The presynaptic and postsynaptic actions of amino acid transmitters gamma-aminobutyrate, glutamate, aspartate and glycine in the central nervous system are reviewed.
Recent neurochemical studies of norepinephrine (NE), dopamine (DA), and serotonin (5HT) in autism are reviewed. Most studies of the catecholamines, their metabolites, and associated enzymes have not found differences between autistic and normal subjects. However, a robust increase in platelet 5HT has been well replicated and characterized. Studies on the possible causes of the increased platelet 5HT in autism suggest that an alteration in platelet physiology is the cause of the increase. Future directions for research on the platelet are discussed as are other potentially fruitful methods for examining monoamine functioning in autism.
The acute effects of buspirone, an anxiolytic with mixed dopamine (DA) agonist-antagonist properties (achieved by blocking pre- and postsynaptic receptors) on serum prolactin (PRL) were studied in cross-over and double-blind trials in ten healthy young males. Sulpiride (200 mg) was used as a control drug; it raised PRL by almost 800%. Buspirone (25, 50 and 100 mg) raised serum PRL dose-dependently; the greatest increases (30, 70, and 320% from baseline, respectively) were seen 1 h after each dose. The results suggest that buspirone blocks postsynaptic DA receptors only at doses higher than those needed for anxiolysis.
Simultaneous administration of 1,25-dihydroxyvitamin-D3, citrate, and aluminum-containing phosphate binders is frequently used in patients with chronic renal failure. In order to investigate whether citrate may represent a risk factor of aluminum intoxication, 16 Sprague-Dawley weanling rats were randomly assigned to four groups: 1,25-dihydroxyvitamin-D3 at 16 ng/kg/day was given to all groups except the control; in addition, two groups received either aluminum hydroxide at 160 mg elemental aluminum/kg/day, or aluminum citrate at 160 mg elemental aluminum/kg/day, respectively. The control group received only the vehicle. Extremely high aluminum concentrations were detected in the hippocampus of rats receiving aluminum compounds. This content of aluminum (microgram/g dry weight) was far higher than that found in other brain areas of the same animals (146.40 +/- 51.23 versus 4.49 +/- 0.62, P less than 0.001) as well as that detected in the hippocampus of the control animals (2.73 +/- 0.40). Thus, in non-uremic, weanling rats supplemented with 1,25-dihydroxyvitamin-D3, the administration of aluminum favors selective accumulation in the hippocampus. No differences between aluminum hydroxide and aluminum citrate administration were observed.
Radioimmunoassays of brain extracts have shown that several peptides occur in high concentrations in the CNS. The releasing-factor peptides TRF, LRF, somatostatin, CRF and GRF have the highest concentration in the hypothalamic extracts. High levels of somatostatin, CCK octapeptide, neuropeptide Y (NPY) and vasoactive intestinal peptide (VIP) are found in cortical extracts. Substance P, CCK, NPY, and enkephalins are present in high concentrations in basal ganglia and mesolimbic areas. Pharmacological doses of these peptides result in several behavioural and vegetative effects. Immunocytochemical studies show that the CNS peptides are localised in neurones and in synaptic vesicles. In vitro studies with brain tissues show that peptides are capable of modifying the ongoing classical neurotransmission. In depressive patients several neuropeptides (CCK, CRF and NPY) have been shown to have low CSF levels. Patients dying of senile dementia have low cortical levels of somatostatin, CRF and substance P. In schizophrenic patients CCK peptides have shown to improve some symptoms. At present the therapeutic potentials of peptides are poorly known. More studies are required to understand their role in neurotransmission and related pathological states.
Selective neuronal loss in the hippocampus following transient forebrain ischaemia appears to be excitotoxic in origin. The early cytological changes in the rat hippocampus (1-2 hours after 10 or 30 minutes of ischaemia) have the ultrastructural appearances of an excitotoxic lesion. Focal injection of an excitatory amino acid antagonist acting competitively on the N-methyl-D-aspartate (NMDA) receptor, 2-amino-7-phosphonoheptanoic acid (2-APH) in one hippocampus protects against the early cytopathology, and, when repeated 4 and 10 hours after the ischaemia, partially protects against selective nerve cell loss. Systemic administration of 2-APH or of a non-competitive antagonist at the NMDA receptor, ketamine, also protects against neuronal loss. Blockade of excitatory transmission at the NMDA receptor may provide a therapeutic approach to the acute treatment of cerebral ischaemia.
