Animal models of neuroleptic-induced acute dystonia.
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Acute Disease↗
Biomedical subjects
P Jenner
Publications and source records attributed to P Jenner.
Do thermodynamic studies provide information on both the binding to and the activation of dopaminergic and other receptors?
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Chemical Phenomena↗
Increased nigral iron content in postmortem parkinsonian brain.
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Aged↗
Pilocarpine-induced purposeless chewing behaviour in rats is dependent on intact central stores of 5-HT.
Pilocarpine-induced purposeless chewing behaviour in rats was partially antagonised by pretreatment with reserpine, tetrabenazine or p-chlorophenylalanine (PCPA). In contrast, pretreatment with alpha-methyl-p-tyrosine (AMPT) had no effect on pilocarpine-induced chewing. These data suggest that enhancement of purposeless chewing by pilocarpine is dependent, in part, on intact central stores of 5-HT.
Animals↗
Localization of neurotensin receptors in the forebrain of the common marmoset and the effects of treatment with the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine.
The distribution of neurotensin binding sites was mapped in the brain of the common marmoset using [3H]neurotensin as the ligand. Autoradiographic techniques show that the density of receptors is particularly high in the substantia nigra, ventral tegmental area, olfactory tubercle and cerebral cortex and that the distribution of neurotensin receptors in the cerebral cortex and striatum is heterogenous. In the cerebral cortex neurotensin receptors are concentrated in layers I, II, III and V, whilst receptor density is generally less in all layers of middle temporal cortex. Striatal neurotensin receptors conformed to a striosomal distribution as defined by acetylcholinesterase staining with the highest density of binding sites in the matrix. The neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine selectively destroyed over 80% of the dopaminergic neurons of the marmoset substantia nigra and almost 60% of those in the adjacent ventral tegmental area. The subsequent loss of a large proportion of neurotensin receptors from marmoset substantia nigra and striatum suggests their presence on the dopaminergic nigrostriatal pathway.
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
Analogues of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine as monoamine oxidase substrates: a second ring is not necessary.
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is oxidised to a neurotoxic metabolite by monoamine oxidase B (MAO B). Using two colorimetric assays, we have examined a range of its structural analogues as possible further substrates of this enzyme in order to identify the types of environmental or endogenous compounds that might also be neurotoxic. Compounds with fully saturated or unsaturated pyridine rings were not substrates; nor were a range of tetrahydro-beta-carbolines or isoquinolines. Four substrates for MAO were found, 1-methyl-4-(2'-methylphenyl)-1,2,3,6-tetrahydropyridine (2'-Me-MPTP), 4-phenyl-1,2,3,6-tetrahydropyridine (PTP), 4-(p-chlorophenyl)-1,2,3,6-tetrahydropyridine (Cl-PTP) and ethyl-1-methyl-1,2,3,6-tetrahydro-4-pyridine-carboxylate (ethyl-MTP-carboxylate). Ethyl-MTP-carboxylate is of particular interest as it shows that a tetrahydropyridine without a phenyl ring can also be a substrate. Cl-PTP, PTP and ethyl-MTP-carboxylate appeared to be partially metabolised by MAO A. The inhibitor sensitivity of 2'-Me-MPTP oxidation was more complex.
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
Chronic trifluoperazine treatment does not induce lipid peroxidation in the rat cortex.
Rats received continuous chronic trifluoperazine hydrochloride (4.4-4.9 mg/kg/day) treatment for 15 months via their drinking water. Drug treatment did not alter the content of polyunsaturated fatty acids in the cerebral cortex when compared to age-matched control animals. Similarly, there was no change in basal levels of malondialdehyde (MDA) when measured by a fluorimetric or spectrophotometric technique. Incubation of cortical homogenates in air, or with FeSO4 plus ascorbic acid or H2O2 plus FeSO4, stimulated MDA production to the same extent in tissue from drug-treated and control animals. The chronic administration of trifluoperazine to rats does not appear to promote lipid peroxidation as has been suggested for haloperidol.
Animals↗
Effects of opioid agonist drugs on the in vitro release of 3H-GABA, 3H-dopamine and 3H-5HT from slices of rat globus pallidus.
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Animals↗
Age-related decreases in the concentration of Met- and Leu-enkephalin and neurotensin in the basal ganglia of rats.
