Biomedical subjects

P Jenner

Publications and source records attributed to P Jenner.

At least 361 records · Page 20Linked to original sources

PubMed1984

Enhancement of stereotypy induced by nomifensine in rats during continuous chronic haloperidol treatment.

Stereotyped behaviour induced by apomorphine (0.125 mg/kg s.c.) was inhibited in rats treated continuously for 20 months with haloperidol (1.4-1.6 mg/kg/day) while that induced by a higher dose of apomorphine (1.0 mg/kg s.c.) was enhanced. Stereotypy induced by nomifensine (3.125-25.0 mg/kg i.p.) was not inhibited at any dosage level in haloperidol-treated rats, and was enhanced by higher doses of nomifensine. The results indicate that the behavioural effects of endogenously released dopamine may not remain inhibited in rats undergoing chronic neuroleptic treatment.

Animals↗

PubMed1984

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced parkinsonism in the common marmoset.

The administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) (1-4 mg/kg i.p.) for 4 days induced dose-dependent parkinsonism in the common marmoset within 48 h. MPTP produced profound akinesia, rigidity of the trunk and limbs, postural abnormalities, loss of vocalization and, in some cases, postural tremor. In a single animal the administration of L-DOPA in conjunction with a peripheral decarboxylase inhibitor, reversed the parkinsonian symptoms. Subsequent biochemical analysis showed a profound loss of dopamine and [3H]dopamine uptake in the caudate-putamen, but no change in specific [3H]spiperone binding.

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

PubMed1984

Repeated administration of N-methyl-4-phenyl 1,2,5,6-tetrahydropyridine to rats is not toxic to striatal dopamine neurones.

N-Methyl-4-phenyl-1,2,5,6-tetrahydropyridine ( MPTP ) (10 mg/kg/day i.p.) was administered to rats for 16 days, which were then observed for a further 9-11 days. MPTP administration did not alter spontaneous locomotor activity or amphetamine (2.5 mg/kg ip)-induced locomotion. Apomorphine (0.25 mg/kg sc) did not alter locomotion in control rats but increased activity in MPTP treated animals. The stereotyped response to apomorphine (0.25 mg/kg sc) and amphetamine (2.5 and 5.0 mg/kg ip) was unaltered by MPTP administration. The striatal content of dopamine, HVA and DOPAC was unaltered by MPTP intake. The uptake of [3H]dopamine and [3H] 5HT in striatal synpatosomes was not changed by MPTP . The results suggest that MPTP , in the dose used, is not toxic to nigro-striatal dopamine neurones in the rat. This contrasts with its neurotoxic actions in monkeys and man.

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

PubMed1984

Functional increase in striatal dopaminergic activity following continuous long-term treatment with trifluoperazine.

Acute administration of trifluoperazine (2-10 mg/kg i.p.) caused a dose-dependent increase in potassium (K+)-evoked release of [3H]acetylcholine from striatal slices, but was without effect on K+-evoked release of [3H]glutamate. K+-evoked [3H]acetylcholine release was not different in striatal tissue from rats receiving 1 year's continuous administration of trifluoperazine (4.5-5.1 mg/kg/day) compared to age-matched control animals. However, K+-evoked striatal [3H]glutamate release was decreased in tissue from chronically trifluoperazine-treated animals compared to age-matched controls. The reversal of the acute action of trifluoperazine on striatal [3H]acetylcholine and the decrease of [3H]glutamate release on chronic administration is consistent with adaptive changes in striatal dopamine transmission during long-term neuroleptic treatment.

Acetylcholine↗

PubMed1984

5-Hydroxytryptamine (5-HT)-dependent myoclonus in guinea pigs is induced through brainstem 5-HT-1 receptors.

Myoclonic jerking in guinea pigs originates from the brainstem. Indole-containing 5-hydroxytryptamine (5-HT) agonists, but not piperazine-containing 5-HT agonists, induced myoclonus in guinea pigs at pharmacologically relevant doses. Guinea pig brainstem preparations possessed specific binding sites for [3H]5-HT but specific [3H]spiperone binding was low and inconsistent. 5-HT-1 receptors appear to predominate in this tissue. High affinity [3H]5-HT binding was potently displaced by indole-containing 5-HT agonists but only weakly displaced by piperazine-containing 5-HT agonists. The [3H]5-HT specific binding site in guinea pig brainstem responsible for the induction of indoleamine-dependent myoclonus has the characteristics of a 5-HT-1 receptor.

