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Biomedical subjects

P Jenner

Publications and source records attributed to P Jenner.

At least 343 records · Page 19Linked to original sources
PubMed1985

Chronic treatment with clozapine, unlike haloperidol, does not induce changes in striatal D-2 receptor function in the rat.

Comparison has been made of the effects on brain dopamine function of chronic administration of haloperidol or clozapine to rats for up to 12 months. In rats treated for 1-12 months with haloperidol (1.4-1.6 mg/kg/day), purposeless chewing jaw movements emerged. These movements were only observed after 12 months' treatment with clozapine (24-27 mg/kg/day). Apomorphine-induced (0.125-0.25 mg/kg) stereotyped behaviour was inhibited during 12 months treatment with haloperidol. Clozapine treatment was without effect. After 12 months, stereotypy induced by higher doses of apomorphine (0.5-1.0 mg/kg) was enhanced in haloperidol, but not clozapine, treated rats. Bmax for striatal 3H-spiperone binding was elevated throughout 12 months of haloperidol administration, but was not altered by clozapine treatment. Bmax for striatal 3H-NPA binding was only elevated after 12 months of haloperidol treatment; clozapine treatment was without effect. Bmax for 3H-piflutixol binding was not altered by haloperidol treatment, but was increased after 9 and 12 months of clozapine treatment. Dopamine (50 microM)-stimulated adenylate cyclase activity was inhibited after 1 month's haloperidol treatment but normal thereafter. Adenylate cyclase activity was not altered by chronic clozapine treatment. Striatal acetylcholine content was increased after 3 and 12 months of haloperidol or clozapine intake. These findings indicate that the chronic administration of the atypical neuroleptic clozapine does not produce changes in brain dopamine function which mirror those of the typical neuroleptic haloperidol. In particular, chronic administration of clozapine, unlike haloperidol, does not appear to induce striatal D-2 receptor supersensitivity. Unexpectedly, clozapine treatment, unlike haloperidol, altered D-1 receptor function.

Acetylcholine↗
PubMed1985

Acute administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine affects the adrenal glands as well as the brain in the marmoset.

A parkinsonian syndrome was induced in marmosets by administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) for 4 days. Ten days following the onset of drug administration, brainstem and adrenal tissues were assayed for levels of monoamines and their metabolites. In the brainstem tegmentum, dopamine, its metabolites homovanillic acid (HVA) and dihydroxyphenylacetic acid (DOPAC), and noradrenaline were reduced, whereas 5-hydroxytryptamine (5-HT) levels were elevated, in comparison with untreated controls. In the adrenal gland, 5-HT and adrenaline levels were unchanged, but dopamine and noradrenaline were substantially elevated.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1985

The dopamine D2 agonist LY 141865, but not the D1 agonist SKF 38393, reverses parkinsonism induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in the common marmoset.

Marmosets treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) (1-4 mg/kg i.p. daily for up to 8 days) develop profound parkinsonian akinesia. Administration of the D1 agonist SKF 38393 (1-20 mg/kg i.p.) 4-6 weeks later had no effect on the motor activity of animals pretreated with MPTP. In contrast, the administration of the D2 agonist LY 141865 (0.1 or 0.5 mg/kg i.p.) caused a marked increase in motor activity lasting for up to 2 h. We conclude that stimulation of D2 dopamine receptors is essential for motor activation of parkinsonian marmosets and that D1 stimulation alone is not sufficient to overcome the akinesia induced by MPTP treatment.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1985

SCH 23390 may alter dopamine-mediated motor behaviour via striatal D-1 receptors.

SCH 23390 potently displaced the specific binding of 3H-piflutixol to D-1 sites in striatal membranes but haloperidol was only weakly effective. SCH 23390 weakly displaced specific 3H-spiperone binding to D-2 sites, but haloperidol was potent. SCH 23390 was more effective than haloperidol in inhibiting dopamine stimulated striatal adenylate cyclase activity. These results confirm the D-1 selectivity of SCH 23390. However, SCH 23390 inhibited apomorphine-induced stereotypy and climbing behaviour in rats with equal potency to haloperidol. Haloperidol dose-dependently increased striatal HVA and DOPAC concentrations without altering dopamine content. Low doses of SCH 23390 elevated striatal DOPAC concentrations but higher doses were without effect; striatal dopamine and HVA overall was unaffected by administration of SCH 23390. Haloperidol did not affect basal 3H-acetylcholine release from striatal slices but reversed the apomorphine-induced inhibition of 3H-acetylcholine release. SCH 23390 did not affect basal 3H-acetylcholine release nor did it reverse the apomorphine-induced inhibition of 3H-acetylcholine release. The ability of SCH 23390 to inhibit motor behaviour in the rat may be due to its action on D-1 receptors since the drug does not cause typical changes in parameters of striatal D-2 receptor function.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1985