Previous studies using radioimmunoassay procedures have failed to show age-related changes in the concentration of Met- and Leu-enkephalin or neurotensin in rat basal ganglia. In contrast, using a combined high-pressure liquid chromatography (HPLC)-radioimmunoassay (RIA) technique we now report considerable decreases in the levels of these neuropeptides in areas of basal ganglia of 22 months old-compared to 3 months-old male Wistar rats. The concentration of Met-enkephalin was greatly reduced in the striatum and nucleus accumbens, but not in substantia nigra, of old compared to young animals. There was a similarly large decrease in Leu-enkephalin content in striatum of old rats with less marked decreases occurring in both the nucleus accumbens and substantia nigra. Neurotensin levels in the striatum and substantia nigra were greatly reduced in old rats, with a less marked decrease in the nucleus accumbens.
Aging↗
Antiparkinsonian activity of (+)-PHNO in the MPTP-treated common marmoset.
Administration of MPTP (1-4 mg/kg ip daily for 5-7 days) to common marmosets induced persistent parkinsonian motor deficits. The subcutaneous administration of (+)-PHNO [(+)-4-propyl-9-hydroxynaphthoxazine; 1-4 micrograms/kg] caused a dose-dependent reversal of the akinesia and incoordination of movement. Similarly, oral administration of (+)-PHNO (5-20 micrograms/kg) caused an equivalent reversal of the motor abnormalities. No dyskinetic phenomena were induced by (+)-PHNO on oral or subcutaneous administration. Oral or subcutaneous administration of (+)-PHNO to normal control marmosets also increased the usual repetoire of motor behaviour, but this was not as marked as in MPTP-treated animals. (+)-PHNO is a potent dopamine agonist drug of potential use in the treatment of Parkinson's disease.
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
Dopamine and somatostatin modulated adenylate cyclase activity in the rat caudate-putamen following unilateral cortical ablation.
Dopamine and somatostatin-14 (SRIF) were incubated with a membrane fraction of rat caudate-putamen (CP) tissue in an adenylate cyclase assay in order to examine the D-1-receptor coupled adenylate cyclase activity 5 days and 3 weeks after unilateral ablation of the left frontal and lateral cortex. Five days after decortication the ipsilateral basal and dopamine stimulated adenylate cyclase activity was increased by about 30% compared to that of the contralateral side. Three weeks after decortication no significant difference could be seen. On either side basal and dopamine stimulated adenylate cyclase activity was not significantly decreased compared to sham operated controls. Somatostatin (10(-7) mol/l) reduced basal adenylate cyclase activity of the ipsilateral CP five days following lesioning and reduced the maximal stimulation induced by dopamine. The effects of somatostatin were most marked in the absence and at low concentrations of dopamine (10(-7)-10(-6) mol/l). The effects of somatostatin in the lesioned CP were no longer apparent three weeks following surgery. These results do not favour a presynaptic localization of D-1-receptors on cortico-striate projection fibers and suggest that somatostatin is involved in the interaction of the cortico-striate and nigro-striatal projection systems and may play a role in the regulation of D-1-receptor linked adenylate cyclase.
Adenylyl Cyclases↗
Alterations in cerebral glutamic acid decarboxylase and 3H-flunitrazepam binding during continuous treatment of rats for up to 1 year with haloperidol, sulpiride or clozapine.
Rats were treated continuously for 12 months with therapeutically equivalent doses of haloperidol (1.4-1.6 mg/kg/day), sulpiride (102-109 mg/kg/day) or clozapine (24-27 mg/kg/day) and examined for alterations in brain glutamic acid decarboxylase (GAD) and 3H-flunitrazepam binding. Administration of haloperidol, but not sulpiride or clozapine, for 6 or 12 months increased striatal GAD activity. None of the drug treatments altered nigral GAD activity when examined after 1, 3, 6, 9 or 12 months administration. The number of specific 3H-flunitrazepam binding sites (Bmax) in striatal membrane preparations were not altered by 12 months administration of haloperidol, sulpiride or clozapine. Surprisingly, Bmax for 3H-flunitrazepam binding to cerebellar membrane preparations was decreased by 12 months administration of all drug treatments. The dissociation constant (Kd) for 3H-flunitrazepam binding in striatal and cerebellar preparations was not altered. The ability of GABA (0.25-100 microM) alone, and in conjunction with sodium chloride (200 mM), to stimulate specific 3H-flunitrazepam binding in striatal and cerebellar preparations was unaltered by haloperidol, sulpiride or clozapine administration for 12 months. The selective effect of haloperidol, but not sulpiride or clozapine, treatment on striatal GAD activity parallels the ability of haloperidol, but not sulpiride or clozapine, to induce striatal dopamine receptor supersensitivity in the same animals. The actions of haloperidol may reflect its greater ability to induce tardive dyskinesia compared to sulpiride or clozapine.
Animals↗
Chronic pharmacological manipulation of dopamine receptors in brain.
