A.J. Bradbury

The toxic actions of MPTP and its metabolite MPP+ are not mimicked by analogues of MPTP lacking an N-methyl moiety.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), its metabolite 1-methyl-4-phenylpyridine (MPP+) and three analogues of MPTP, lacking an N-methyl moiety, namely, 4-phenylpiperidine (I), 4-phenyl-1,2,3,6-tetrahydropyridine (II) and 4-phenylpyridine (III), were infused continuously for a period of 4 days into the rat substantia nigra. Within 12 h of commencing the bilateral infusion of MPTP or MPP+, rats showed marked motor deficits with reduction in locomotor activity, loss of ability to move the forelimbs and grip with forepaws and, following MPP+ infusions, similar loss of movement in the hindlimbs associated with the development of limb and body rigidity. These motor deficits were not induced by the 3 analogues of MPTP on infusion into the substantia nigra. After 4 days of infusion, the motor deficits caused by MPTP and, in particular, MPP+, were still marked, and for MPP+ these correlated with marked loss of striatal dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid. 4-Phenyl-1,2,3,6-tetrahydropyridine caused a small loss in striatal DA and DOPAC, but the other analogues failed to modify the striatal content of DA or its metabolites. Small alterations of chemical structures related to MPTP and its metabolite can critically alter ability to induce behavioural and neurochemical changes reflecting toxicity on the nigrostriatal DA system.

The effect of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) on striatal and limbic catecholamine neurones in white and black mice. Antagonism by monoamine oxidase inhibitors.

Albino mice and pigmented mice were treated for 6 days with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) at the maximum tolerated doses (2 days at 30 mg/kg i.p., 2 days at 40 mg/kg i.p. and 2 days at 50 mg/kg i.p. in white mice, 6 days at 30 mg/kg i.p. in pigmented mice) and the effects of simultaneous treatment with the monoamine oxidase inhibitors, deprenyl (1 mg/kg, i.p.), MDL 72145 (0.5 mg/kg, i.p.) and clorgyline (5 mg/kg, i.p.), determined behaviourally (daily for 6 days and for 4 days after withdrawal) and biochemically (92 hr after withdrawal of drug). In albino mice MPTP caused depletions of dopamine (90%), dihydroxyphenylacetic acid (DOPAC; 82%) and homovanillic acid (HVA; 65%) in the striatum and in dopamine (54%), DOPAC (51%) and HVA (53%) in the nigra. However, MPTP was not selective in its action since the levels of dopamine and its metabolites were also reduced in limbic tissue. Further, MPTP affected the function of noradrenaline, with reduced levels in tissues of the striatum (74%) and nigra (46%). Pigmented mice were as susceptible as albino mice to the actions of MPTP to reduce the levels of dopamine and metabolites in the striatum. However, the limbic areas and substantia nigra of the pigmented mouse were more resistant to the actions of MPTP. Treatment with deprenyl and MDL 72145 (but not clorgyline) could be shown to reduce the biochemical and behavioural consequences of the action of MPTP (although behavioural changes, development of severe motor incapacitation and prostrate appearance, appeared to be non-specific).(ABSTRACT TRUNCATED AT 250 WORDS)

5-Hydroxytryptamine involvement in the locomotor activity suppressant effects of amphetamine in the mouse

Abstractd-Amphetamine, in doses lower than required to increase motor activity, reduced mouse spontaneous locomotor activity when this was assessed using cages equipped with photocell units, using treadwheels, or the measurement of spontaneous climbing behaviour. Actue treatments with the serotonergic agonists quipazine and 5-hydroxy-dl-tryptophan also reduced wheel running activity, spontaneous locomotor activity assessed using photocell cages, and spontaneous climbing behaviour; fenfluramine caused a similar effect. Pretreatment with 5-hydroxy-dl-tryptophan enhanced the inhibitory effects of d-amphetamine. A 3-day treatment with fenfluramine, or lesions of the median raphe nucleus (but not the dorsal raphe nucleus) abolished the ability of d-amphetamine to reduce motor activity in the three test systems. It is concluded that low doses of d-amphetamine can reduce locomotor activity and that the effects may be mediated via an enhancement of the release of 5-hydroxytryptamine from the system arising in the median raphe nucleus.

A comparison of dopamine agonist action to inhibit locomotor activity and to induce stereotyped behaviour in the mouse.

