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Biomedical subjects

P Jenner

Publications and source records attributed to P Jenner.

At least 397 records · Page 22Linked to original sources
PubMed1983

Long-term adaptive changes in striatal dopamine function in response to chronic neuroleptic intake in rats.

Chronic neuroleptic drug administration to rats reverses initial dopamine receptor blockade so that animals exhibit striatal dopamine receptor supersensitivity. This effect may be of functional significance in the whole animal for it is accompanied by increased striatal acetylcholine content and by reversal of the acute increase in striatal acetylcholine release. Continuous drug intake may increase the number of striatal 3H-spiperone binding sites while decreasing the number of 3H-N, n-propylnorapomorphine binding sites. While D-2 adenylate cyclase independent dopamine receptor binding sites increase in number, no change occurs in the number of D-1 sites labelled by 3H-piflutixol despite increased adenylate cyclase activity. Haloperidol and sulpiride differentially alter striatal 3H-acetylcholine and 3H-glutamate release in a manner suggesting selective changes in dopamine receptors lying on striatal cell bodies and on the terminals of corticostriate glutamate terminals. In summary, neuroleptic drugs induce a series of adaptive changes on chronic administration consistent with the development of functional striatal dopamine receptor supersensitivity.

Acetylcholine↗
PubMed1982

Increased striatal acetylcholine after 14 months cis-flupenthixol treatment in rats suggests functional supersensitivity of dopamine receptors.

Rats received continuous administration of cis-flupenthixol (0.8-1.2 mg/kg/day) or trans-flupenthixol (0.9-1.2 mg/kg/day) in drinking water for 14 months. The administration of cis-flupenthixol, but not trans-flupenthixol, caused apparent cerebral dopamine receptor supersensitivity. Thus, animals receiving cis-flupenthixol, but not trans-flupenthixol, showed enhanced apo-morphine-induced stereotyped behaviour. Dopamine concentration in striatum was not altered by drug treatment but striatal HVA and DOPAC concentrations were reduced in animals receiving cis-flupenthixol, but not trans-flupenthixol. No consistent change in Bmax of KD for specific striatal 3H-spiperone binding was observed after 14 months drug intake. However, in cis-flupenthixol treated animals a 40% increase in Bmax was observed following 2 weeks drug withdrawal. Continuous cis-flupenthixol intake increased striatal acetylcholine concentrations; trans-flupenthixol was without effect. This suggests the apparent increase in cerebral dopamine receptor supersensitivity caused by continuous long-term cis-flupenthixol administration is of functional importance in the intact animal.

Acetylcholine↗
PubMed1982

Myoclonus in guniea pigs is induced by indole-containing but not piperazine-containing 5HT agonists.

L-5-Hydroxytryptophan (5HTP) induces in guinea pigs a myoclonic jerking which is dependent upon stimulation of brainstem 5-hydroxytryptamine (5HT) receptors. We have investigated the ability of 5HT precursors and a range of synthetic 5HT agonists to produce myoclonus. The 5HT precursors and 5HT agonists containing an indole nucleus induced dose-dependent jerking in guinea pigs. In contrast, 5HT agonists possessing a piperazine moiety induced occasional jerking only at toxic doses, but not a those doses normally associated with 5HT agonist activity. The difference in activity between the indole-containing compounds and piperazine-containing 5HT agonists suggests that myoclonus is due to activation of an indole-selective brainstem 5HT receptor and provides further evidence for multiple cerebral 5HT receptors.

Animals↗
PubMed1982

Repeated administration of sulpiride for three weeks produces behavioural and biochemical evidence for cerebral dopamine receptor supersensitivity.

Administration of sulpiride (2 X 100 mg/kg i.p.) or haloperidol (5 mg/kg i.p.) to rats for 3 weeks with subsequent withdrawal for 3 or 4 days induced cerebral dopamine receptor supersensitivity. Apomorphine-induced stereotyped behaviour after drug withdrawal was enhanced by pretreatment with either haloperidol or sulpiride both of which increased the number of specific striatal binding sites (Bmax) for [3H]spiperone, [3H]N,n-propylnorapomorphine and [3H]sulpiride. Neither drug altered the dissociation constant (KD) for the ligand binding assays. Striatal dopamine sensitive adenylate cyclase activity was unaltered by such a pretreatment with either haloperidol or sulpiride. The data show that sulpiride, like haloperidol, is capable of inducing behavioural and biochemical supersensitivity of cerebral dopamine receptors.