Dopamine receptors in the brain play an important role in the treatment of schizophrenia and in the development of tardive dyskinesia. In Parkinson's disease the loss of dopamine innervation and the use of chronic administration of L-DOPA or therapy with dopamine agonists also affects the function of dopamine receptors in brain. Subacute administration of neuroleptic drugs to rodents for a few weeks followed by the withdrawal of the drug induces supersensitivity of dopamine receptors in the striatum. However, the long-term administration of neuroleptic drugs to rodents shows that typical neuroleptic drugs can induce functional supersensitivity of dopamine receptors despite continued administration of drug. In contrast, atypical neuroleptics such as sulpiride, do not appear to induce the same changes in the activity of dopamine receptors. The functional supersensitivity of dopamine receptors produced by repeated administration of neuroleptic is reflected in changes in cholinergic, gamma-aminobutyric acid (GABA), 5-hydroxytryptamine (5-HT) and peptide neuronal systems. Chronic treatment of parkinsonian patients with drugs may obscure the changes in the function of dopamine receptors caused by the disease process. However, chronic administration of L-DOPA to normal rats and to rats with a unilateral lesions of the nigrostriatal pathway induced with 6-hydroxydopamine does not produce a down-regulation of the number of dopamine receptors. Rather, these experiments indicate the development of a functional supersensitivity of dopamine receptors in the absence of any obvious change in the nature of dopamine receptor populations in brain. In conclusion, while pharmacological manipulation, using neuroleptic drugs, produces the expected development of receptor supersensitivity, studies involving chronic treatment with agonists suggests that dopamine receptors do not always respond as would be predicted. It appears that there are aspects of the regulation of dopamine receptors in brain following pharmacological manipulation which remain to be resolved.
Acetylcholine↗
In vitro characterisation of dopamine receptors in the superior colliculus of the rat.
In membrane preparations of superior colliculus of the rat, the binding of [3H]spiperone (0.15 nM) was displaced by the incorporation of (+)-butaclamol, haloperidol, apomorphine and (+/-)-sulpiride, but not by (-)-butaclamol, prazosin, propranolol, ketanserin or cinanserin. The Ki values for the displacement of [3H]spiperone by (+/-)-sulpiride, (+)-butaclamol and haloperidol were similar in tissue preparations from superior colliculus and striatum. Equilibrium analysis of the specific binding of [3H]spiperone (0.03-1.0 nM), defined by 10(-5) M (+/-)-sulpiride, to membrane preparations of the superior colliculus, showed the interaction to be saturable and of high affinity. However, the Bmax was only approximately 10% of that found in preparations of striatum; the apparent dissociation constant (KD) was the same in both preparations of the superior colliculus and striatum. Uptake of [3H]dopamine into synaptosomal preparations of the superior colliculus was approximately 20% of that found in synaptosomes from the striatum. In preparations of striatum nomifensine, but not desipramine or fluoxetine, inhibited the uptake of [3H]dopamine. However, in preparations from the superior colliculus, nomifensine, desipramine and fluoxetine were without effect on the uptake of [3H]dopamine. Dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC) and 3-methoxytyramine (3-MT) were present in small concentrations in the superior colliculus. Homovanillic acid (HVA) was present in larger concentrations and the HVA plus DOPAC/dopamine ratios were greater in the superior colliculus than in the striatum. The superior colliculus contained only small amounts of noradrenaline but 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) were present in larger amounts.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Effects of continuous administration for 12 months of amine-depleting drugs and chlorpromazine on striatal dopamine function in the rat.
Rats received either chlorpromazine (33-36 mg/kg/day), 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) continuously for up to 12 months. Chlorpromazine and tetrabenazine reduced spontaneous locomotor activity of animals after 1 month of treatment. Thereafter, locomotor activity in animals treated with chlorpromazine returned to control levels, whereas treatment with tetrabenazine increased locomotion. Oxypertine enhanced spontaneous locomotor activity after 9 months of administration only, whereas treatment with reserpine did not alter this activity at any time during the study compared to age-matched controls. Treatment with tetrabenazine enhanced stereotyped behaviour induced by apomorphine (0.063-1.0 mg/kg s.c.) throughout the study. In contrast, stereotypy in animals administered chlorpromazine, oxypertine or reserpine was the same as in control animals throughout the 12 months of treatment. Levels of dopamine in the striatum were reduced after the first month of administration of chlorpromazine, but thereafter returned to control values. Treatment with oxypertine for up to 12 months did not alter concentrations of dopamine in the striatum, whereas administration of tetrabenazine and reserpine caused a decrease. All treatments with drugs consistently reduced the content of homovanillic acid in the striatum during the study. The Bmax for specific binding of [3H]spiperone in the striatum was increased by continuous treatment of animals with chlorpromazine, oxypertine or tetrabenazine, although the effects of oxypertine and tetrabenazine were only transient. Administration of reserpine did not alter the Bmax for specific binding of [3H]spiperone. The Bmax for specific binding of [3H]piflutixol in the striatum was unchanged by any treatment for up to 12 months.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
An immunohistochemical study of the acute and long-term effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in the marmoset.