Antisera against two mammalian peptides related to the molluscan cardioexcitatory peptide Phe-Met-Arg-Phe-NH2 were used to locate immunoreactive neurons in the rat brain, nerve fibres and terminals in the spinal cord, sympathetic ganglion cells and adrenal chromaffin cells. Immunoreactivity for the newly characterised octa- and octadecapeptide was detected in nerve cell bodies in the hypothalamic area, including parts of the dorsomedial, periventricular and paraventricular nuclei, and in the nucleus tractus solitarii. Nerve terminals in the superficial laminae of the spinal cord were also immunoreactive for these peptides, while the sensory ganglia were nonreactive. Some principal ganglion cells in the superior cervical ganglia exhibited bright immunofluorescence for the peptides, and a few adrenal medullary cells were immunoreactive. The presence of these peptides in the substantia gelatinosa of the spinal cord suggests that they may be involved in sensory neurotransmission, especially in the mechanisms mediating pain. In the hypothalamo-hypophysial system these peptides may be involved in the regulation of hormonal systems. They may also act as co-transmitters in the sympathetic nervous system.
The EEG-effects induced by intraperitoneal administration of clonidine, prazosin and yohimbine to 8 and 22 month old rats were compared. Clonidine (0.01 mg/kg) and prazosin (1 mg/kg) increased spectral powers, yohimbine (0.5 mg/kg) decreased them. In the older rats, EEG variations were smaller for prazosin and yohimbine, but larger for clonidine. These findings show that alpha receptor mediated influences on EEG are changed during aging and show that quantified EEG gives a picture of age related changes in the functional state of the neurotransmitter systems.
Time relationships and mediators of the inhibitory effect of pinealectomy on cold-induced TSH secretion were studied in male Sprague-Dawley rats. Pinealectomy but not sham operation significantly reduced the TSH cold-response (30 min at +4 degrees C) in 6-8 week-old rats on the 3rd postoperative day. Longer postoperative periods resulted in gradual attenuation of the effect of pinealectomy. Pinealectomy did not modify basal TSH levels on the 3rd or 7th postoperative day. Melatonin, arginine vasotocin and crude pineal extracts failed to antagonise the suppressed cold-response in pinealectomised rats. 5-Hydroxytryptamine and 6-methoxy-tetrahydro-beta-carboline, however, antagonised partially but significantly the pinealectomy-induced reduction in TSH cold-response. Although transient, the suppression of cold-stimulated TSH secretion by pinealectomy may be caused by lack of two pineal indoleamines 5-hydroxytryptamine and/or 6-methoxy-tetrahydro-beta-carboline.
Enzymatic deamination activity was determined with tritium-labelled substrates in seven established hematopoietic cell lines, in order to compare deamination rates in intact vs. broken cells with cytosine arabinoside, deoxycytidine and 5-methyldeoxycytidine. Deaminase activity was found in all the cell lines, although it was very low in mouse leukemia L1210 cells. The deamination activity of intact cells varied from 1.0 to 38.3 pmoles/micrograms protein/30 min, being highest in the human null-cell ALL line (NALL-1), the human promyelocytic leukaemia line (HL-60) and the human T-ALL line (JM). The variation in specific activities in the broken cells was between 0.9 and 30.2 pmoles/micrograms protein/30 min. The deamination rate of deoxycytidine was in general higher than that of 5-methyldeoxycytidine or cytosine arabinoside.