Lack of effect of intranigral administration of a dopamine analogue, (+/-)-3-(3-hydroxyphenyl)-N,n-propylpiperidine [(+/-)-3-PPP], on nigrostriatal dopamine neurones.

Bilateral injection of apomorphine into the zona reticulata of substantia nigra in rats reduced locomotor activity and striatal dopamine (DA) turnover. In contrast, bilateral injection of (+/-)-3-(3-hydroxyphenyl)-N,n-propylpiperidine [(+/-)-3-PPP] into the zona reticulata (ZR) did not reduce locomotor activity and did not affect striatal DA turnover. A high dose of (+/-)-3-PPP increased locomotor activity. Unilateral injection of (+/-)-3-PPP, but not of apomorphine, into the ZR induced a brief period of contraversive rotation. (+/-)-3-PPP may not alter nigral DA autoreceptor function but may interact with DA receptors located on non-dopaminergic nigral neurones.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1985

Differential alteration of striatal D-1 and D-2 receptors induced by the long-term administration of haloperidol, sulpiride or clozapine to rats.

Rats received haloperidol, sulpiride, or clozapine in their daily drinking water for up to 1 year in clinically equivalent doses. After 12 months' drug intake, and while drug administration continued, striatal dopamine function was assessed. Haloperidol induced D-2 receptor hypersensitivity as shown by enhanced apomorphine-induced stereotypy, elevated Bmax for specific 3H-spiperone and 3H-NPA binding, and an increase in striatal acetylcholine content. D-1 receptor sites appeared unaffected, since dopamine-stimulated adenylate cyclase and specific 3H-piflutixol binding were not altered. In contrast, neither sulpiride nor clozapine enhanced apomorphine-induced stereotypy or increased Bmax for 3H-spiperone binding. Sulpiride, but not clozapine, increased Bmax for 3H-NPA binding; clozapine, but not sulpiride, elevated striatal acetyl choline concentrations. In general, both sulpiride and clozapine enhanced D-1 function as assessed by dopamine-stimulated adenylate cyclase or 3H-piflutixol binding. On acute administration sulpiride and clozapine appear to act at D-2 sites, but continuous chronic administration of these compounds does not result in the development of striatal D-2 receptor hypersensitivity. The absence of change in D-2 function during chronic treatment, coupled with an ability to enhance D-1 function, may contribute to the low incidence of tardive dyskinesia produced by these drugs in man.

Animals↗
PubMed1985

Pharmacological characterisation of spontaneous or drug-associated purposeless chewing movements in rats.

Continuous administration of haloperidol, sulpiride, or cis-flupenthixol, but not of domperidone or apomorphine, to Wistar rats for up to 3 weeks caused an increase in spontaneous purposeless chewing movements. Treatment with physostigmine and pilocarpine, but not neostigmine, for up to 3 weeks increased chewing, whilst scopolamine decreased chewing. Metergoline and cyproheptadine, but not quipazine, increased chewing after only 1 and 7 days but not thereafter. Chewing was not altered following treatment with compounds acting on GABA or noradrenaline systems or by a range of non-neuroleptic agents inducing dystonia in man. The enhancement of chewing induced by neuroleptic and cholinomimetic drugs was reduced by acute treatment with scopolamine, and reverted to control levels following drug withdrawal. Neuroleptic-induced purposeless chewing in Wistar rats appears to be primarily influenced by cerebral dopamine and acetylcholine function and may resemble acute dystonia, rather than tardive dyskinesia.

Acetylcholine↗
PubMed1985

Effects of discontinuous drug administration on the development of dopamine receptor supersensitivity during chronic trifluoperazine or cis-flupenthixol administration to rats.

