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Biomedical subjects

A Lajtha

Publications and source records attributed to A Lajtha.

At least 181 records · Page 10Linked to original sources
PubMed1986

Structural requirements for cocaine congeners to interact with dopamine and serotonin uptake sites in mouse brain and to induce stereotyped behavior.

We report here saturation analysis of [3H]cocaine binding in various mouse brain regions, and the necessary structure-activity relationships for cocaine congeners to inhibit Na+-dependent [3H]cocaine binding and [3H]dopamine uptake in the mouse striatum, and to inhibit [3H]cocaine binding that cannot be stimulated by Na+ and [3H]serotonin uptake in the mouse cerebral cortex. Generally similar structure-activity relationships were noted for all these processes. The ester linkage between the tropane and phenyl rings was not required for activity, in contrast to the configuration of the groups on C2, and to a lesser extent C3, in the tropane ring. Stereospecificity was evident from the differences between cocaine and (+)-pseudococaine, and between WIN 35,065-2 and WIN 35,065-3. There were remarkable differences between the above structure-activity relationships and those for local anesthetic activity of cocaine congeners, indicating that sodium channels were not labeled to a measurable extent with [3H]cocaine under the present conditions. Preliminary data indicated a significant correlation between the potencies of cocaine congeners in inhibiting the Na+-dependent binding of [3H]cocaine and their potencies in inducing stereotyped sniffing upon intraventricular administration.

Animals↗
PubMed1986

Rates of amino acid incorporation into particulate proteins in vivo and in slices of young and adult brain.

Incorporation of a flooding dose of valine into brain proteins was measured in vivo and in brain slices, according to subcellular fraction and to solubility. In particulate fractions in vivo in the immature brain, soluble cytosol proteins had the highest synthesis rates (2.0% per hr), followed by microsomes (1.7%), mitochondria, nuclei (1.4%), and synaptosomes (0.85%). In adult, the rates were about half of those of immature animals except for microsomes, which were the same. In young, rates of incorporation into particles in brain slices were about 80% of in vivo rates, and adult rates were 10-20% of the in vivo rates. When brain proteins were fractionated into four groups--isotonic soluble, hypotonic soluble, Triton X-100 soluble, and the remainder solubilized in 0.2% SDS--in both young and adult brain in vivo, the isotonic fraction had the highest rate of protein synthesis, followed by the Triton-soluble fraction, the SDS-soluble fraction, and the hypotonic fraction. Also, with this method of separation in vitro rates for immature brain were 10-20% lower than in vivo rates, while in vitro adult rates were 80-90% lower. The results indicate that the most proteins are synthesized at a higher rate in the immature brain, and that the difference between in vivo and brain slice protein synthesis is not as great in the immature as in the mature brain in all the fractions examined.

Amino Acids↗
PubMed1986

Antagonism of phencyclidine-induced hyperactivity by glycine in mice.

We tested the effect of glycine on phencyclidine (PCP)-induced hyperactivity in mice. Glycine antagonized the locomotor stimulating effect of PCP. Correlation was found between the degree of antagonistic effect and the size of the increase in glycine in the brain. The antagonism is not due to changes in uptake, since the elevation of glycine in plasma and brain had no effect on the cerebral uptake of PCP. This pharmacological action of glycine appears to be a central effect, but some peripheral effect can not be excluded. Since glycine is not toxic at levels needed for PCP antagonism, it could be considered for ameliorating PCP psychosis. The locomotor stimulating effect of PCP is strain dependent in mouse. Some strains are responsive, such as BALB/cBy and CXBK, and some are unresponsive, such as C57BL/6 and CXBH.

Animals↗
PubMed1986

Amino acid incorporation in relation to molecular weight of proteins in young and adult brain.

Rates of protein synthesis were studied in immature and adult rat brain tissue. After an amino acid incorporation period, in vivo or in incubated slices from brain, the soluble protein was fractionated according to molecular weight by column chromatography. In examining soluble whole proteins, no direct correlation between molecular weights and synthesis rates could be established; the highest synthesis rates were found in fractions around 70,000 MW and below 10,000. Incorporation into the subunits after fractionation by SDS gel electrophoresis was proportional to subunit molecular weight, with rates of incorporation into the largest subunits being the highest. The results suggest a relationship between turnover rate and structure of subunits of brain proteins.

