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PubMed1993

Calcium-dependent and -independent acetylcholine release from electric organ synaptosomes by pardaxin: evidence of a biphasic action of an excitatory neurotoxin.

The effect of pardaxin, a new excitatory neurotoxin, on neurotransmitter release was tested using purely cholinergic synaptosomes of Torpedo marmorata electric organ. Pardaxin elicited the release of acetylcholine with a biphasic dose dependency. At low concentrations (up to 3 x 10(-7) M), the release was calcium-dependent and synaptosomal structure was well preserved as revealed by electron microscopy and measurements of occluded lactate dehydrogenase activity. At concentrations from 3 x 10(-7) M to 10(-5) M, the pardaxin-induced release of acetylcholine was independent of extracellular calcium, and occluded synaptosomal lactate dehydrogenase activity was lowered, indicating a synaptosomal membrane perturbation. Electron microscopy of 10(-6) M pardaxin-treated synaptosomes revealed nerve terminals depleted of synaptic vesicles and containing cisternae. At higher toxin concentrations (> or = 10(-5) M), there were striking effects on synaptosomal morphology and occluded lactate dehydrogenase activity, suggesting a membrane lytic effect. We conclude that, at low concentrations, this neurotoxin is a promising tool to investigate calcium-dependent mechanisms of neurotransmitter release in the nervous system.

Acetylcholine↗

PubMed1993

The effect of neurocatin on protein phosphorylation in striatal synaptosomes from rat brain.

Neurocatin, a neuroregulatory factor isolated from mammalian brain, is a powerful affector of protein phosphorylation in rat striatal synaptosomes. Two major synaptosomal phosphoproteins of approximately 80 and approximately 60 kDa, possibly synapsin I and tyrosine hydroxylase, were especially sensitive to neurocatin. Immunoprecipitation experiments confirmed that the 60-kDa protein is the enzyme tyrosine hydroxylase. At low concentrations of neurocatin (to approximately 7.5 ng/100 microliters of suspension), incorporation of 32P orthophosphate into these proteins increased with increasing neurocatin concentration. At 7.5 ng of neurocatin, incorporation of the label into the two proteins increased by 22 and 26%, respectively. Concentrations of neurocatin > 7.5 ng/100 microliters caused progressive decrease in incorporation of 32P into many synaptosomal proteins; by a concentration of neurocatin of approximately 45 ng/100 microliters, the level of 32P incorporation into many proteins was < or = 70% of control. The effects of neurocatin on synaptosomal protein phosphorylation were also dependent on the time of incubation. At a constant concentration of approximately 7.5 ng/100 microliters of neurocatin, increased incorporation of 32P into many proteins was measurable within 0.5 min and was maximal by 1 min. Incubation times > 2.0 min, showed progressive decrease in 32P incorporation. Removing extrasynaptosomal Ca2+ with EGTA attenuated the increased 32P incorporation induced by low neurocatin concentrations, suggesting that calcium plays a role in neurocatin-induced phosphorylation of rat striatal synaptosomal proteins. The reduced incorporation of label induced by high neurocatin concentrations, however, was not calcium dependent. The effects of neurocatin on the level of 32P incorporation into proteins were observed only in intact synaptosomes, consistent with this compound acting through receptors on the plasma membrane.

Animals↗

PubMed1985

Depolarization-induced release of propranolol and atenolol from rat cortical synaptosomes.