Administration of the drug 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine induces a parkinsonian syndrome in primates. Intraperitoneal injections of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in the common marmoset (Callithrix jacchus) produced symptoms of rigidity, akinesia and tremor which persisted for at least one month. However, after this time, considerable behavioural recovery occurred, although animals were still severely bradykinetic compared with controls. Marmosets were allowed to survive for 1, 3 1/2 or 7 months prior to histological and immunocytochemical analysis. Detection of catecholaminergic neurons using antibodies directed against the enzyme tyrosine hydroxylase revealed a profound (80%) loss of dopaminergic cells from the substantia nigra one month after initiation of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine treatment. This was accompanied by a severe gliosis. Fewer cells were lost from the adjacent ventral tegmental area (45%), but dopamine-containing cells in other brain areas were not obviously affected. At longer survival times the substantia nigra was less damaged, with a proliferation of glia in the pars compacta and a loss of approximately 20% of the dopaminergic perikarya. Using immunohistochemical techniques, the distribution of neuropeptides substance P, [Met]enkephalin and dynorphin 1-17-like immunoreactivity were examined and found to exhibit distinctive patterns in the marmoset substantia nigra. The integrity of these systems appeared intact at all times after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine treatment. These results support the hypothesis that the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine produces a clinical syndrome, indistinguishable from Parkinson's disease, via a selective destruction only of neurons with perikarya in the substantia nigra pars compacta and the ventral tegmental area. The findings that the peptidergic input to these cells together with most non-nigral dopaminergic cell groups are not damaged, indicate that the selectivity of the lesion produced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine appears greater than that seen in idiopathic Parkinson's disease. The neurotoxic effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in the marmoset may not be permanent since both behavioural and biochemical recovery were observed after several months.
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
Selegiline in narcolepsy.
We examined the effect of the specific monoamine oxidase-B (MAO-B) inhibitor selegiline (deprenyl, Eldepryl), 20-30 mg p.o. daily, in 21 subjects with the narcoleptic syndrome for 4 weeks. Selegiline was compared to no treatment (7 subjects) or conventional central stimulant drugs, including dexamphetamine or mazindol (14 subjects). Severity and frequency of narcolepsy, accessory symptoms, and effects of selegiline on mood were measured. Selegiline, as well as causing MAO-B inhibition, is interconverted to amphetamine. Urinary amphetamine and methamphetamine excretion were determined in 18 subjects after 4 weeks on selegiline and the results were compared with amphetamine excretion in subjects on dexamphetamine. The effect of selegiline, 20-30 mg p.o., on alertness and mood was similar to that of dexamphetamine in the same dosage, with comparable sympathomimetic side effects. Selegiline, 20 mg p.o., caused a subjective increase in alertness for 4-8 h. Mean urinary amphetamine excretion on dexamphetamine, 15-70 mg daily (mean 29 mg) at pH 5.6-6.6, was 5,184 micrograms/24 h, and on selegiline, 20-30 mg daily (mean 22.5), was 4,127 micrograms/24 h. We conclude that selegiline, 20-30 mg daily, requires further evaluation in narcolepsy.
Adult↗
Pharmacological characterization of binding sites identified in rat brain following in vivo administration of [3H]-spiperone.
[3H]-spiperone is commonly used to label dopamine receptors in vitro in brain tissue. However, spiperone also interacts with brain 5-hydroxytryptamine and noradrenaline receptors. In vivo, [3H]-spiperone has been used for identifying dopamine receptors in both animals and man but the nature of the sites identified is unknown. The in vivo administration of [3H]-spiperone to rats leads to a selective accumulation of radioactivity in the olfactory lobes, tuberculum olfactorium, nucleus accumbens, striatum, substantia nigra, hippocampus, frontal cortex and hypothalamus, when compared to the cerebellum. In vivo drug displacement studies suggest that the binding of [3H]-spiperone in these areas may be to dopamine, 5-HT or noradrenaline receptors. [3H]-spiperone in vivo mainly labels dopamine receptors in striatum, tuberculum olfactorium, hypothalamus, substantia nigra and olfactory lobes. However, in the frontal cortex and nucleus accumbens specific binding involves not only dopamine receptors but also 5-HT and/or noradrenaline receptors. Interpretation of in vivo studies in man using radioactive spiperone and its derivatives must take into account the fact that this ligand only labels dopamine receptors in some brain areas.
Animals↗