51 purported dopamine agonists from the phenylethylamine, tetralin, octahydrobenzo(f)- and (g)quinoline, benzocycloheptene, aporphine and ergoline series were tested in the mouse for ability to cause motor inhibition at low doses and stereotyped responding (motor facilitation) at higher doses. Motor inhibition was characterised either by a freezing akinesia (spiroperidol sensitive) or by sedation (resistant to spiroperidol). Agents potent to induce the freezing response could, if the dose was raised sufficiently (at least 10 fold), cause stereotypy. Within all series tested N-n-propyl substitution generally conferred greatest selectivity of motor inhibitory action. Radioligand binding assays using [3H]ADTN as ligand and rat striatal tissue showed correlations between abilities to associate with the dopamine receptor and to cause motor inhibition or facilitation, but discrepancies were apparent, particularly within the tetralin series. It is concluded that whilst there exists clear potency differences to inhibit locomotor activity and to induce stereotyped behaviour, it is difficult to demonstrate unequivocally an absolute selectivity of dopamine agonist action for the motor inhibitory dopamine system.

MPP+ can disrupt the nigrostriatal dopamine system by acting in the terminal area

Acute intracerebral injections of MPP+ in the mouse can cause behavioural and biochemical correlates of nigrostriatal dopamine dysfunction, but these are most marked and consistent when injections are directed at the dopamine nerve terminal area (CP) rather than the cell body area (SN). This adds further support to the hypotheses that a locus of neurotoxic action of MPTP/MPP+ may reside in the dopamine cell terminal regions.

Inhibition and facilitation of motor responding of the mouse by actions of dopamine agonists in the forebrain

The actions of dopamine and agonists of dopamine to influence forebrain structures and modify spontaneous locomotion of the mouse were studied, firstly, by injecting agents from different chemical series into the nucleus accumbens (phenylethylamine, aporphine, benzo[g]quinoline, tetralin, dopamine, N-n-propyl-N-phenethyldopamine, N-n-propyl-N-butyldopamine, apomorphine, trans-N-n-propyl-6,7- and -7,8-dihydroxyoctahydrobenzo[g]quinoline, 2-di-n-propylamino-5,6- and -6,7-dihydroxytetralin, 2-di-ethylamino-5,6-dihydroxytetralin) and, secondly, by selecting a potent agent (2-di-n-propylamino-5,6-dihydroxytetralin) for injection into 43 other forebrain areas. Agents from all chemical series were shown to reduce locomotor activity on injection into the nucleus accumbens. The most effective agents were the dialkylated tetralin derivatives and the N-propyl benzo[g]quinoline compound (0.025-0.5 micrograms); inhibition of motor activity generally decreased as dose was increased. The inhibitory effects on motor activity of the propyl substituted tetralin and [g]quinoline were specifically antagonised by sulpiride and/or spiperone (prazosin, yohimbine and methysergide were ineffective). Injections of tetralin (0.1 micrograms) not only into the nucleus accumbens but also into the tuberculum olfactorium, septal nucleus, anterior olfactory nucleus, anteromedial fibre system, claustrum and caudate-putamen could effect inhibition of motor activity. Generally, injections away from these structures were ineffective. It is suggested that small doses of dopamine and agonists of dopamine can influence dopamine receptors which are sensitive to neuroleptic drugs (presynaptic in limbic and striatal regions, but with a possibility of postsynaptic involvement in cortical regions) to effect inhibition of motor activity from a number of discrete areas of the forebrain of the mouse.

Motor inhibition induced by aporphine derivatives in the mouse

The ability of some aporphine and benzylisoquinoline derivatives to inhibit mouse spontaneous locomotor activity at low doses, and at higher doses to have a reduced motor inhibitory effect, was used to determine whether motor inhibitory and facilitatory potentials could be dissociated, and the optimal structure required to cause these behavioural changes. Ability to displace [3H]2‐amino‐6,7‐dihydroxy‐1,2,3,4‐tetrahydro‐naphthalene [3H]ADTN from its binding sites in rat striatal tissue was used as a broad measure of the abilities of the test compounds to bind to the ‘dopamine receptor’. The order of potency for ‘low dose’ inhibition of mouse spontaneous locomotion was (1) (‐)N‐n‐propylnorapomorphine>(2) apomorphine > (3) (‐)2,10,11‐trihydroxy‐N‐n‐propylnoraporphine > (4) (‐)2,10,11‐trihydroxyaporphine > (5) f‐10,11‐dihydroxy‐N‐(hydroxy‐ethyl)noraporphine > (6) norapomorphine > (7) (±)10‐hydroxy‐N‐n‐propylnoraporphine > (8) 1‐(3,4‐dihydroxybenzyl)‐2‐n‐propyl‐1,2,3,4‐tetrahydroiso‐ quinoline. The latter two compounds were only weakly active and (±)8‐hydroxy‐N‐n‐propylnoraporphine and 1‐(4‐hydroxybenzyl)‐2‐n‐propyl‐1,2,3,4‐tetrahydroisoquinoline were inactive. The reduction in motor inhibitory effect as dose of agonist was increased (indicative of facilitation of locomotion) was only observed with compounds 1 and 2, other compounds (3 and 4) caused non‐specific changes which interfered with motor performance or the doses required were so large as to render testing impractical (5,6,7 and 8). The potent motor inhibitory actions of compounds 1–4 were antagonized by pretreatment with spiperone but not with prazosin or yohimbine. Specific binding of 2·0nM [3H]ADTN was displaced by nanomolar concentrations of (±)‐ADTN and aporphine derivatives. Isoapomorphine and the two benzylisoquinoline derivatives were ineffective at 10−6M. The optimal structure for those derivatives examined was shown in all tests to be (‐)N‐n‐propylnorapomorphine.