The accumulation and release of [3H]-propranolol and [3H]-atenolol were examined in synaptosomes from rat cerebral cortex. Synaptosomes accumulated 20 pmol propranolol and 0.6 pmol atenolol mg-1 protein when incubated at 30 degrees C with radiolabelled drugs (0.1 microM). Exposure of propranolol-loaded synaptosomes to elevated K+, Rb+ or Cs+ evoked a concentration-dependent increase in propranolol efflux. The action of these ions in releasing propranolol was highly correlated with their ability to produce synaptosomal membrane depolarization, as estimated with the voltage-sensitive dye diS-C3-(5). Elevated K+ also promoted atenolol release from synaptosomes in a concentration-dependent manner. Veratridine (10 microM) released propranolol and atenolol from synaptosomes and these effects were antagonized by tetrodotoxin (1 microM). Under Ca2+-free conditions, K+-induced release of propranolol was reduced by 37% and atenolol release was diminished by 68%. The results support the concept that both polar and non-polar beta-adrenoceptor blocking drugs may be accumulated by nerve endings for release by membrane depolarization and suggest that neural storage and release of these molecules may influence their concentrations at localized sites of action.

Animals↗

PubMed1988

Effect of chronic ethanol treatment and selective breeding for hypnotic sensitivity to ethanol on intracellular ionized calcium concentrations in synaptosomes.

The effect of chronic ethanol treatment and of selective breeding for hypnotic sensitivity to ethanol on intracellular ionized calcium concentrations (Cai) were examined in mouse whole brain synaptosomes. Following treatment with a liquid diet for 7 days, resting Cai and KCl-stimulated increases in Cai were measured in synaptosomes isolated from chronic ethanol-treated and pair-fed animals. Ethanol (350-700 mM) increased resting Cai and reduced KCl-stimulated increases in Cai in synaptosomes isolated from pair-fed animals. Ethanol-induced changes in Cai were reduced in synaptosomes isolated from chronic ethanol-treated animals. The effect of ethanol on synaptosomal Cai in long-sleep (LS) and short-sleep (SS) mice, selectively bred for differential sensitivity to the hypnotic actions of acute ethanol, was also investigated. In the absence of ethanol, resting values of Cai and KCl-stimulated increases in Cai did not differ between the two lines of mice. Ethanol (200-600 mM) increased resting Cai and reduced depolarization-stimulated increases in Cai in both long-sleep and short-sleep mice to the same degree. Similarly, KCl-stimulated increases in Ca uptake did not differ in synaptosomes isolated from whole brains and cortices of LS and SS mice, in the absence of presence of ethanol. These findings demonstrate that tolerance develops to the effect of ethanol on neuronal Cai following chronic treatment. However, sensitivity to the hypnotic action of ethanol is not related to changes in neuronal Cai in LS and SS mice.

Animals↗

PubMed1992

Surface exposure of synaptosomal gangliosides from long-sleep and short-sleep mice.

A galactose oxidase/NaB[3H]4 technique was used to examine the relative surface exposure of gangliosides from whole brain synaptosomes of long-sleep (LS) and short-sleep (SS) mice. The surface exposure of the monosialoganglioside, GM1, did not differ between the two lines. Surface exposure of the polysialogangliosides GD1a, GD1b, and GT1b, however, was significantly greater in LS synaptosomes than in SS. Hydrolysis of the polysialogangliosides by neuraminidase to the end-product, GM1, at early time periods occurred more rapidly in LS than in SS synaptosomes. Upon exposure to either 250 mM or 50 mM ethanol, LS synaptosomal ganglioside surface exposure was decreased, but that of SS was increased. Pairwise comparisons of the individual ganglioside classes indicated that the decrease in LS synaptosomal ganglioside surface exposure was attributable to decreases in the polysialogangliosides, compared with controls. The ethanol-induced increase in SS synaptosomal ganglioside surface exposure, however, was mainly due to an increased surface exposure of only GD1a. These results suggest that intrinsic differences in the surface exposure of gangliosides and/or the magnitude and direction of ethanol-induced changes in ganglioside surface distribution may reflect biophysical or modulatory mechanisms by which this class of compounds modifies membrane sensitivity to ethanol. These results suggest that further studies should be performed to determine whether gangliosides are factors in genetically determined sensitivity to ethanol.

