Familial fatal Parkinsonism with alveolar hypoventilation and mental depression.

The clinical, pathological, and neurochemical characteristics of a newly recognized inherited neurological disorder are reported. Lethargy and mental depression are early symptoms, followed by mild parkinsonism and progressive weight loss. Failure of automatic respiratory control develops and may result in sudden death. Advanced degeneration of the substantia nigra, cell loss and gliosis of the basal ganglia, and focal gliosis in the medulla are seen on pathological study. Degeneration of the nigrostriatal dopaminergic system is evidenced by low levels of tyrosine hydroxylase, dopamine, homovanillic acid, and L-dopa decarboxylase in postmortem brain samples. Taurine concentrations in fasting plasma and CSF are somewhat depressed; brain contents of taurine are within normal limits.     

Effects of cannabinoids on testosterone and protein synthesis in rat testis Leydig cells in vitro.

Various water-insoluble cannabinoids as well as SP-111A, the water-soluble derivative of delta 9-tetrahydrocannabinol (delta 9-THC), reduced hCG and dibutyryl-cAMP stimulated testosterone production by rat testicular Leydig cell preparations. With 0.15 microM (0.05 micrograms/ml) 8-beta-OH-delta 9-THC the inhibition was about 50% of stimulated testosterone synthesis. Dose-related inhibitions were apparent with other cannabinoids and their order of potency in inhibiting stimulated steroidogenesis by the interstitial cells in vitro was found to be: 8-beta-OH-delta 9-THC greater than or equal to 11-OH-delta 9-THC greater than CBN = CBD = CBG greater than or equal delta 9-THC = delta 8-THC. The non-stimulated, basal, steroidogenesis was not affected even with 15 microM cannabinoids. The incorporation of L-[U-14C]leucine into the protein of Leydig cells was markedly reduced by 15 microM cannabinoids under both basal and stimulated conditions. The inhibition of steroidogenesis as well as protein synthesis in rat testicular Leydig cell preparations by various cannabinoids cannot be correlated with their psychoactivity. The present data suggest that cannabinoids at very low concentrations may interfere directly in Leydig cells with both protein and testosterone synthesis, and thus with their function.     

Brainstem projecting neurons in the rat basal forebrain: neurochemical, topographical, and physiological distinctions from cortically projecting cholinergic neurons

Magnocellular regions of the basal forebrain contain cholinergic neurons that project to the cerebral cortex. Neurons in the same basal forebrain regions innervate the brainstem. The present study investigated whether these brainstem projecting neurons are cholinergic, project also to the cortex, and share similar physiological properties as cortically projecting neurons. Data with retrograde tracing from various regions of the pons, medulla, and cortex combined with choline acetyltransferase immunofluorescence indicated that: 1) brainstem projecting neurons are usually segregated from cortically projecting and/or cholinergic neurons in the basal forebrain, 2) virtually no brainstem projecting neurons in the basal forebrain are cholinergic, and 3) only rarely do basal forebrain neurons have axon collaterals that project to both cortex and brainstem. Extracellular recordings from basal forebrain neurons confirmed the paucity of axonal collateralization and the topographic segregation between cortically and brainstem projecting basal forebrain neurons, and, in addition, showed that brainstem projecting neurons have a slower mean conduction velocity than cortically projecting neurons. These observations suggest that basal forebrain neurons projecting to the brainstem (pons, medulla) and the cortex represent separate cell populations in terms of projections, neurotransmitter content, distribution, and physiological properties.     

Rotatory effects of intracerebral tetanus toxin injections

Injection of tetanus toxin into the substantia nigra or thalamus of rats produced almost immediately marked ipsilateral turning. Injection into the caudate led to similar turning, delayed 3 to 5 days in onset. Available data suggest the effects were not mediated by the dopaminergic system.     

Effects of globus pallidus lesions and Parkinson's disease on brain glutamic acid decarboxylase

Cats with unilateral lesions in the region of the globus pallidus showed a highly significant loss (to 39%) of glutamic acid decarboxylase (GAD) activity in the substantia nigra on the lesioned side. GAD was unaffected in the caudate nucleus or other structures. Tyrosine hydroxylase was reduced to 49% of the control values in the substantia nigra and to 23.7% in the caudate, while choline acetyltransferase and cholinesterase were not significantly affected in either structure. The data suggest that the lesion interrupted the known dopaminergic pathway between caudate and substantia nigra and interfered with another pathway concerned with GABA metabolism involving the substantia nigra but not the caudate. There appeared to be no major cholinergic pathway coursing through the lesioned area.     

Influence of noncholinergic drugs on rat striatal acetylcholine levels

Rat striatal acetylcholine levels were measured in rats following the administration of drugs that primarily affect dopamine metabolism. Reserpine, clozapine and chlorpromazine caused decreases in striatal acetylcholine levels of 33%, 38% and 54% respectively. Apomorphine, L-DOPA, methamphetamine and amantadine caused increases of 27%, 14%, 17% and 45% respectively. The decrease in acetylcholine levels following drugs that deplete or block dopamine, and the increase following drugs that enhance dopamine or stimulate its receptors, is consistent with a direct inhibitory action of dopamine on cholinergic striatal interneurons. Increased levels of acetylcholine would accompany decreased firing of cholinergic neurons due to dopaminergic inhibitory action. Decreased levels would accompany increased firing due to reduced dopaminergic inhibitory action.     

Thrombin accumulation in brains of patients with Alzheimer's disease.

Thrombin was detected immunohistochemically in brain tissue of Alzheimer's disease (AD) patients and age-matched controls. Positive staining was restricted to vessels and residual plasma in controls but was also present in senile plaques, some diffuse amyloid deposits and neurofibrillary tangles in AD. Positive staining was abolished by absorption of antibody with purified human thrombin but not by absorption with prothrombin. The data suggest that thrombin formation from prothrombin probably takes place in AD brain.     

Appearance of paired nucleated, Tau-positive glia in patients with progressive supranuclear palsy brain tissue.

Many Tau-positive glia with paired nuclei and astrocyte type morphology were identified in three brains from patients with progressive supranuclear palsy (PSP). They were positive by Bielschowsky's and Bodian's silver staining as well as by immunostaining with Tau-2, Alz-50, anti-GFAP and anti-paired helical filament antibodies, but not with anti-ubiquitin antibody. They were predominantly localized in the striatum, thalamus and frontal cortex but were not seen in white matter and were not plentiful in areas of heavy neuronal degeneration. Electron microscopy clearly showed the nuclear pairing and localized the Tau protein to bundles suggestive of microtubules in the cytoplasm and proximal processes. Such glial cells were rarely seen in cases of other neurodegenerative diseases or neurologically normal controls. These data suggest that there is an unusual gliotic reaction in PSP in brain areas which show relatively little neuronal loss.