The concentrations of glucocorticoid receptors were assayed in various chick embryo tissues by a cytosol charcoal-dextran method using [3H]dexamethasone as ligand. The highest levels of receptors were found in muscle on developmental day 15-16. The order of maximum binding of dexamethasone in various tissues was muscle greater than heart greater than skin greater than tendon greater than kidney greater than cartilage greater than liver. However, marked variation in the level of receptors was found even in the same tissue during development of the chick-embryo. The highest levels of receptors were generally found on days 15-17. For example, in tendon the difference between the highest and lowest level of receptors was about 6-7 fold. Thus the results show that specific glucocorticoid receptors may be found in various tissues of developing chick-embryos.
The aim was to study changes in brain monoamine neurons in an experimental animal model with an extrapyramidal motor syndrome of the parkinsonian type. The neurological signs were observed in rats after acute cobaltous acetate intoxication under mild ischemic conditions. Histofluorescence studies showed a decrease in catecholamine fluorescence (which signifies a decrease in the amine content) in the hypothalamus and mesencephalic reticular formation, but not in the substantia nigra or basal ganglia. Serotonin fluorescence was increased in nerve cell bodies of the dorsal and median raphe nuclei and in nerve terminals in some thalamic and preoptic regions. Histological staining of sections adjacent to the fluorescent ones showed no neuronal loss and some pathology of myelin. The disturbing effect of cobaltous ions on the neuronal transmission, and/or the imbalance between dopamine and serotonin in the extrapyramidal motor syndrome observed in poisoned rats have been discussed.
The role of hormones in regulating the complex network of immune responses has lately been emphasized. In particular, glucocorticoids and sex hormones have been shown to modulate both cellular and humoral immunity. Reports concerning the mechanisms of hormonal action are still somewhat conflicting, and there are reports of both inhibitory and stimulatory effects on various phases of the immune response.
The influence of verapamil on cardiovascular effects of prostacyclin (PGI2) in rats was examined. PGI2 administered into the lateral brain ventricle (i.c.v.) or intravenously (i.v.) in a dose of 2.7 x 10(-8)mol evoked hypotension and tachycardia. Pretreatment with verapamil in a dose of 2.0 x 10(-5)mol/kg given intraperitoneally (i.p.) diminished hypotensive effect of PGI2 i.c.v. as well as inhibiting the influence of PGI2 i.c.v. and i.v. upon the heart rate. Bolus injection of PGI2 in a dose of 2.7 x 10(-10), 2.7 x 10(-9) or 2.7 x 10(-8)mol evoked biphasic inotropic and chronotropic effects on isolated rat heart. Short-term increase of the contractile force together with bradycardia and afterwards long-lasting decrease of contractility with sustained, slight tachycardia were observed. Verapamil in a concentration of 1.0 x 10(-6)M blocked biphasic inotropic effect and bradycardia after PGI2 administration. Because some central and peripheral cardiovascular effects of PGI2 were inhibited by verapamil, it is concluded that PGI2 may participate in transmembrane calcium ions movements.
Acute graft-versus-host disease (aGVHD) remains one of the major obstacles in bone marrow transplantation. The histological changes of aGVHD have been documented thoroughly; much less is known about the inflammatory cell populations causing the reaction. This review focuses on the inflammatory cells isolated from the different target organs during aGVHD.
The re-aggregation of dispersed islet cells from non-inbred ob/ob-mice was studied by light and electron microscopy. After 3 days of culture, spontaneously formed aggregates with more than 95% beta-cells were up to 0.5 mm in diameter and exhibited a high degree of viability on dye exclusion tests. In comparison with cultures at 1 or 3 mM D-glucose, or 1 mM D-glucose in combination with 19 mM 3-0-methyl-D-glucose, aggregates formed in 20 mM D-glucose were more closely packed, had a smoother circumference with elongated peripheral beta-cells, and exhibited well developed micro-villi in localized intercellular widenings. A stereological analysis of electron micrographs showed that beta-cells aggregated at 20 mM D-glucose exhibited the same individual profile area but a significantly lower form factor, and a significant reduction in granule volume density as compared with aggregates at 3 mM D-glucose. It is concluded that D-glucose has morphogenetic effects on both the cellular and the micro-anatomical level of pseudo-islet structure in culture.