Animals↗

PubMed1984

Gamma-aminobutyric acid and basal ganglia outflow pathways.

Neurons containing gamma-aminobutyric acid (GABA) are important outflow pathways from the striatum to the pallidal complex and substantia nigra. From these areas GABA-containing neurons pass to the thalamus and to various areas of the brainstem. Manipulation of GABA function in outflow zones in the rat can produce catalepsy, locomotor hyperactivity, stereotypy or circling behaviour, so mimicking the effect of altered dopamine function within basal ganglia. However, the behaviours produced by such manipulation do not form part of the animal's normal activities. Consequently manipulation of GABA action in the outflow zones of the basal ganglia may mimic extrapyramidal movement disorders more closely than the normal functions of these regions of the brain.

Animals↗

PubMed1984

Behavioural effects mediated by unilateral nigral dopamine receptor stimulation in the rat.

Unilateral intranigral injections of dopamine in conscious rats pretreated with nialamide resulted in either ipsiversive or contraversive rotation depending upon the site of injection. Injection of dopamine (50 micrograms) into the zona compacta of the substantia nigra induced weak ipsiversive or mixed ipsiversive and contraversive rotation. Injection of dopamine (12.5-50.0 micrograms) into zona reticulata of substantia nigra induced only contraversive circling. Destruction of the ipsilateral medial forebrain bundle (MFB) using 6-hydroxydopamine (6-OHDA) abolished ipsiversive circling but enhanced contraversive circling produced by dopamine or apomorphine. The combination of a unilateral 6-OHDA lesion of MFB with a kainic acid or electrolesion of the ipsilateral strio-nigral and pallido-nigral pathways reduced contraversive circling to intranigral apomorphine (10 micrograms). Ipsiversive circling produced following intranigral injection of dopamine is dependent upon the integrity of ascending dopamine neurones. Contraversive rotation is independent of ascending dopamine pathways but is reliant upon afferent input to the substantia nigra from the striatum and/or globus pallidus.

Animals↗

PubMed1984

Enhanced GABA function in the angular complex (lateral periaqueductal grey matter and adjacent reticular formation) alters the postural component of striatal- or nigral-derived circling.

Unilateral injection of muscimol into the angular complex (lateral periaqueductal grey matter and adjacent reticular formation) caused ipsiversive rotation. Focal injection of picrotoxin into the same site produced contraversive rotation. Administration of apomorphine to animals with a unilateral 6-OHDA lesion of the left medial forebrain bundle caused contraversive rotation. Focal injection of muscimol into the angular complex reversed the direction of rotation such that apomorphine administration now produced ipsiversive circling. Unilateral injection of muscimol into substantia nigra zona reticulata caused contraversive rotation. Focal injection of picrotoxin into the same site produced ipsiversive rotation. The prior injection of muscimol into the ipsilateral angular complex prevented the contraversive rotation induced by intranigral administration of muscimol such that animals now showed ipsiversive circling. In both 6-OHDA-lesioned animals and animals receiving intranigral muscimol, focal injection of muscimol into the angular complex caused a reversal in the direction of circling through loss of the postural component with no obvious change in locomotor activity. Bilateral electrolytic lesions of the angular complex overall had no effect on amphetamine-induced locomotion. Manipulation of GABA function in the angular complex alters circling behaviour initiated from the striatum or substantia nigra by altering the postural component without affecting the locomotor response of the animals. The data suggest a critical role for the angular complex as an outflow station from basal ganglia.

Animals↗

PubMed1984

Differential effects of continuous administration for 1 year of haloperidol or sulpiride on striatal dopamine function in the rat.