Aging↗
PubMed1986

Modulation of the serotonin S2-receptor in brain after chronic lithium.

In vivo effects of chronic lithium administration on dopaminergic and serotonergic receptor binding were studied in the striatum and cerebral cortex of the rat. [3H]Domperidone was used as the ligand for the dopaminergic receptor, and [3H]ketanserin for the serotonergic system. Long-term ingestion of lithium (2-3 months) resulted in high levels of lithium in the cerebral cortex and significantly higher potassium levels; the sodium content remained at normal levels. The kinetic constants (Kd and Bmax) of [3H]domperidone binding sites measured in the striatum did not show any deviation from control values, but the receptor concentration (Bmax) of [3H]ketanserin binding sites was significantly reduced in the cerebral cortex of lithium-treated rats. The apparent dissociation constant (Kd) was not changed. The results indicate that the serotonergic component of the [3H]spiperone binding site, which we had previously found to be affected by chronic lithium treatment and which was shown by Peroutka and Snyder to be the 5-HT2 receptor, is selectively affected by lithium.

Animals↗
PubMed1986

Genetic determination of striatal tyrosine hydroxylase activity in mice.

An additive major gene effect is described for tyrosine hydroxylase activity in mouse corpus striatum (CS). Quantitative genetic analysis indicated the presence of a segregating Mendelian factor with robust additive effect in F2 generations derived from crossing two highly inbred mouse strains, C57BL/6ByJ and BALB/cJ, with intermediate (INT) and high (HI) TH activity in CS. Significant positive correlation was found between striatal and mesencephalic TH activity in the segregating generations, raising the possibility that a common single gene may express its effect through pleiotropy or linkage. Genetic preparations taking advantage of the major gene effect should serve well as animal models of DA-mediated neuropsychiatric disorders.

Animals↗
PubMed1986

Separation and purification of individual neurofilament proteins by reverse-phase high-performance liquid chromatography.

A reverse-phase HPLC method was developed to separate individual neurofilament proteins (210,000, 160,000 and 70,000 Da) from the glial fibrillary acid protein. It is useful for analytical or preparative methods, with yields higher than 80%. The method represents improvement over previous methods in speed, efficiency, and purity. Combining this HPLC method with the conventional chromatographic method on DEAE-cellulose, highly purified individual neurofilament proteins can be obtained in large scale.

Animals↗
PubMed1986

Effect of amphetamine on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) neurotoxicity in mice.

Amphetamine has been shown to either potentiate or protect against MPTP neurotoxicity. The time course of changes in dopamine and its metabolites was examined after MPTP, amphetamine, or MPTP plus amphetamine administration. Results suggest that under conditions of granular depletion and release of dopamine by 10 mg/kg amphetamine, increased MPTP neurotoxicity occurs. Amphetamine injections at 2-5 mg/kg prevents the decline in dopamine possibly by blockade of the uptake of MPP+, rather than by an inhibition of monoamine oxidase.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1986

Effect of nicotine and amphetamine on the neurotoxicity of N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in mice.

The present results show the potentiating effect of amphetamine on the ability of MPTP to destroy dopaminergic neurons in striatum of the mouse. A single injection of MPTP (8 mg/kg, retro-orbital) reduced the binding of [3H]mazindol, a marker for dopamine terminals, by 24%. When D-amphetamine (10 mg/kg, s.c.) was given 20 min prior to MPTP, the binding of [3H]mazindol, measured 3-5 days later, was reduced by 58%. It is proposed that the mechanism of this potentiation primarily involves an increased release of dopamine by D-amphetamine, and free radical-mediated processes. Although nicotine also releases dopamine from the striatum, no effect was observed when it was administered prior to MPTP. The lack of effect is probably related to short duration of action of nicotine and the modest effect on release of dopamine as compared to that of amphetamine.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1986

Locomotor depression in mice by norcocaine does not involve central alpha 2-adrenergic or presynaptic dopamine receptors.