Rats received continuous or discontinuous administration of trifluoperazine or cis-flupenthixol in drinking water for up to 12 months. Continuous and discontinuous trifluoperazine administration had no consistent effect on apomorphine-induced stereotyped behaviour and there was no difference between drug treatments. Continuous and discontinuous cis-flupenthixol administration enhanced apomorphine-induced stereotypy, but there was no difference in the effect of the two drug treatments. Both continuous and discontinuous administration of trifluoperazine increased the number of specific striatal 3H-spiperone binding sites (Bmax). Over the period of treatment there was no difference in the effects of the different treatments. Continuous or discontinuous cis-flupenthixol intake did not increase Bmax after 6 or 12 months intake. Continuous or discontinuous neuroleptic treatment produced no difference in functional striatal dopamine receptor activity as judged by apomorphine-induced stereotyped behaviour. Ligand binding studies also suggest that the overall change in striatal receptor function is not affected by the use of a discontinuous drug regime.

Animals↗
PubMed1985

Mesolimbic dopamine function is not altered during continuous chronic treatment of rats with typical or atypical neuroleptic drugs.

Rats were treated continuously for up to 20 months with either haloperidol (1.4-1.6 mg/kg/day), sulpiride (102-109 mg/kg/day) or clozapine (24-27 mg/kg/day). Bmax for specific mesolimbic binding of 3H-spiperone, 3H-N, n-propylnorapomorphine or 3H-piflutixol did not differ in tissue taken from animals treated for up to 12 months with haloperidol, sulpiride or clozapine by comparison to age-matched control rats. Mesolimbic dopamine (50 microM)-stimulated adenylate cyclase activity was not altered in any drug treatment group. Spontaneous locomotor activity was transiently decreased during treatment with haloperidol for 1 or 3 months, but not by chronic sulpiride or clozapine treatment. Locomotor activity was not consistently increased in any drug treatment group. After 20 months of continuous drug treatment, focal bilateral application of dopamine (12.5 or 25 micrograms) into the nucleus accumbens caused equivalent increases in locomotor activity in control rats and in animals receiving haloperidol, sulpiride or clozapine. These findings suggest that dopamine receptor blockade is not maintained in the mesolimbic area following chronic treatment with haloperidol, sulpiride or clozapine, and indicate that, under these conditions, clozapine and sulpiride may not act selectively on mesolimbic dopamine receptors.

Adenylyl Cyclases↗
PubMed1985

Myoclonus in the rat induced by p,p'-DDT and the role of altered monoamine function.

Administration of p,p'-DDT to rats produced myoclonus, but unlike previous studies in mice, this was not decreased by administration of clonazepam. Precursors of 5-hydroxytryptamine (5-HT) (L-tryptophan and L-5-HTP) reduced the intensity of myoclonus, but the 5-HT agonists, quipazine and Org 6582 did not. Antagonists of 5-HT (methergoline, methysergide and cinanserin) did not potentiate the myoclonus induced by p,p'-DDT. Drugs altering the function of dopamine and noradrenaline (apomorphine, clonidine or phenoxybenzamine) also had no effect on this myoclonus. Administration of monoamine oxidase inhibitors (MAOIs; pargyline, nialamide and tranylcypromine) markedly attenuated the myoclonus, an effect that could not be attributed to an action on any one monoamine system. No observable changes in cerebral biochemical parameters of 5-HT occurred at the onset of myoclonus, although tryptophan and 5-hydroxyindoleacetic acid (5-HIAA) in brain were increased following periods of prolonged myoclonus. Electrophysiological analysis of the myoclonus in the rat induced by p,p'-DDT revealed changes in EEG and EMG activity which suggested an origin for the myoclonus in the brainstem. Although this was similar to electrophysiological findings in some human patients with post-anoxic action myoclonus, the pharmacological studies suggest that the myoclonus induced by p,p'-DDT in the rat is not a suitable model for screening potential drugs to be used in the treatment of this disorder.

Animals↗
PubMed1985

Comparison of the effects of benzodiazepines and other anticonvulsant drugs on synthesis and utilization of 5-HT in mouse brain.