Administration of haloperidol (1.4-1.6 mg/kg/day) for up to 12 months or sulpiride (102-109 mg/kg/day) for between 6 and 12 months increased the frequency of purposeless chewing jaw movements in rats. N,n-propylnorapomorphine (NPA) (0.25-2.0 mg/kg SC) did not induce hypoactivity in haloperidol-treated rats at any time; sulpiride treatment for 9 and 12 months caused a reduction in the ability of NPA to induce hypoactivity. Haloperidol, but not sulpiride, treatment enduringly inhibited low dose apomorphine effects (0.125 mg/kg SC). After 12 months, stereotypy induced by high doses of apomorphine (0.5-1.0 mg/kg) was exaggerated in haloperidol-, but not sulpiride-treated rats. Bmax for specific striatal 3H-spiperone binding was increased by haloperidol, but not sulpiride, treatment throughout the study. Bmax for 3H-piflutixol binding was not altered by chronic haloperidol or sulpiride treatment. Striatal dopamine-stimulated adenylate cyclase activity was inhibited for the 1st month of haloperidol treatment, thereafter returning to control levels; dopamine stimulation was increased after 12 months of sulpiride treatment. Striatal acetylcholine content was increased after 3 and 12 months of treatment with haloperidol, but was not affected by sulpiride. Chronic administration of sulpiride does not induce identical changes in striatal dopamine function to those caused by haloperidol.

Acetylcholine↗

PubMed1984

Differential alterations in striatal dopamine receptor sensitivity induced by repeated administration of clinically equivalent doses of haloperidol, sulpiride or clozapine in rats.

Rats received therapeutically equivalent doses of either haloperidol (1.7-1.9 mg/kg/day), sulpiride (112-116 mg/kg/day) or clozapine 30-35 mg/kg/day) continuously for 4 weeks. Treatment with haloperidol, but not sulpiride or clozapine, caused inhibition of stereotyped behaviour induced by apomorphine (0.125-0.25 mg/kg SC). Following drug withdrawal for up to 7 days, haloperidol and sulpiride, but not clozapine treatment caused an exaggeration of stereotyped behaviour induced by apomorphine. Bmax values for striatal 3H-spiperone binding were elevated in animals treated for 2 and 4 weeks with haloperidol, but not with sulpiride or clozapine. Following drug withdrawal, haloperidol, but not sulpiride or clozapine, treatment caused an increase in Bmax for striatal 3H-spiperone binding. Bmax values for striatal 3H-NPA binding revealed no change during haloperidol or clozapine treatment. Sulpiride treatment for 1 week caused an increase in Bmax for 3H-NPA binding, which returned to control levels at 2 and 4 weeks. Following drug withdrawal, there was an increase in Bmax for 3H-NPA binding in rats treated with haloperidol and sulpiride, but not clozapine. On continuous treatment and following withdrawal from haloperidol, sulpiride, or clozapine the ability of dopamine to stimulate striatal adenylate cyclase activity did not differ from that in control animals. Repeated administration of sulpiride or clozapine may not induce striatal dopamine receptor supersensitivity when given in clinically relevant doses, although haloperidol does.

Animals↗

PubMed1984

Interpretation of changes in apomorphine-induced stereotyped behaviour in rats receiving continuous administration of trifluorperazine for 15 months.

Rats treated continuously with trifluoperazine dihydrochloride (4.4-4.9 mg/kg per day) for 15 months showed an exaggerated stereotyped response to large doses of apomorphine (1.0 mg/kg, s.c.), but inhibition of stereotyped behaviour by a small dose of apomorphine (0.125 mg/kg, s.c.) as compared to responses obtained in age-matched control animals. Apomorphine (0.03-1.0 mg/kg, s.c.) produced more hyperactivity in trifluoperazine-treated rats than in control animals. After withdrawal of the drug for a period of 2 weeks or more, the stereotyped responses to all doses of apomorphine (0.0625-0.5 mg/kg, s.c.) were exaggerated in animals treated with trifluoperazine compared with age-matched control rats. Acute administration of trifluoperazine (4.5 mg/kg, p.o., 3 hr previously) to animals withdrawn from trifluoperazine abolished the stereotyped behaviour induced by a small dose of apomorphine (0.125 mg/kg) but a maximal response still was obtained with large doses (1.0 mg/kg). In contrast, acute challenge with trifluoperazine (4.5 mg/kg, p.o.) in control animals inhibited the stereotyped behaviour at virtually all doses of apomorphine, as compared with the responses to apomorphine in both animals withdrawn from trifluoperazine, given the same treatment, and naive control rats. Administration of trifluoperazine (0.28 and 0.56 mg/kg, p.o.) inhibited stereotypy induced by small doses of apomorphine (0.125 mg/kg, s.c.) in control animals but the response in animals withdrawn from trifluoperazine was exaggerated. Larger doses of trifluoperazine (1.125-4.5 mg/kg) totally inhibited apomorphine-induced (0.125 mg/kg, s.c.) stereotypy in both groups. These findings do not support the concept of separate mechanisms controlling low grade and high grade stereotyped behaviour during chronic treatment with neuroleptics.

