketanserin to 5-HT2 receptors in the frontal cortex. Both drugs were moderately effective in displacing the specific binding of [3H]clonidine from cortical alpha 2-adrenoreceptors. Tetrabenazine only weakly displaced the specific binding of [3H]WB 4101, [3H] clonidine and [3H]ketanserin. The incorporation of reserpine into tissue incubates had little effect on the binding of any of these ligands. Administration of chlorpromazine (33-36 mg/kg/day) to rats for up to 12 months reduced the number of specific binding sites (Bmax) for [3H]ketanserin in the frontal cortex, but did not alter the specific binding of [3H]WB 4101 or specific [3H]clonidine to cortical membranes. In contrast, treatment with oxypertine (6.3-7.3 mg/kg/day), tetrabenazine (6.0-6.7 mg/kg/day) or reserpine (0.28-0.30 mg/kg/day) increased the Bmax for the specific binding of [3H]WB 4101, but did not alter the specific binding of [3H]clonidine or [3H]ketanserin. Oxypertine resembles chlorpromazine in its ability to interact with alpha-adrenoreceptors and 5-HT2 receptors in brain. Tetrabenazine and reserpine have few direct actions on post-synaptic monoamine receptors. However, on long-term administration, oxypertine, like tetrabenazine and reserpine, predominantly altered alpha 1-adrenoreceptors, whereas chlorpromazine influenced the population of 5-HT2 receptors.
Animals↗
Levels of Met-enkephalin, Leu-enkephalin, substance P and cholecystokinin in the brain of the common marmoset following long term 1-methyl-4-phenyl-1,2,3,6,-tetrahydropyridine treatment.
Common marmosets were treated daily with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP, 7-9 mg/kg i.p.) for 25 days, and then kept out of drug for three months before biochemical measurements in various brain areas. This treatment induced a dramatic fall (-80%) in dopamine, homovanillic acid and dihydroxyphenylacetic acid levels in the putamen and caudate nucleus, and a significant but less pronounced reduction (less than or equal to 50%) in the levels of these compounds in the nucleus accumbens. In contrast, the concentrations of four neuropeptides: met-enkephalin, leu-enkephalin, substance P, and cholecystokinin, remained unaltered in all brain areas examined in MPTP-treated marmosets. Therefore the neuropeptide alterations previously reported in Parkinson's disease are probably not secondary to the severe lesion of dopaminergic neurones, but constitute another intrinsic feature of the disease.
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
The interaction of substituted benzamides with brain benzodiazepine binding sites in vitro.
1. The interaction of substituted benzamides with brain benzodiazepine (BDZ) binding sites was examined by their ability to displace [3H]-flunitrazepam ([3H]-FNM) from specific binding sites in bovine cortical membranes in vitro. 2. Clebopride, Delagrange 2674, Delagrange 2335 and BRL 20627 displayed concentration-dependent displacement of [3H]-FNM with IC50 values of 73 nM, 132 nM, 7.7 microM and 5.9 microM, respectively. Other substituted benzamides including metoclopramide, sulpiride, tiapride, sultopride and cisapride were inactive at 10(-5) M. 3. Inhibition by clebopride and Delagrange 2674 of [3H]-FNM binding was apparently competitive and readily reversible. 4. In the presence of gamma-aminobutyric acid (GABA), the ability of diazepam and Delagrange 2674 to displace [3H]-Ro 15-1788 binding was increased 3.6 and 1.6 fold respectively, compared to the absence of GABA, while ethyl beta-carboline-3-carboxylate (beta CCE) and clebopride were less potent in the presence of GABA. 5. Diazepam was 30 fold less potent at displacing [3H]-Ro 15-1788 in membranes that had been photoaffinity labelled with FNM than in control membranes, whereas the potency of beta CCE did not differ. Clebopride and Delagrange 2674 showed a less than two fold loss of potency in photoaffinity labelled membranes. 6. The pattern of binding of clebopride and Delagrange 2674 in these in vitro tests is similar to that found previously with partial agonists or antagonists at BDZ binding sites. 7. Clebopride and Delagrange 2674 inhibited [3H]-FNM binding with similar potency in rat cerebellar and hippocampal membranes, suggesting they have no selectivity for BDZ1 and BDZ2 binding sites. 8. Clebopride and Delagrange 2674 are structurally dissimilar to other BDZ ligands and represent another chemical structure to probe brain BDZ binding sites.
Affinity Labels↗
Definition of the in-vivo accumulation of [3H]spiperone in brain using haloperidol and sulpiride to determine functional dopamine receptor occupation.
