The effects of the monoamine depleting drugs oxypertine, tetrabenazine and reserpine were compared with those of the dopamine receptor antagonists, chlorpromazine and trifluoperazine, on behavioural and biochemical indices of dopamine function in the brain. Oxypertine (0.625-20 mg/kg, i.p.), chlorpromazine (0.625-20 mg/kg i.p.) and trifluoperazine (0.0625-2.0 mg/kg i.p.), administered to rats 1 hr previously, inhibited stereotyped behaviour induced by both amphetamine (5.0 mg/kg i.p.) and apomorphine (1.0 mg/kg, s.c.) in a dose-dependent manner. Tetrabenazine (0.625-20 mg/kg i.p., 1 hr previously) inhibited stereotypy induced by amphetamine but not that induced by apomorphine. Reserpine (0.1 10 mg/kg i.p., 6 hr previously) did not inhibit, but in larger doses, tended to enhance the stereotyped responses to both amphetamine and apomorphine. Oxypertine (10 mg/kg, i.p., 1 hr previously), tetrabenazine (5 mg/kg i.p., 1 hr previously) and reserpine (2.5 mg/kg i.p., 6 hr previously) reduced the content of dopamine in the striatum but increased the concentrations of homovanillic acid (HVA) and 3,4-dihydroxyphenylacetic acid (DOPAC). Chlorpromazine (5 mg/kg i.p.) and trifluoperazine (0.5 mg/kg i.p.), given 1 hr previously, did not alter concentrations of dopamine in the striatum but increased those of HVA and DOPAC. Oxypertine, chlorpromazine and trifluoperazine weakly inhibited dopamine-stimulated adenylate cyclase in homogenates of the striatum in the rat. Tetrabenazine and reserpine had no effect. Similarly, trifluoperazine and chlorpromazine displaced the specific binding of [3H]piflutixol to membranes from the striatum. Oxypertine also was weakly effective, but tetrabenazine and reserpine were without effect. Trifluoperazine, chlorpromazine and oxypertine displaced specific binding of [3H]spiperone and [3H]N,n-propylnorapomorphine (NPA) to preparations of the striatum.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

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Long-term effects of pergolide and (-)-deprenyl on 3H-mazindol and 3H-spiperone binding in rat brain.

The effects of long-term administration of the putative neuroprotective agents pergolide and (-)-deprenyl was assessed by studying 3H-mazindol and 3H-spiperone binding at 12 and 20 months in the major dopamine brain regions. Male Wistar rats were treated from 3 to 20 months, together with their respective untreated and saline injected control groups. The main findings were: 1) there was a decrease in both 3H-mazindol and 3H-spiperone binding with age between 12 and 20 months; 2) there were no differences at 20 months between the pergolide or the (-)-deprenyl treated groups and their controls, thus providing no evidence for long-term neuroprotection; and 3) there was a marked decrease in 3H-mazindol binding in the injected controls compared with the untreated controls at both 12 and 20 months. This raises the possibility that mild chronic stress may accelerate the aging of the dopamine system.

Animals↗

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1-methyl-4-phenylpyridine is neurotoxic to the nigrostriatal dopamine pathway.

Systemic administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is neurotoxic to cerebral dopaminergic neurones in several animal species, and can cause parkinsonism in man. The mechanism of this action may be indirect. MPTP is oxidized in the brain to a pyridinium species, 1-methyl-4-phenylpyridine (MPP+)6. This oxidation is greatly decreased by inhibition of monoamine oxidase B6, as are the biochemical effects of MPTP in the mouse and its neurotoxicity in the monkey. We now show that MPP+ exerts a powerful neurotoxic action on the nigrostriatal dopamine system of the rodent.

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

PubMedDate not supplied

Transdermal administration of piribedil reverses MPTP-induced motor deficits in the common marmoset.

The ability of transdermal administration of the dopamine D2/D3 agonist piribedil (1-[3,4-methylenedioxybenzyl)]-4-[(2-pyrimidinyl)]piperazine) to reverse hypokinesia and other motor deficits observed in MPTP-treated common marmosets was investigated. Piribedil (2.5-10.0 mg/animal), applied directly to the skin of the abdomen as a paste, produced a long-lasting and concentration-dependent reversal of motor deficits. The antiparkinsonian actions of piribedil occurred within 10 minutes of drug administration and lasted as long as 10 hours. Transdermally applied piribedil produced a pattern of locomotor activity characteristic of normal motor behavior in this species. Symptoms of nausea (marked excessive salivation, retching, and/or vomiting) were not observed after transdermal application of piribedil. Additionally, pretreatment with the peripheral dopamine antagonist domperidone enhanced the antiparkinsonian effects of piribedil. Application to the skin of monolayer or bilayer patches impregnated with piribedil also produced a marked increase in locomotor activity and reversal of motor deficits. After application of various patch fractions (whole, one-half, or one-fourth), the increase in locomotor activity and reversal of disability correlated well with the surface area of skin covered. Measurement of serum levels of piribedil after single application of bilayer patches showed a positive relationship between drug levels and antiparkinsonian activity. Repeated daily application of piribedil bilayer patches for 5 days to MPTP-treated common marmosets primed to show dyskinesia by previous exposure to L-Dopa produced antiparkinsonian activity accompanied by dyskinetic movements. Transdermal administration of dopamine agonists such as piribedil may provide a useful means of producing a long-lasting reversal of motor deficits in Parkinson's disease while avoiding acute adverse effects such as nausea.

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

PubMedDate not supplied

Effect of experimental ischemia on neurotransmitter amines in the gerbil brain.

In the gerbil cerebral infarction was produced by unilateral carotid ligation. 3.5 hours later, when the neurological deficit was fully developed, hemisphere dopamine (DA) showed little change from normal. It seems unlikely that changes in DA are the direct cause of the turning behavior shown by these animals. Slight changes in norepinephrine (NE) occurred on the operated side but 4 hydroxy-3-methoxy phenyl-ethyleneglycol sulphate (MOPEG-SO4) levels were not affected. Significant falls in 5-hydroxytryptamine (5-HT) and 5-hydroxyindole acetic acid (5-HIAA) were found on the operated side but there was also a trend for both 5HT and 5-HIAA to fall on the unoperated side. These changes occurred in clincally affected and unaffected animals and their clinical significance is unproven.

Animals↗

PubMedDate not supplied

The role of nitrogen oxidation in the excretion of drugs and foreign compounds.

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Amphetamine↗

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Comparative C- and N-oxidation of (plus)- and (minus)-nicotine by various species.

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Animals↗

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Neuroleptic-induced tardive dyskinesia.

Prolonged exposure to neuroleptic drugs induces tardive dyskinesia which may be persistent or permanent. Predisposing factors to tardive dyskinesia are not apparent although the aging brain appears more vulnerable. The drug treatment of tardive dyskinesia is at present unsatisfactory. Preventive measures, other than limiting neuroleptic use have not been established. The pathophysiology of tardive dyskinesia may relate to cerebral dopamine overactivity. However, although this may be a primary change responsible for tardive dyskinesia alterations in other neuronal systems such as acetylcholine, 5HT or GABA may be involved.

Adult↗