Animals↗

PubMed1984

Behavioural and biochemical alterations in the function of dopamine receptors following repeated administration of L-DOPA to rats.

Rats received L-DOPA (40 or 200 mg/kg, i.p.) for 14 days, followed by a 3 day withdrawal period. Spontaneous locomotor activity was not altered by repeated administration of L-DOPA. Rats treated with L-DOPA (200 mg/kg) showed identical locomotor hypoactivity in response to small doses of apomorphine when compared to saline-treated control animals. However, hyperactivity induced by large doses of apomorphine was reduced by prior treatment with L-DOPA (200 mg/kg). The smaller dose of L-DOPA (40 mg/kg) did not alter the locomotion induced by apomorphine. Stereotyped behaviour induced by apomorphine was enhanced by prior treatment with both 40 and 200 mg/kg of L-DOPA. The treatment regimes with L-DOPA had no effect on the concentrations of apomorphine in the striatum. Administration of L-DOPA (40 or 200 mg/kg) followed by withdrawal for 3 days, had no effect on the concentrations of dopamine, homovanillic acid (HVA) or 3,4-dihydroxyphenylacetic acid (DOPAC) in the striatum. The Bmax and KD for the binding of [3H]spiperone, [3H]N,n-propylnorapomorphine (NPA) and [3H] piflutixol in the striatum was not altered by drug treatment. Similarly, the formation of dopamine-stimulated cyclic AMP in homogenates of striatum was unaltered by repeated administration of L-DOPA. Repeated administration of L-DOPA for 14 days in the rat appears to result in altered behaviour mediated by dopamine in the absence of any apparent change in the function of dopamine receptors in the striatum.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1984

Alterations in different populations of striatal dopamine receptors produced by 18 months continuous administration of cis- or trans-flupenthixol to rats.

Administration of cis-flupenthixol (0.8-1.2 mg/kg per day) for 18 months enhanced stereotyped behaviour induced by apomorphine, bromocriptine and lergotrile, but not that induced by amphetamine or lisuride. Catalepsy induced by acute administration of haloperidol, trifluoperazine or cis-flupenthixol was reduced by continuous chronic intake of cis-flupenthixol. The number (Bmax) and dissociation constant (KD) of specific [3H]spiperone binding sites on striatal membranes was increased by chronic administration of cis-flupenthixol, but not trans-flupenthixol. In contrast, the Bmax and KD for specific binding of [3H]N,n-propylnorapomorphine were decreased by administration of cis-flupenthixol compared to the effect of the trans-isomer. Specific binding of [3H]piflutixol was unaffected by chronic administration of cis- or trans-flupenthixol, but chronic administration of cis-flupenthixol enhanced stimulation by dopamine of the activity of striatal adenylate cyclase. As a result of chronic continuous administration of cis-flupenthixol dopamine receptors in the striatum appeared to be supersensitive to most dopamine agonists but sub-sensitive to dopamine antagonists. This was reflected by increased numbers of D-2 antagonist receptor sites of decreased affinity, but by a decreased number of agonist sites of higher affinity. The D-1 recognition sites appeared to be unaltered, but activity of adenylate cyclase stimulated by dopamine was enhanced, suggesting post-junctional changes. The D-2 receptors appear to be primarily concerned with altered function of dopamine receptors.

Adenylyl Cyclases↗

PubMed1984

A comparison of the effects of acute and one year's continuous neuroleptic treatment on the release of [3H]glutamate and [3H]acetylcholine from rat striatal slices.