Adenylyl Cyclases↗
PubMed1982

Tryptamine-induced myoclonus in guinea-pigs pretreated with a monoamine oxidase inhibitor indicates pre- and post-synaptic actions of tryptamine upon central indoleamine systems.

Tryptamine (1-320 mg/kg) evoked only slight muscle jerking in naive guinea-pigs but, in animals pretreated with pargyline (75 mg/kg; 1 hr previously), tryptamine induced a dose-dependent (6-160 mg/kg) myoclonus. The myoclonus induced by tryptamine (40 mg/kg) plus pargyline (75 mg/kg) was differentially inhibited by the indoleamine receptor antagonists, methergoline (5 mg/kg) which was more potent than methysergide (10 mg/kg), mianserin (10 mg/kg) which was more potent that cyproheptadine (10 mg/kg) and propranolol (20 mg/kg) which was more potent than cinanserin (10 mg/kg). This rank order of potency differed from that observed for the order of potency of these drugs in inhibiting the myoclonus induced by L-5-hydroxytryptophan (5HTP) plus carbidopa in guinea-pigs (Luscombe, Jenner and Marsden, Neuropharmacology, 1981), perhaps indicating involvement of pharmacologically distinct indoleamine receptors. Manipulation of presynaptic function of 5-hydroxytryptamine (5HT) by tryptophan hydroxylase inhibition with p-chlorophenylalanine to produce depletion of cerebral 5HT, or by an L-tryptophan load to elevate 5HT in brain, suggested that the functional integrity of serotonergic neurones is required for the expression of myoclonus induced by tryptamine plus pargyline. A range of blockers of 5HT re-uptake did not alter the jerking produced by tryptamine (40 mg/kg) in guinea pigs pretreated with pargyline (75 mg/kg; 1 hr previously), or the threshold myoclonus induced by a smaller dose of tryptamine (10 mg/kg; plus pargyline 75 mg/kg). It is suggested that myoclonus induced by tryptamine in guinea pigs pretreated with pargyline involves activation of post-synaptic indoleamine receptors by tryptamine by a mechanism which requires intact presynaptic function of 5HT.

5-Hydroxytryptophan↗
PubMed1982

Are dopamine receptors present on human lymphocytes?

The characteristics of [3H] spiperone binding to human lymphocytes have been examined. The haloperidol displaceable component of [3H] spiperone binding to human lymphocytes was not saturable, and stereoselective displacement by the isomers of butaclamol was not observed. These was no correlation between the ability of known dopamine active drug to cause displacement of the ligand and their rank order of potency. Chloroquine, a drug with no dopaminergic action, was the most potent displacing agent examined. Fragmentation of the cells caused a marked decrease in the haloperidol displaceable component of [3H] spiperone binding, and saturable binding to the lymphocyte membrane fragments was not observed. lysis of cells after equilibrium incubation with [3H] spiperone caused a marked reduction in the haloperidol displaceable component of ligand binding. Association of [3H] spiperone with lymphocytes was unaffected by the metabolic inhibitor iodoacetate or by replacement of sodium ions by lithium ions in the incubation medium, suggesting that such association did no involve an active process. We cannot confirm the existence of dopamine receptors on the surface of human lymphocytes. We suggest that the apparent association of [3H] spiperone with lymphocytes is due to some passive uptake process causing accumulation of the ligand within the cells.

Binding, Competitive↗
PubMed1982

The mode of action of sulpiride as an atypical antidepressant agent.

It can be said that sulpiride exerts a disinhibitory effect in both depression and schizophrenia but this is not associated with mechanisms through which typical antidepressant or anxiolytic agents act. Sulpiride acts selectively as a dopamine receptor antagonist in the brain, its effects on other neuronal systems being extremely limited. Indeed, it may act even selectively within the dopamine systems in that it would appear it specifically interacts with one sub-population of cerebral dopamine receptors. Within a given dopamine receptor system sulpiride may exert a differential pre-synaptic action on dopamine neurones although the evidence for this remains controversial. The disinhibitory effects in depression may be due to a preferential pre-synaptic action of the drug on dopamine neurones causing over-activation of cerebral dopamine post-synaptic receptors causing behavioural arousal and motor facilitation. On the other hand, the disinhibitory effect of sulpiride in schizophrenia may also involve the preferential pre-synaptic action of the drug coupled with the specificity of post-synaptic action to result in little sedation or motor retardation. Sulpiride may also differentially antagonise post-synaptic dopamine receptors in different brain areas and this may also be critically involves in its unusual spectrum of neuroleptic action.