Acute administration of clonazepam (0.5-8.0 mg/kg, i.p.), diazepam (2-32 mg/kg, i.p.), chlordiazepoxide (1-40 mg/kg, i.p.) or diphenylhydantoin (5-320 mg/kg, i.p.), caused a dose-related elevation of the concentrations of, 5-hydroxytryptamine (5-HT), 5-hydroxyindoleacetic acid (5-HIAA) and tryptophan in whole mouse brain. Carbamazepine (5-100 mg/kg, i.p.), and phenobarbitone (10-80 mg/kg, i.p.) raised the concentrations of 5-HT and 5-HIAA in the brain, whereas flurazepam (5-80 mg/kg, i.p.) only elevated the level of 5-HIAA. After administration of L[G-3H]tryptophan (25 microCi, s.c.), clonazepam (4 mg/kg), diazepam (32 mg/kg, i.p.), chlordiazepoxide (40 mg/kg) or diphenylhydantoin (40 mg/kg), but not carbamazepine (50 mg/kg), flurazepam (40 mg/kg) or phenobarbitone (80 mg/kg), increased the content of labelled tryptophan in brain. However, administration of drugs did not alter the incorporation of the label into [3H]5-HT, suggesting that the synthesis of 5-HT was unaffected. When incorporation of [3H]tryptophan into [3H]5-HT was complete and the pool of labelled 5-HT was decreasing, clonazepam, diazepam, chlordiazepoxide and diphenylhydantoin elevated the content of [3H]5-HT in brain. Flurazepam, phenobarbitone and carbamazepine were without apparent effect. Calculation of the rate of utilization of 5-HT (Km) showed that all drugs, apart from flurazepam, reduced the utilization of 5-HT. Using the rate of disappearance of 5-HT after inhibition of tryptophan hydroxylase by p-chlorophenylalanine (PCPA), all drugs, except flurazepam, diphenylhydantoin and phenobarbitone, decreased the utilization of 5-HT. The major action of the anticonvulsant drugs on the function of 5-HT in brain appears to be a decrease in the utilization of 5-HT without altering synthesis.

Animals↗
PubMed1985

Behavioural effects in rats of unilateral and bilateral injections of opiate receptor agonists into the globus pallidus.

Unilateral injections of a putative kappa-opiate receptor agonist, ethylketocyclazocine, into the globus pallidus of rats caused dose-dependent ipsiversive circling which was inhibited by prior systemic administration of the opiate receptor antagonist naloxone. Neither a putative delta-opiate receptor agonist ( [D-Ala2, D-Leu5]enkephalin) nor a putative mu-opiate receptor agonist (Tyr-D-Ala-Gly-MePhe-Met(0)-ol) induced circling behaviour after unilateral intrapallidal injection. Bilateral intrapallidal injection of the delta-opiate receptor agonist or the mu-opiate receptor agonist caused an increase in locomotor activity which in both cases was reduced by systemic administration of naloxone. A specific delta-receptor antagonist, (N,N-bisalyl-Tyr-Gly-Gly-psi-(CH2S)-Phe-Leu-OH) had no effect on the increase in locomotor activity caused by the delta-opiate receptor agonist. Bilateral intrapallidal injection of the kappa-opiate receptor agonist had no effect on locomotor activity. It is suggested that different opiate receptor subtypes within the globus pallidus differentially mediate circling and locomotor behaviour.

Animals↗
PubMed1985

Evidence that [3H]dopamine is taken up and released from nondopaminergic nerve terminals in the rat substantia nigra in vitro.

Potassium chloride (25 mM) and (+)-amphetamine (100 microM) both stimulated the release of radioactivity from slices of substantia nigra preincubated with [3H]3,4-dihydroxyphenylethylamine [( 3H]dopamine). Potassium chloride (25 mM) released radioactivity from slices of both zona compacta and zona reticulata. Prior 6-hydroxydopamine (6-OHDA) lesions of one nigrostriatal pathway did not reduce the spontaneous release of radioactivity, or the potassium chloride- or amphetamine-induced release of radioactivity from slices of nigra ipsilateral to the lesion after preincubation with [3H]dopamine. The accumulation of radioactivity following incubation of nigral slices from 6-OHDA-lesioned animals with [3H]dopamine was increased when compared to uptake into slices from intact tissue. In synaptosomal preparations of striatum, nomifensine but not desipramine or fluoxetine inhibited [3H]dopamine uptake. In contrast, nomifensine, desipramine, and fluoxetine all inhibited [3H]dopamine uptake in nigral synaptosomal preparations. Following 6-OHDA lesions of one nigrostriatal pathway the uptake of [3H]dopamine into nigral synaptosomal preparations was unchanged but uptake into striatal preparations was substantially decreased. In contrast, bilateral electrolesions of the dorsal and medial raphe nuclei reduced [3H]dopamine uptake into nigral preparations but not into striatal synaptosomes. The uptake of [3H]5-hydroxytryptamine ([3H]5-HT) into synaptosomal preparations of substantia nigra was abolished by fluoxetine and reduced by desipramine, but was unaffected by nomifensine. In contrast, fluoxetine, desipramine, and nomifensine all inhibited [3H]5-HT uptake into striatal synaptosomal preparations. Following 6-OHDA lesions of one nigro-striatal pathway the uptake of [3H]5-HT into nigral synaptosomal preparations was unchanged but uptake into striatal preparations was reduced.(ABSTRACT TRUNCATED AT 250 WORDS)

