Further treatment with MPTP does not produce parkinsonism in marmosets showing behavioural recovery from motor deficits induced by an earlier exposure to the toxin.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), or 0.9% saline, was administered to a group of common marmosets initially treated with the toxin 12-18 months previously. Initial treatment had consisted of a cumulative dose of 6-22 mg/kg (i.p.) which caused marked parkinsonism. Subsequently, the animals gradually recovered normal motor function. Further treatment consisted of a cumulative dose of MPTP of 78-83 mg/kg (i.p.) but this produced only modest akinesia. At 12-18 months after the initial treatment with MPTP, the content of dopamine, HVA and DOPAC in the caudate and putamen was markedly reduced. However, levels of dopamine, HVA and DOPAC in the nucleus accumbens were normal. Three months after the second treatment with MPTP there was no further decrease in the content of dopamine in the caudate-putamen. However, in the nucleus accumbens the content of dopamine, HVA and DOPAC was now reduced. The initial treatment with MPTP substantially decreased the binding of [3H]mazindol in the caudate-putamen but less so in the nucleus accumbens. Only a small additional decrease occurred upon further treatment with MPTP. The density of tyrosine hydroxylase (TH) immunoreactive cells in substantia nigra was reduced after the initial treatment with MPTP. However, the cell loss was far less marked than the decrease in terminal density, assessed by the binding of [3H]mazindol. Subsequent treatment with MPTP caused a small further loss of tyrosine hydroxylase-positive cells. Initial treatment with MPTP may kill the majority of MPTP-sensitive dopamine cells in the nigra. Compensation by the remaining nigrostriatal neurones may account for the behavioural recovery observed.(ABSTRACT TRUNCATED AT 250 WORDS)

Definition of the in-vivo binding of [3H]spiperone in rat brain using substituted benzamide drugs.

The ability of some substituted benzamide drugs to define in-vivo the binding of [3H]spiperone to brain dopamine receptors in rats was assessed using behaviourally effective doses in comparison with haloperidol. As judged using haloperidol, [3H]spiperone identified dopamine receptors in the substantia nigra, striatum, tuberculum olfactorium and hypothalamus, but not in frontal cortex or nucleus accumbens. The substituted benzamide compounds alizapride, metoclopramide, clebopride and YM 09151-2 prevented the accumulation of [3H]spiperone in the substantia nigra, striatum, tuberculum olfactorium and hypothalamus. However, YM 09151-2 also caused displacement of [3H]spiperone accumulation in the nucleus accumbens and frontal cortex. (+/- )-Sulpiride, (+/- )-sultopride, amisulpiride and prosulpride all prevented the accumulation of [3H]spiperone in the hypothalamus but were ineffective in one or more of the other regions containing dopamine receptors defined by [3H]spiperone. The isomers of sulpiride and sultopride stereoselectively defined the accumulation of [3H]spiperone in dopamine containing brain regions. The (-)-isomers of both drugs prevented the accumulation of [3H]spiperone in the substantia nigra, striatum, tuberculum olfactorium and hypothalamus. In contrast, (+)-sulpiride and (+)-sultopride were ineffective. Selected substituted benzamide drugs can be used to define the interaction of ligands with dopamine receptors in-vivo. These substances may be useful in PET studies in man. The isomers of some substituted benzamine drugs may be used to define dopamine receptors in-vivo by enantiomeric selectivity.

Definition of the in-vivo accumulation of [3H]spiperone in brain using haloperidol and sulpiride to determine functional dopamine receptor occupation.

The in-vivo administration of [3H]spiperone caused an accumulation of radioactivity in the substantia nigra, tuberculum olfactorium, nucleus accumbens, striatum and frontal cortex when compared with cerebellar levels. Haloperidol (0.01-1.0 mg kg-1 i.p.) dose-dependently prevented the accumulation of [3H]spiperone in the substantia nigra, tuberculum olfactorium, striatum and nucleus accumbens. Sulpiride (10-160 mg kg-1 i.p.) dose-dependently prevented the accumulation of [3H]spiperone only in the substantia nigra. The effects of sulpiride on other areas were not consistent; there was a suggestion of a reduction in the accumulation of [3H]spiperone in tuberculum olfactorium and striatum, but not in nucleus accumbens. Neither haloperidol (0.01-1.0 mg kg-1 i.p.) nor sulpiride (10-160 mg kg-1 i.p.) caused displacement of [3H]spiperone from the frontal cortex. Both haloperidol (0.01-0.5 mg kg-1) and sulpiride (10-80 mg kg-1) increased striatal and mesolimbic HVA concentrations. Haloperidol potently blocked apomorphine-induced stereotypy but sulpiride was only effective at the highest dose employed. The functional effect produced by haloperidol correlated with its ability to define [3H]spiperone binding in-vivo to dopamine receptors in the substantia nigra, striatum and tuberculum olfactorium. In contrast, there was no correlation between functional effect of sulpiride and its ability to define [3H]spiperone binding in-vivo.

Comparison of the in-vitro receptor selectivity of substituted benzamide drugs for brain neurotransmitter receptors.

The in-vitro selectivity of a group of substituted benzamide drugs for brain neurotransmitter receptors was determined to assess the most appropriate drugs for use in human PET studies. All substituted benzamide drugs studied inhibited [3H]haloperidol and [3H]spiperone binding to rat striatal membranes. The most potent compounds were YM 09151-2, clebopride and raclopride. However, these substances also interacted in differing degrees with alpha-1, alpha-2, beta-adrenergic, 5-HT-1, 5-HT-2, and opiate sites. Sulpiride, alizapride, SL 74205, TER 1546 and tiapride were specific for D-2 receptors, but these drugs were active only in the 10(-7)-10(-6) M range. Raclopride, amisulpiride and sultopride showed a 100-1000 differentiation between action on dopamine sites compared with other neurotransmitter receptors. No such selectivity was observed for clebopride or YM 09151-2. Specific substituted benzamides such as alizapride, may be appropriate in high concentrations for defining the interaction of PET ligands with brain dopamine receptors. More potent, but selective, drugs such as raclopride and amisulpiride, may be effective in low concentrations as ligands for labelling dopamine receptor sites. However, the ability of these various substituted benzamide drugs to penetrate into brain and in-vivo to identify dopamine receptors in all brain areas must be assessed.

Dopamine receptor binding sites in the rat superior colliculus.

Following intravenous administration of [3H]spiperone or [3H]N,n-propylnorapomorphine (NPA) to rats, radioactivity derived from the ligands accumulated in the striatum and superior colliculus when compared with cerebellar levels. The accumulation of [3H]spiperone in both areas was prevented by intraperitoneal administration of (+)-butaclamol, haloperidol and sulpiride but not by (-)-butaclamol, cinanserin, propranolol or prazosin. The accumulation of [3H]NPA was prevented by administration of (+)-butaclamol, haloperidol and apomorphine but not by (-)-butaclamol. In in-vitro experiments, membrane preparations from the superior colliculus showed a small number of specific binding sites for both [3H]spiperone and [3H]NPA. The dissociation constant (KD) for [3H]NPA was not different from that for striatal preparations but that for [3H]spiperone was 10-fold higher. We conclude that dopamine receptors may be present within the superior colliculus.