The neurotoxic actions of 1-methyl-4-phenylpyridine (MPP+) are not prevented by deprenyl treatment

1-Methyl-4-phenylpyridine (MPP+) injected into the cerebral ventricles (ICV) of mouse caused depletions of striatal dopamine (DA)(-42%), 3,4-dihydroxyphenylacetic acid (DOPAC) (-34%) and homovanillic acid (HVA) (-16%) content without significant reductions in levels of noradrenaline (NA), serotonin (5-HT) or 5-hydroxyindoleacetic acid (5-HIAA). When deprenyl was administered before MPP+, striatal DA and its metabolites were further depleted, and striatal NA and 5-HT levels also were reduced. Further, whilst ICV MPP+ alone failed to influence the biochemistry of the limbic areas (nucleus accumbens plus tuberculum olfactorium), in the presence of deprenyl MPP+ caused 20-40% reductions in levels of limbic NA, DA, DOPAC, HVA, 5-HT and 5-HIAA. Therefore, deprenyl treatment does not prevent the neurotoxic actions of MPP+; indeed, a more extensive neurotoxicity for MPP+ is revealed in the presence of this monoamine oxidase inhibitor.

Biochemical correlates of motor changes caused by the manipulation of dopamine function in the substantia nigra of the mouse

2-Di-n-propylamino-5,6-dihydroxytetralin, injected bilaterally into the substantia nigra of the mouse, caused dose-dependent motor inhibition which was associated with decreased levels of DOPAC and increased levels of dopamine in the striatum. (-)Sulpiride, injected into the substantia nigra, antagonised the locomotor depression although the partial antagonism of the elevation in the level of dopamine in the striatum and of the reduction in levels of DOPAC did not achieve significance. The specificity of the action of tetralin on dopamine receptors was shown by the failure of prazosin and yohimbine to antagonise the locomotor depression induced by tetralin and the reduction in levels of DOPAC. The selectivity of the action of tetralin for the dopamine system was shown by its failure to affect levels of noradrenaline, serotonin and 5-hydroxyindoleacetic acid in the striatum. The injection of tetralin into the substantia nigra also caused biochemical changes in limbic areas (nucleus accumbens and tuberculum olfactorium), where the levels of dopamine and DOPAC were elevated, and in the frontal cortex where the levels of DOPAC were reduced. These changes were antagonised by a concomitant injection of (-)sulpiride into the substantia nigra. It is concluded that the action of dopamine agonists in the midbrain can decrease the functional activity in the ascending dopaminergic pathways.

Inhibition of Serum Melatonin Concentration and Synthesis of Brain Indolealkylamines by Monofluoromethyldopa in the Rat

The simultaneous effect of α‐monofluoromethyldopa (MFMD) on the synthesis of rat brain indolealkylamines has been investigated both in the daytime and in the dark phase. The effect on serum melatonin concentration has also been determined in the dark period. MFMD inhibits 5‐hydroxytryptophan decarboxylase in the pineal gland, hypothalamus, and the cerebral cortex. Simultaneous measurement of 5‐hydroxytryptophan (5‐HTP), 5‐hydroxytryptamine (5‐HT), and 5‐hydroxyindoleacetic acid (5‐HIAA) levels in the three brain areas revealed that MFMD caused (1) large increases in pineal 5‐HTP concentrations and substantial decreases in pineal 5‐HT and 5‐HIAA both in the light and dark phases; (2) a significant decrease in daytime hypothalamic 5‐HT content after 7‐h pretreatment; and (3) a large increase in dark‐phase cortical 5‐HT concentration after 4‐h pretreatment. Serum melatonin levels were also reduced by the action of MFMD in the dark period. The evidence suggests that differences occur in the rate‐limiting steps in the indolealkylamine biosynthesis in the three brain areas.