The inhibition of spontaneous locomotor behavior of mice by norcocaine was antagonized neither by the adrenoceptor antagonists yohimbine and phentolamine, nor by the neuroleptics haloperidol and spiperone, at low doses aimed at presynaptic dopamine receptors. In contrast, the antagonists were effective in reducing the hypomotility induced by clonidine and apomorphine, respectively. These results make it unlikely that central alpha 2-adrenergic or presynaptic dopamine receptors are involved in the hypomotive effect of norcocaine.

Animals↗
PubMed1986

Regional and cellular differences in rat brain protein synthesis in vivo and in slices during development.

We compared the rate of protein synthesis in immature and adult rat brain in vivo to that in brain slices. After the incorporation of a flooding dose of [14C]valine, in vivo and in brain slices, the label in proteins was measured in CNS regions and in neuron- and glia-enriched fractions. In regions in vivo in the adult, incorporation rates in corpus callosum were lower than in other regions, which were similar; in the young, cerebellum showed the highest rates and hypothalamus and cord the lowest. Since hypothalamus and cord were low in the young, there was no change during development in these two areas; in other areas incorporation rates in young were 2-3 times higher than in adult brain proteins. Incorporation rates in slices were lower than in vivo. In the young, cerebellum, olfactory bulb, and cord were close to in vivo, and other areas in slices from young incorporated at 60-90% of in vivo rates. In adult slices incorporation was 5-15% of that in vivo except in olfactory bulb, where it was 30%. In the cellular fractions, incorporation in vivo in young was close in the neuronal and glial fractions; in adults incorporation rates in neurons were higher, as the decrease in development was less in neurons than astrocytes. In slices in young, astrocytes incorporated amino acids at 100% of the in vivo rates, neurons at 60%; in adult slices, incorporation was at only 4-7% of the in vivo rate. The results show that developmental changes in protein metabolism occur in all brain areas and brain cells, with metabolic rates in young 2-3 times that in adult.(ABSTRACT TRUNCATED AT 250 WORDS)

Aging↗
PubMed1986

Binding sites for [3H]cocaine in mouse striatum and cerebral cortex have different dissociation kinetics.

[3H]Cocaine dissociates from its binding sites in the mouse cerebral cortex with a half-time of 25 s. The dissociation kinetics in the striatum is consonant with the presence of two populations of sites with dissociation half times of 2 s and 27 s, comprising 88% and 12%, respectively, of the total binding sites. On the basis of previous pharmacological characterization of [3H]cocaine binding, we propose that the slowly dissociating component represents the sites associated with 5-hydroxytryptamine (serotonin) uptake, and the rapidly dissociating component the 3,4-dihydroxyphenylethylamine (dopamine)-related sites. Evidence is presented that the extremely high dissociation rates do not preclude the measurement of [3H]cocaine binding by rapid filtration. The dissociation of [3H]cocaine from cerebrocortical membranes is slowed to a small but statistically significant extent by serotonin.

Animals↗
PubMed1986

Superoxide radical-mediated alteration of synaptosome membrane structure and high-affinity gamma-[14C]aminobutyric acid uptake.

Mouse cortical synaptosomal structure and function are altered when exposed to hypoxanthine/xanthine oxidase (HPX/XOD)-generated active oxygen/free radical species. The structure of both the synaptic vesicle and plasma membrane systems are altered by HPX/XOD treatment. The alteration of synaptic vesicle structure is exhibited by a significant increase in the cumulative length of nonsynaptic vesicle membrane per nerve terminal. With respect to the nerve terminal plasma membrane, the length of the perimeter of the synaptosome is increased as the membrane pulls away from portions of the terminal in blebs. The functional lesion generated by HPX/XOD treatment results in a reduction in selective high-affinity gamma-[14C]aminobutyric acid (GABA) uptake. Kinetic analysis of the reduction in high-affinity uptake reveals that the Vmax is significantly altered whereas the Km is not. Preincubation with specific active oxygen/free radical scavengers indicates that the super-oxide radical is directly involved. This radical, most probably in the protonated perhydroxyl form, initiates lipid peroxidative damage of the synaptosomal membrane systems. Low-affinity [14C]GABA transport is unaltered by the HPX/XOD treatment. The apparent ineffectiveness of free radical exposure on low-affinity [14C]GABA transport coupled with its effectiveness in reducing high-affinity transport supports the idea that two separate and different amino acid uptake systems exist in CNS tissue, with the high-affinity being more sensitive (lipid-dependent) and/or more energy-dependent (Na+,K+-ATPase) than the low-affinity system.

