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Dopamine agonist induced self-mutilative biting behavior in monkeys with unilateral ventromedial tegmental lesions of the brainstem: possible pharmacological model for Lesch-Nyhan syndrome.

We have investigated the effects of various dopamine (DA) agonists on induction of abnormal involuntary movements (AIM) in a group of monkeys which had denervated nigro-striatal DA neurons for 10-14 years rendered by a unilateral surgical ventromedial tegmental (VMT) lesion of the brainstem. The surgical lesions were placed when the monkeys were 2-4 years old. The administration of mixed DA agonists, such as L-DOPA, apomorphine (Apo) and abeorphine 201-678, elicit a self-mutilative biting behavior (SMB) of the forelimb digits contralateral to the lesion, and spasticity of the contralateral hindlimb. These dysfunctions resemble, in some aspects, the neurological disturbances associated with Lesch-Nyhan syndrome. The SMB behavior was elicited by mixed DA agonists which predominantly stimulate D1, but not D2 DA receptors, and was prevented or abolished by the D1 DA antagonist SCH 23390 or by the D1 and D2 DA antagonist fluphenazine (Flu), but not by the D2 antagonist (+/-)sulpiride. These results suggest that DA agonist-induced SMB behavior is mediated by D1 and/or by both D1 and D2 DA receptor pathways. To study the relationships between HPRT, the defective enzyme in Lesch-Nyhan syndrome, and the DA neuronal systems, we have measured the effects of nigro-striatal DA degeneration and intrastriatal neuronal degeneration on HPRT activity. The unilateral 6-OHDA-induced nigro-striatal DA degeneration does not significantly alter the HPRT activity on the lesioned side of the striatum, while the quinolinic acid-induced intrastriatal neuronal degeneration significantly reduces the enzyme activity. These results suggest that HPRT is localized on intrastriatal neurons which are also known to contain DA receptors. It is postulated that HPRT deficiency in Lesch-Nyhan syndrome results in abnormal guanine nucleotide metabolism which may affect the regulation of DA receptors.

Animals↗

MPTP-induced parkinsonism: relative changes in dopamine concentration in subregions of substantia nigra, ventral tegmental area and retrorubral field of symptomatic and asymptomatic vervet monkeys.

Dopamine (DA) and homovanillic acid (HVA) concentrations were measured in subregions of substantia nigra, ventral tegmental area and retrorubral field in vervet monkeys 1 to 2 months after treatment with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Identical MPTP treatment regimens produced animals with different degrees of parkinsonism. In asymptomatic monkeys, changes in DA and HVA concentrations in the midbrain DA regions were relatively small and involved central substantia nigra and dorsomedial ventral tegmental area. In contrast, changes in symptomatic monkeys were more severe and widespread, significantly affecting all examined subregions of substantia nigra (greater than 75% DA depletion), both dorsomedial and ventromedial ventral tegmental area and lateral, but not medial, retrorubral field. The data indicate that DA neurons in subregions of substantia nigra, ventral tegmental area and retrorubral field are not equally susceptible to MPTP toxicity. The pattern of MPTP-induced DA and HVA losses in the vervet monkey mesostriatal dopaminergic system may resemble postencephalitic Parkinson's disease more closely than idiopathic Parkinson's disease.

Animals↗

Calcitonin gene-related peptide immunoreactive sensory and motor nerves of the rat, cat, and monkey esophagus.

In the mammalian esophagus calcitonin gene-related peptide (CGRP)-immunoreactive nerves form abundant subepithelial plexuses and penetrate the mucosa. The levels of extractable CGRP in separated epithelial layers are 15.8 +/- 2.4 pmol/g wet wt of tissue (n = 8, mean +/- SEM). Treatment of neonatal rats with capsaicin and ablation of the central portion of the feline nodose ganglion led to a marked reduction in the numbers of CGRP-immunoreactive nerve fibers. The loss of CGRP nerves demonstrated by immunocytochemistry was accompanied by a parallel reduction in the tissue content of CGRP, as measured by radioimmunoassay (1.5 +/- 0.5 pmol/g in capsaicin-treated animals compared with 9.4 +/- 1.9 pmol/g in vehicle-treated controls; p less than 0.0025). These findings indicate the sensory nature of the CGRP-immunoreactive nerves. Substance P-immunoreactive nerve fibers innervated in particular the blood vessels of the lamina propria; very few penetrated the esophageal epithelium and these were only partially depleted after removal of the central portion of the nodose ganglion. The esophageal muscle contained nerves immunoreactive for substance P and, in particular, for CGRP which was also found in the motor end plates of the striated muscle. No changes in the CGRP-containing motor end plates were observed either after treatment of neonatal rats with capsaicin or ablation of cell bodies from the central portion of the nodose ganglion. These nerve fibers may originate from rostral areas of the nucleus ambiguus, where CGRP-immunoreactive motor neurons have previously been described. Thus, our findings reveal dual components, motor and sensory, of the CGRP-containing innervation of the esophagus.