Animals↗
PubMed1981

Circling behavior following unilateral kainic acid injections into rat striatum.

Unilateral injection of kainic acid (2.5-25 nmol) into rat anterior caudate putamen induced dose-related circling behaviour. Kainic acid (10 nmol) consistently caused initial weak ipsiversive circling lasting 1 h followed by prolonged strong contraversive rotation lasting in excess of 10 h. Unilateral intrastriatal administration of L-glutamic acid, or of monosodium L-glutamate, to normal rats, or administration of monosodium L-glutamate to rats with extensive decortication, did not induce circling behaviour. The simultaneous unilateral injection of monosodium L-glutamate (1 mumol) with kainic acid (10 nmol) did not modify circling behaviour induced by kainic acid. However, extensive decortication greatly reduced circling induced by unilateral intrastriatal kainic acid (10 nmol), and effect not reversed by the simultaneous administration of monosodium L-glutamate (1 mumol). Unilateral 6-hydroxydopamine lesions of the left nigrostriatal pathway abolished the initial ipsiversive rotation and potentiated the subsequent contraversive rotation for up to 4 h after intrastriatal injection of kainic acid (10 nmol). Peripheral administration of haloperidol (1 mg/kg i.p.) also abolished initial ipsiversive rotation and decreased the subsequent contraversive rotation. Electro-coagulation of the ipsilateral strio-nigral pathway prolonged the initial ipsiversive rotation produced by kainic acid, but markedly attenuated contraversive rotation. These findings suggest that circling induced by intrastriatal administration of kainic acid depends on intact corticostriate pathways, but it cannot be reproduced or modified by intrastriatal administration of glutamate. Kainic acid circling appears to be mediated via strio-nigral pathways, and to be modulated by dopaminergic function.

Animals↗
PubMed1981

Hypophysectomy does not prevent development of striatal dopamine receptor supersensitivity induced by repeated neuroleptic treatment.

Hruska et al. (1980) reported that hypophysectomy prevented the onset of dopamine receptor supersensitivity. We have repeated this investigation administering haloperidol (0.75 mg/day) or sulpiride (2 X 15 mg/day) or saline for 17 days, followed by a 3 day drug washout period, to sham-operated or hypophysectomised rats. Haloperidol or sulpiride pretreatment caused an enhancement of apomorphine-induced stereotyped behaviour and increased the number of specific striatal [3H]spiperone binding sites (Bmax) in both hypophysectomised and sham-operated animals compared to their respective saline controls. We conclude that hypophysectomy does not prevent the onset of striatal dopamine receptor supersensitivity induced by repeated neuroleptic treatment in the rat.

Animals↗
PubMed1981

Kainic acid lesions of striatum and decortication reduce specific [3H]sulpiride binding in rats, so D-2 receptors exist post-synaptically on corticostriate afferents and striatal neurons.

Unilateral kainic acid lesions of rat striatum reduced specific striatal [3H]spiperone and [3H]sulpiride binding sites (Bmax) by 52 and 67% respectively compared with the intact side. The dissociation constant (KD) for [3H]spiperone binding was unchanged but that for [3H]sulpiride binding was reduced. Specific striatal [3H]spiperone and [3H]sulpiride binding was reduced by 22 and 37% respectively in unilateral decorticate animals, but there was no change in KD. Unilateral 6-hydroxydopamine lesions of the medial forebrain bundle caused no change in striatal [3H]spiperone binding sites or KD value, but produced a 27% increase in [3H]sulpiride binding sites with no change in KD. These data support the hypothesis of D-2 receptors located on cortico-striate glutamate fibres, but also indicate the presence of both D-1 and D-2 receptors on the cell bodies of striatal neurons.

Animals↗