The in-vivo administration of [3H]spiperone caused an accumulation of radioactivity in the substantia nigra, tuberculum olfactorium, nucleus accumbens, striatum and frontal cortex when compared with cerebellar levels. Haloperidol (0.01-1.0 mg kg-1 i.p.) dose-dependently prevented the accumulation of [3H]spiperone in the substantia nigra, tuberculum olfactorium, striatum and nucleus accumbens. Sulpiride (10-160 mg kg-1 i.p.) dose-dependently prevented the accumulation of [3H]spiperone only in the substantia nigra. The effects of sulpiride on other areas were not consistent; there was a suggestion of a reduction in the accumulation of [3H]spiperone in tuberculum olfactorium and striatum, but not in nucleus accumbens. Neither haloperidol (0.01-1.0 mg kg-1 i.p.) nor sulpiride (10-160 mg kg-1 i.p.) caused displacement of [3H]spiperone from the frontal cortex. Both haloperidol (0.01-0.5 mg kg-1) and sulpiride (10-80 mg kg-1) increased striatal and mesolimbic HVA concentrations. Haloperidol potently blocked apomorphine-induced stereotypy but sulpiride was only effective at the highest dose employed. The functional effect produced by haloperidol correlated with its ability to define [3H]spiperone binding in-vivo to dopamine receptors in the substantia nigra, striatum and tuberculum olfactorium. In contrast, there was no correlation between functional effect of sulpiride and its ability to define [3H]spiperone binding in-vivo.
Animals↗
Comparison of the in-vitro receptor selectivity of substituted benzamide drugs for brain neurotransmitter receptors.
The in-vitro selectivity of a group of substituted benzamide drugs for brain neurotransmitter receptors was determined to assess the most appropriate drugs for use in human PET studies. All substituted benzamide drugs studied inhibited [3H]haloperidol and [3H]spiperone binding to rat striatal membranes. The most potent compounds were YM 09151-2, clebopride and raclopride. However, these substances also interacted in differing degrees with alpha-1, alpha-2, beta-adrenergic, 5-HT-1, 5-HT-2, and opiate sites. Sulpiride, alizapride, SL 74205, TER 1546 and tiapride were specific for D-2 receptors, but these drugs were active only in the 10(-7)-10(-6) M range. Raclopride, amisulpiride and sultopride showed a 100-1000 differentiation between action on dopamine sites compared with other neurotransmitter receptors. No such selectivity was observed for clebopride or YM 09151-2. Specific substituted benzamides such as alizapride, may be appropriate in high concentrations for defining the interaction of PET ligands with brain dopamine receptors. More potent, but selective, drugs such as raclopride and amisulpiride, may be effective in low concentrations as ligands for labelling dopamine receptor sites. However, the ability of these various substituted benzamide drugs to penetrate into brain and in-vivo to identify dopamine receptors in all brain areas must be assessed.
Animals↗
Leukocyte glutamate dehydrogenase activity in patients with degenerative neurological disorders.
Leukocyte glutamate dehydrogenase (GDH) activity was measured in 39 normal subjects, 32 neurological controls, 66 patients with progressive ataxic disorders, 32 with multiple system atrophy, 40 with Parkinson's disease, eight with Steele-Richardson-Olszewski syndrome, eight with juvenile Parkinsonism and four with the dystonia-Parkinsonism syndrome. GDH activity was reproducible to within 10% in leukocyte pellets stored at -70 degrees C for up to 9 months, and did not vary with sex or age in control subjects. There was marked variation in the relative proportions of heat stable and heat labile forms of GDH between control subjects and on repeated assay in the same subject. Total leukocyte GDH activity was similar in normal subjects and neurological controls. Mean total GDH activity was reduced in all patient groups by between 15 to 29% compared with controls. Fourteen patients had total GDH activity below 50% of the control mean, but low values were not specific for any one disease (five had ataxic disorders, four Parkinson's disease, three multiple system atrophy, one juvenile Parkinsonism, and one dystonia-Parkinsonism). The heat labile fraction of GDH represented about 20% of total activity in control subjects, and 27% in the patients with reduced total GDH activity. Thus low GDH activity was not disease-specific in this study, and the heat-labile GDH fraction was not selectively affected. "Reduced" leucocyte GDH activity in some patients may represent no more than the lower end of a normal distribution.
Adult↗
In vitro inhibition by stiripentol of rat brain cytochrome P-450-mediated naphthalene hydroxylation.
1. The formation of 1-naphthol from naphthalene was investigated in rat brain 105,000 g particulate fraction. The reaction showed NADPH dependency and was inhibited by carbon monoxide. Michaelis-Menten kinetics were apparent with Vmax = 0.264 pmol/mg protein per min and Km = 22.6 microM. 2. Stiripentol, an antiepileptic drug containing a methylenedioxybenzene moiety, proved to be a potent inhibitor of the reaction, with an IC50 value close to 1 microM under the conditions of study and without preincubation. 3. The inhibitory activity of stiripentol was seen mainly after metabolic activation of the drug. The inhibitory effect appeared progressively when substrate and inhibitor were added together to the incubates, whereas its appearance was more rapid following preincubation of stiripentol.
Animals↗
Adaptive changes in brain dopamine function as a result of neuroleptic treatment.
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Animals↗