Animals↗
PubMed1986

Effect of several amino acid phosphonates and other compounds on rat brain and kidney peptidases.

A series of N-terminal phosphonate derivatives, H2O3PCHPhNHR (R = Leu, Phe, Trp, and/or Tyr), were synthesized with the aim of mimicking phosphoramidon, a potent inhibitor of enkephalinase, while avoiding the lability of the scissile P-N bond. All of the N-phosphonobenzyl derivatives of the amino acids, including the substituted succinylhydrazobenzophenone compounds, were inactive toward rat brain aminopeptidase and rat kidney carboxypeptidase. The N-monobenzylphosphonobenzyl derivatives, PhCH2OPO(OH)CHPhNHR, of individual amino acids and several of the N-phosphonobenzyl dipeptides showed inhibition in the micromolar range toward the soluble exopeptidase but were inactive with both the brain and kidney endopeptidase.

Aminopeptidases↗
PubMed1985

Sodium-independent binding of [3H]cocaine in mouse striatum is serotonin related.

There was a highly significant correlation between IC50 values of various drugs in inhibiting the Na+-independent [3H]cocaine binding in the mouse striatum and their values in inhibiting the synaptosomal uptake of [3H]serotonin. In contrast, there was no correlation between the inhibition of binding in the absence of Na+ and the inhibition of [3H]dopamine uptake. Lesioning of serotonergic nerve terminals with 5,7-dihydroxytryptamine reduced the Na+-independent [3H]cocaine binding, without affecting the Na+-dependent binding. These results indicate that the bulk of the Na+-independent [3H]cocaine binding in the mouse striatum is associated with serotonergic nerve terminals.

5,7-Dihydroxytryptamine↗
PubMed1985

Proctolin: a potent inhibitor of aminoenkephalinase.

Proctolin is a potent selective inhibitor of aminoenkephalinase. The specificity of its inhibition of various aminopeptidases is similar to that of puromycin; it inhibits aminoenkephalinase, but not leucine aminopeptidase or aminopeptidase M. Enkephalin breakdown by synaptic plasma membrane, but not by brain slices, is sensitive to proctolin. The inhibition by proctolin is partially caused by its resistance to enzymatic breakdown. The inhibition is of mixed type and is concentration dependent, and the two amino acids at the N-terminal are important for its action. The minimal structure for inhibition is a dipeptide with a basic amino acid at the N-terminal and a basic or an aromatic amino acid at the C-terminal.

Aminopeptidases↗
PubMed1985

Proteolytic activity in brains of rabbits treated with aluminum.

Aluminum injection in rabbits leads to neurofibrillary changes which are at light microscopic level similar to those found in Alzheimer's disease. We used this animal model to see whether changes in proteolytic activity occur that may affect protein degradation in the altered neurofibrillary structure. Rabbits were injected via the cisterna magna with aluminum chloride, and after ten days tissue was excised from the spinal cord, hippocampus, occipital lobe, and cerebellum. Sections from the hippocampus and spinal cord were examined for neurofibrillary changes; enzyme activity was measured in all four areas. The enzymes studied were cathepsins A, B, and D, and the angiotensin-converting enzyme. No significant differences could be established in enzymatic activity in aluminum-injected animals compared to controls. However, a significant decrease in Triton-soluble proteins was observed in the treated animals, which correlated with changes in neurofibrillary structure. This decrease was most noticeable in the spinal cord (from 16.6 to 12.5 mg/g).

Aluminum↗