The effect of neuroleptic drugs administered acutely or continuously for 1 year on the release of [3H]glutamate and [3H]acetylcholine from striatal slices in vitro has been compared. Acute in vivo administration of haloperidol, trifluoperazine and clozapine increased the potassium-evoked release of [3H]acetylcholine from striatal slices in a dose-dependent fashion, whereas sulpiride was without effect. None of the neuroleptics given acutely had any effect on the potassium-evoked striatal release of [3H]glutamate. Potassium-evoked striatal release of [3H]acetylcholine in animals receiving 1 year's continuous administration of haloperidol, trifluoperazine or sulpiride was no different from that in age-matched control animals, but was less than controls in animals receiving clozapine for 1 year. All drugs caused a decrease in potassium-evoked striatal [3H]glutamate release following drug administration for 1 year compared to age-matched controls. The reversal of the acute action of neuroleptic drugs on striatal [3H]acetylcholine and [3H]glutamate release is consistent with a functional increase in striatal dopamine transmission following long-term neuroleptic treatment.

Acetylcholine↗

PubMed1984

L-Dopa methyl ester--a candidate for chronic systemic delivery of L-Dopa in Parkinson's disease.

Continuous intravenous infusions of L-Dopa as a treatment for response swings in Parkinson's disease are limited by the insolubility and acidity of L-Dopa. Its methyl ester is a soluble neutral derivative that might be of benefit to these patients, and is examined in the present study in behavioural and biochemical animal models. On intraperitoneal or subcutaneous administration to mice L-Dopa methyl ester was equivalent to L-Dopa in reversing reserpine-induced akinesia and producing contraversive circling behaviour in rats with a 6-hydroxydopamine lesion of the medial forebrain bundle. On oral administration the methyl ester was more active. The administration of L-Dopa or the methyl ester produced equivalent changes in striatal and mesolimbic dopamine, homovanillic acid, and 3,4-dihydroxyphenylacetic acid metabolite levels. We suggest that systemic or subcutaneous infusion of L-Dopa methyl ester to patients who experience response fluctuations may provide a means of maintaining mobility.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1984

Multiple dopamine receptors in brain and the pharmacological action of substituted benzamide drugs.

Neuroleptic drugs are believed to control schizophrenia by blocking brain dopamine receptors, although most act also on a number of other neuronal systems in brain. Substituted benzamide drugs in general, are more specific for the dopamine system. Brain dopamine receptors, however, are not a single entity. They can be divided on the basis of their linkage to adenylate cyclase. Substituted benzamide drugs are selective antagonists of the adenylate cyclase independent dopamine receptor population. They may be selective antagonists of one sub-population of these adenylate cyclase independent receptors, for unlike typical neuroleptics the receptor interaction of substituted benzamide drugs with brain dopamine receptors depends upon the presence of sodium ions. The specificity of substituted benzamide drugs for brain dopamine receptors is reflected in their behavioural profile. Typical substituted benzamide drugs do not cause catalepsy and, in general, only weakly inhibit motor phenomena. This inability to act in vivo cannot be entirely explained by the poor penetration of these drugs into brain. The unique properties of the substituted benzamide drugs might explain their clinical value in the treatment of schizophrenia and in the treatment of dyskinesias.

Adenylyl Cyclases↗

PubMed1984

Dopamine receptor binding sites in the rat superior colliculus.

Following intravenous administration of [3H]spiperone or [3H]N,n-propylnorapomorphine (NPA) to rats, radioactivity derived from the ligands accumulated in the striatum and superior colliculus when compared with cerebellar levels. The accumulation of [3H]spiperone in both areas was prevented by intraperitoneal administration of (+)-butaclamol, haloperidol and sulpiride but not by (-)-butaclamol, cinanserin, propranolol or prazosin. The accumulation of [3H]NPA was prevented by administration of (+)-butaclamol, haloperidol and apomorphine but not by (-)-butaclamol. In in-vitro experiments, membrane preparations from the superior colliculus showed a small number of specific binding sites for both [3H]spiperone and [3H]NPA. The dissociation constant (KD) for [3H]NPA was not different from that for striatal preparations but that for [3H]spiperone was 10-fold higher. We conclude that dopamine receptors may be present within the superior colliculus.

Animals↗

PubMed1984

Anticonvulsant drugs alter plasma tryptophan concentrations in epileptic patients: implications for antiepileptic action and mental function.

In epileptic patients carbamazepine and diphenylhydantoin have opposite effects on whole and free plasma tryptophan concentrations, the former elevating and the latter depressing them. It is unlikely that these observations relate to the similar anti-epileptic properties of these two drugs but they may relate to their different effects on mental function and mood.

Adolescent↗