Animals↗

Resting cortisol levels and the emergence of dominant status among male vervet monkeys.

Resting serum cortisol was measured in adult male vervet monkeys (Cercopithicus aethiops sabaeus) in four different conditions: (1) among groups with unaltered group membership and established dominance hierarchies; (2) among groups from which the original dominant male had been removed and in which the remaining males competed for dominant status; (3) among newly formed groups of three unfamiliar males each of which had been the dominant male in his previous group; and (4) among groups from which a dominant male was temporarily separated and returned. In Condition 1, cortisol concentrations did not differ between dominant and subordinate males. The second condition showed that cortisol levels were highest among males who eventually emerged as the dominant male. In the third condition, however, cortisol levels did not differentiate eventually dominant from eventually subordinate males. In the last condition, cortisol levels were highest in the animals that became or remained dominant following reintroduction. These data indicate that cortisol concentration does not differ between dominant and subordinate males in stable groups and that cortisol rises during competition for dominance among familiar males.

Animals↗

Lysosomal acid deoxyribonuclease from vervet monkey livers--I. Purification and physico-chemical characterization.

Acid DNase from monkey liver lysosomes was purified to homogeneity by salt extraction of lysosomal membranes at pH 3.8; (NH4)2SO4 fractionation; low salt precipitation; SP-C50 and G-150 Sephadex chromatography; and polyacrylamide gel electrophoresis. The pH for optimum activity was dual in character with a labile optimum at pH 3.8 and a less active but stable one at pH 4.2. The estimated molecular weight was 40K and the pI was 4.4. Inorganic ions such as Ca2+, Mg2+, Mn2+ and SO2-4 were more than 80% inhibitory at 10-mM levels. Fe3+ ions were 80% inhibitory at 0.1-mM levels. NaCl at 100 mM is essential for activity but becomes 100% inhibitory above 200 mM.

Amino Acids↗

Lysosomal acid deoxyribonuclease from vervet monkey livers--II. Enzymic properties.

Primate liver lysosomal acid DNase is an endonucleolytic enzyme. The enzyme has both 3'- and 5'-nucleotidohydrolase activities. The oligonucleotides produced by DNase are polymers mainly about 30 mononucleotides long. The Arrhenius plot shows a discontinuity with a transition temperature at 47 degrees C, with an activation energy of 107 kJ/mol below and 67 kJ/mol above this temperature. The activation enthalpy is 104 kJ/mol and the entropy -0.498 kJ/mol/K. The enzyme is subject to substrate inhibition and the Km value is 159 X 10(-3) mM DNA-P.

Animals↗

Connective tissue composition of aortas from non-human primates. A comparative study.

Connective tissue composition of aortas from several non-human primate species has been studied in an effort to relate collagen, elastin, ang glycosaminoglycan (GAG) content to species susceptibility to atherosclerosis. Among the species studied the baboon contained the highest content of GAG in the aorta. While the distribution of individual GAG varied from species to species, heparan sulfate (HS) was the highest GAG in aortas from most of the species. The ratio of HS to chondroitin sulfates (CS) plus dermatan sulfate (DS) was lowest in the baboon, a species relatively less susceptible to atherosclerosis, and highest in the squirrel monkey, a very susceptible primate. If a relationship exists between HS to CS + DS ratio in the aorta and atherosclerosis, the primates can be arranged in the following decreasing order of susceptibility: squirrel, chimpanzee, stump-tailed, rhesus, African green, patas, baboon. In studies of other connective tissue components, the proportion of total collagen to elastin was found lowest in the baboon. Such observations emphasize the importance of connective tissue in the pathogenesis of atherosclerosis.

Animals↗

Influence of dietary fats and an oral contraceptive on plasma lipids, high density lipoproteins, gallstones, and atherosclerosis in african green monkeys.