Amphetamine↗
PubMed1985

Properties of rat striatal D-2 dopamine receptors solubilized with the zwitterionic detergent CHAPS.

The specific binding of [3H]spiperone was determined in membrane preparations of rat striatum and following solubilization treatment with the zwitterionic detergent CHAPS. Membrane protein solubilization was confirmed by ultrafiltration, gel filtration and increased heat sensitivity. Specific binding of [3H]spiperone to the solubilized preparation was saturable and of high affinity, although solubilization led to an approximate 10 fold decrease in receptor affinity for [3H]spiperone. The drug displacement profile of binding to the CHAPS solubilized preparation corresponded to that of the dopamine D-2 receptor; binding was stereoselectively displaced by the isomers of butaclamol. The sodium dependence of sulpiride displacement of specific [3H]spiperone binding was retained in the CHAPS solubilized preparation. GTP (100 microM) only altered the ability of dopamine to displace [3H]spiperone binding to the solubilized preparation in the presence of 120 mM sodium chloride. The GTP effect was small compared with that observed in the membranes. Specific [3H]spiperone binding sites in the solubilized preparation were preferentially retained by a wheat germ agglutinin affinity column and subsequently eluted with N-acetyl-D-glucosamine. Gel filtration of the solubilized preparation using a Sepharose column resulted in two peaks of specific [3H]spiperone binding, the larger component had a Stokes radius of 7.7 nm. CHAPS treatment of rat striatal membranes results in solubilization of the D-2 receptor in an active form. The D-2 site appears to be a glycoprotein of high molecular weight.

Adsorption↗
PubMed1984

The binding of [3H]N-(chloroethyl)-norapomorphine to rat striatal membranes.

N-(chloroethyl)-norapomorphine (NCA) irreversibly inhibits striatal dopamine function, the binding of dopamine agonist ligands and dopamine-stimulated adenylate cyclase. A selective interaction of [3H]NCA with dopamine receptor sites would be of use in the characterisation and isolation of brain dopamine receptors. In this study the binding of [3H]NCA to homogenates of rat striatum was investigated. Binding of [3H]NCA to striatal preparations was saturable and irreversible and prevented with high affinity by dopamine agonist drugs with a catechol moiety. However, binding was not prevented in a stereoselective manner by the isomers of butaclamol, flupenthixol or sultopride. Nor was [3H]NCA binding specific to brain areas containing dopamine receptors. We conclude that [3H]NCA binding is not selective for dopamine receptors, although NCA inhibited both [3H]N,n-propylnorapomorphine (NPA) and [3H]spiperone binding in a non-competitive manner.

Amisulpride↗
PubMed1984

Correlation of [3H]5-hydroxytryptamine (5HT) binding to brain stem preparations and the production and prevention of myoclonus in guinea pig by 5HT agonists and antagonists.

In guinea pig brain stem preparations [3H]5-hydroxytryptamine (5HT) bound specifically to both high and low affinity sites, but specific [3H]spiperone binding was low and could not be consistently detected. This indicates a prevalence of 5HT-1 type receptors in this tissue. High affinity-specific [3H]5HT binding was more potently displaced by indole-containing 5HT agonists than by piperazine-containing 5HT agonists. This agreed with the observation that indole-containing, but not piperazine-containing compounds induced dose-dependent myoclonus in guinea pigs which originates from brain stem. The capacity of indoleamine antagonists to displace [3H]5HT-specific binding from guinea pig brain stem was similar to their reported potency in displacing [3H]5HT from 5HT-1 receptors. The [3H]5HT-labelled binding site in guinea pig brain stem is a 5HT-1 receptor and appears to be responsible for the induction of indoleamine-dependent myoclonus.

Animals↗