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The pharmacology of N-methyl-D-aspartate (NMDA) receptors shows regional differences in affinity for various agonists and antagonists. We have investigated the modulatory mechanisms acting via the polyamine, redox and proton sites in the cerebral cortex and the spinal cord of adult, male rats using [3H]MK-801 binding. The affinity for glycine-independent spermine stimulation was one magnitude higher in cerebrocortical than in spinal cord membranes while the affinity for the spermine antagonist arcaine was similar. Spermine abolished the inhibiting effect of low pH in both regions. Thus, the difference in the polyamine site between the two regions seems to be restricted to agonist binding. The proportion of high affinity/total ifenprodil binding was approximately 35% both in the spinal cord and the cerebral cortex, suggesting similar relative amounts of the NMDA receptor subunit 2B. The affinity of ifenprodil to the high affinity site was however significantly higher in the cerebral cortex. Redox modulatory agents had similar effects in the two regions but spermine fully counteracted the inhibiting effect of 0.2 mM 5,5'-dithio-bis(2-nitrobenzoic acid) (DTNB) in the cerebral cortex while there was only a partial effect in the spinal cord. These data show that the regional pharmacological heterogeneity involves several of the mechanisms regulating the function of the NMDA receptor. The data also indicate that the NMDA receptor subunit 2B is much more common in spinal cord than previously suggested.

Three steps in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) neurotoxicity were compared with the neurodegenerative effects of the toxin in mice and rats. Firstly, we compared the neurotoxicity of MPTP, mediated by monoamine oxidase (MAO)-B, to that of 1-methyl-4-(2'-methylphenyl)-1,2,3,6-tetrahydropyridine (2'-CH3-MPTP), an analogue oxidized by MAO-A and MAO-B. Both toxins caused degeneration of dopamine terminals in mice but not in rats. In NMRI mice noradrenaline terminals were also affected by both toxins. Pretreatment with deprenyl to prevent MAO-B-mediated oxidation in the capillary endothelium enhanced dopamine toxicity to 2'-CH3-MPTP in nucleus accumbens but no potentiation was seen in striatum and the olfactory tubercle. Secondly, synaptosomal uptake of the 1-methyl-4-phenylpyridinium ion (MPP+) was studied. Uptake in rats was not significantly different from that in the two mice strains. Thirdly, no significant differences were found in MPP(+)-induced lactate production in striatal slices or synaptosomes. We conclude that the lack of effect of MPTP in rats is not due to mechanisms specific for MPTP but probably to the ability of rat catecholamine neurons to cope with, and survive, impaired energy metabolism.

Two experiment were performed to study the effect of combining bromocriptine with SKF 38393 (SKF), or vice/versa, upon parameters of spontaneous motor activity in MPTP treated and saline (control) treated mice. Treatment with MPTP (2 x 40 mg/kg, subcutaneously) induced a hypoactive condition compared with saline treated mice. Bromocriptine (10 mg/kg, subcutaneously), administered to MPTP mice 2 hr, but not 1 or 4 hr, after SKF (6 mg/kg, subcutaneously) caused a marked increase in locomotion and rearing behaviour. The administration of bromocriptine (10 mg/kg, subcutaneously) 4 hr before SKF (6 mg/kg, subcutaneously) elevated all three parameters of spontaneous activity in the MPTP treated mice, independent of the injection of SKF. Bromocriptine injection 1 or 2 hr before SKF decreased locomotion in both MPTP and control mice. Neurochemical analysis confirmed the dopamine depletion in the MPTP treated mice. These results are discussed in terms of the reliability of the MPTP model of parkinsonism in mice and the dopamine D1/D2 receptor hypersensitivity following denervation with the neurotoxin.

Three experiments were performed to study the subchronic effects of treatment with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP, 2 x 40 mg/kg subcutaneously two weeks before testing) in C57 BL/6 mice upon spontaneous motor activity and the reversal of the long-term behavioural changes by acute treatment with L-Dopa. Mice treated with MPTP showed a drastic reduction of striatal dopamine levels (-88%) associated with reductions of all three parameters of spontaneous motor activity, i.e. locomotion, rearing and total activity, during both the initial, exploratory, stage (first 90 min), and later stages of the 3- or 4-hr test periods. L-Dopa (5-80 mg/kg subcutaneously) injected 60 min. after the start of testing dose-dependently improved all three parameters studied in MPTP treated mice with 10 mg/kg being the lowest dose causing a significant effect, while doses above 20 mg/kg caused hyperactivity. During the initial period, rearing activity in MPTP mice was to a variable degree suppressed by the L-Dopa treatment (20-80 mg/kg); these reductions were followed by enormous increases in motor activity by the 40 mg/kg (locomotion) and 80 mg/kg (total activity) L-Dopa groups. Both the degree and duration of the L-Dopa-induced hypoactivity for locomotor behaviour increased dose-dependently in control mice. No suppressive effects of L-Dopa were obtained for total activity in control mice, although the 80 mg/kg L-Dopa doses evoked hyperactivity for up to 90 min. following treatment for both locomotion and total activity.(ABSTRACT TRUNCATED AT 250 WORDS)

Conditions for the assay of the intra- and extrasynaptosomal rates of deamination of dopamine and noradrenaline by the two forms of monoamine oxidase (MAO) have been determined in striatal and frontal cortical homogenates, respectively, from C57 BL/6 mice. The activities obtained were compared with the corresponding activities found for NMRI mice, a strain less sensitive to the neurotoxic effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) than the C57 BL/6 strain. In both strains, the intra- and extrasynaptosomal deamination of dopamine in the striatal homogenates was brought about predominantly by MAO-A. No significant differences between the two strains were found for the intra- or extrasynaptosomal MAO-A or -B activities towards dopamine in striatal homogenates. On the other hand, the striatal dopamine concentrations were higher in the C57 BL/6 mice than in the NMRI mice. The concentrations of the dopamine metabolites DOPAC and HVA were similarly higher, suggesting that the rate of turnover of dopamine is the same for the two strains. In frontal cortical homogenates, MAO-A predominated in the deamination of noradrenaline both intra- and extrasynaptosomally. The extrasynaptosomal rates of deamination of noradrenaline were similar in the two mice strains, whereas the intrasynaptosomal MAO-A activity was significantly higher for the C57 BL/6 mice. These results concur with and extend to the noradrenergic system the conclusion previously made by Jossan et al. (1987) for the dopaminergic system that although MAO-B activity is necessary for expression of MPTP neurotoxicity, it is not the rate-limiting step for the development of the neurotoxic effects.

The effects of the stimulant drugs, d-amphetamine and methylphenidate, upon the motor activity of male and female off-spring of pregnant rats, treated on gestation day 15 with the antimitotic agent methylazoxymethanol (MAM, 25 mg/kg) were studied in four experiments. Cortical and striatal hypoplasia induced by prenatal administration of MAM resulted in increased concentrations of catecholamines in those regions. Administration of d-amphetamine and methylphenidate caused significant increases in motor activity; this effect was markedly potentiated in the MAM-treated rats, both the male and female off-spring. Thus, the locomotion and total activity parameters showed similar, but not identical, drastic increases in behaviour induced by the stimulant drugs as a result of the prenatal MAM treatment whereas for the rearing parameter a lesser potentiation by the MAM treatment was observed. This potentiation of the excitatory effects of the stimulant compounds upon the behavioural parameters is interpreted in terms of a relative increase in the density of catecholaminergic terminals in the forebrain regions of the central nervous system. The present results are discussed with regard to the utility of prenatal MAM treatment as a possible animal model for certain neurological disorders.