Twenty-nine African green monkeys were fed diets for 22 months containing 0.79 mg cholesterol/kcal and 40% of calories as either safflower oil or butter with or without the addition of an estrogen- and progestin-containing oral contraceptive. Plasma cholesterol concentrations ranged from 199 to 250 mg/dl. Animals consuming the safflower oil diet had plasma cholesterol concentrations that averaged 61 mg/dl lower than those consuming butter. At least 72% of this lowering was due to a reduction in low density lipoproteins. Triglyceride concentrations were also slightly lower in animals consuming the safflower oil diet. The oral contraceptive lowered total plasma cholesterol concentrations in both diet groups by an average of 41 mg/dl with 54% of this lowering (22 mg/dl) due to a reduction in high density lipoprotein cholesterol. This effect occurred only during the 3 weeks while the contraceptive was being administered and was not apparent 1 week after stopping the drug. Animals consuming safflower oil had bile that was more lithogenic and had more gallstones than did those consuming butter. Addition of the oral contraceptive caused a slight increase in bile lithogenicity, but this increase was not statistically significant. There was no significant interaction between the oral contraceptive and either of the diets to exacerbate cholelithiasis. At the plasma cholesterol concentrations achieved only minimal amounts of atherosclerosis developed and there were no indications of differences due to diet or oral contraceptive in the extent of atherosclerosis.

Animals↗

Diets realistic for westernized people significantly effect lipoproteins, calcium, zinc, vitamins C, E, B6 and haematology in vervet monkeys.

This report describes measurements of 50 variables in adult, female, reproductively inactive Vervet monkeys during prolonged nutrition realistic for westernized people. Dietary treatments consisted of an atherogenic Western diet (WD) and a prudent Western diet (PD). Ingredients were normal foods for man and no extra cholesterol was added. Fortification of both diets with vitamin C after cooking was necessary to prevent deficiency. Randomised groups of Vervet monkeys received either the PD or WD for 47 months, while a third group was fed WD for 20 months and then PD for 27 months (WD-PD). Before the dietary treatments nourishment was by a high carbohydrate diet (HCD) and baseline and reference values (RV) apply to this nutritional status. Plasma total cholesterol (mg/dl) was increased from 147 (HCD) to 174 (PD) and 376 (WD). Individual cholesterolaemio response ranged from mild to severe and was stable (PD and WD). Dietary reversal (WD-PD) reduced cholesterolaemia promptly. Statistically significant increases in calcium, zinc and vitamin E and decreased vitamin B6 were associated with the WD relative to the PD (in serum and plasma). Two cholesterol metabolising microsomal enzymes in liver were notably increased and one unchanged (WD). There were no dietary effects on triglycerides, vitamin A and glucose in plasma; insulin, glucagon, electrolytes, copper, magnesium or enzymes reflecting liver, muscle or brain cell damage in serum. Red blood cells, platelets and directly associated parameters increased (WD), haemoglobin was the same and haemoglobin per red cell decreased. Bleeding time was not affected. Bivariate correlations across the diets confirmed that Western nutrition promoted inherent individual susceptibility to cholesterolaemia. There were notable differences from RVs in total cholesterol, calcium, packed cell volume and haemoglobin, which emphasise excesses and deficiencies of the WD and PD.

Animal Nutritional Physiological Phenomena↗

Promotion and regression of atherosclerosis in vervet monkeys by diets realistic for westernized people.

We have described and measured aortic and arterial atherosclerosis in adult female Vervet monkeys (n = 61) after application of dietary treatments for 47 months. The diets were compounded entirely of normal food items for westernized people, with no extra cholesterol added. A 'Western' diet (WD), known to induce hypercholesterolaemia, was found to be atherogenic in aortas and some arteries. A more 'prudent' diet (PD) induced much less lipid infiltration into aortic intimas and was not associated with serious atherosclerotic changes. However, when this PD was used as a treatment for 27 months, following 20 months of nutrition by the WD, minimal regression of cholesterol crystals and non-lipid components of atherosclerotic plaque was detected. There was no significant coronary artery or myocardial disease in these adult females after 47 months of feeding on the WD whereas males do develop coronary atherosclerosis and myocardial fibrosis. For this model the PD would be more effective in preventing atherosclerosis than treating advanced lesions. We believe this is the first time that the pathology of atherosclerosis promoted by realistic diets has been modelled in adult females of this species.

Animal Nutritional Physiological Phenomena↗