Alcoholic Intoxication↗

PubMed1975

Tricyclic antidepressant agents. I. Comparison of the inhibition of the uptake of 3-H-noradrenaline and 14-C-5-hydroxytryptamine in slices and crude synaptosome preparations of the midbrain-hypothalamus region of the rat brain.

The simultaneous uptake of 3-H-l-noradrenaline (NA) and 14-C-5-hydroxytryptamine (5-HT) in slices from the midbrain-hypothalamus region of the rat brain was compared with the corresponding uptake in crude synaptosome preparations of the same brain region. In both preparations the uptake of the two amines was selective at the concentration used (1 times 10- minus 7 M or lower). The KM values for the amines (NA: 2 times 10- minus 7 M in synaptosomes and 5 times 10- minus 7 M in slices; 5-HT: 8 times 10- minus 8 M in synaptosomes and 6 times 10- minus 7 M in slices) and the inhibitory concentrations (IC50) of the antidepressant agents were lower in the synaptosome experiments than in the slices experiments. Moreover the order of the inhibitory activities differed between the two preparations. In the slices experiments the NA uptake was inhibited most markedly by desipramine followed by imipramine greater than chlorimipramine = nortriptyline greater than or equal to amitriptyline greater than or equal to chlordesipramine whereas in the synaptosome experiments the order was desipramine greater than nortriptyline greater than or equal to chlordesipramine greater than or equal to imipramine greater than amitriptyline greater than or equal to chlorimipramine. For the 5-HT uptake in slices the order of activity was: chlorimipramine greater than imipramine greater than or equal to amitriptyline greater than or equal to chlordesipramine = desipramine greater than or equal to nortriptyline whereas in the synaptosome preparations the order was: chlorimipramine greater than imipramine greater than or equal to amitriptyline greater than or equal to chlordesipramine greater than nortriptyline = desipramine. The role of protein binding and diffusion barriers in the causation of the difference in the results obtained with the two preparations is discussed.

Amitriptyline↗

PubMed1993

On the usefulness of Fura-2 measurements of intrasynaptosomal calcium levels in rat cortical synaptosomes to study mechanisms of presynaptic function.

Levels of [Ca2+]i in rat cortex synaptosomes were measured using the Ca2+ indicator Fura-2. Ca2+ influx was induced by veratridine in a concentration-dependent manner (1-10 microM). The resulting increase in [Ca2+]i was inhibited by tetrodotoxin (TTX). K+ (18 mM) increased the [Ca2+]i which was not influenced by TTX. K(+)-channel blockers such as 4-aminopyridine, alpha- and delta-dendrotoxin pre se were ineffective. The veratridine-induced Ca2+ influx in synaptosomes was reduced by L-type Ca(2+)-channel blockers, such as felodipine, nifedipine and PN-200-110, verapamil and diltiazem. omega-Conotoxin, and N-type Ca(2+)-channel blocker, did not inhibit the veratridine-stimulated [Ca2+]i increase. Bay K 8644, and L-channel agonist, stimulated an increase of [Ca2+]i in synaptosomes which was not sensitive to TTX. R-N6-Phenyl-isopropyl-adenosine (R-PIA) and clonidine, agonists at adenosine A1-receptors and alpha 2-adrenoceptors, respectively, did not influence the veratridine-stimulated [Ca2+]i increase. R-PIA did not interact with Bay K 8644-stimulated [Ca2+]i increase in synaptosomes. The results for all the substances used show major differences between the effects on Ca2+ influx in synaptosomes and on the electrically evoked neurotransmitter release in slice preparations. Thus, the synaptosome preparation is not a generally applicable experimental model for the study of Ca2+ mechanisms of presynaptic neuromodulation.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗

PubMed1990

Fatty acid release in incubations of serum with synaptosome and myelin subfractions of brain.

To study lipid breakdown in brain membranes following hemorrhage, synaptosome and myelin fractions isolated from rat brain were incubated with rat serum. After 3 h in vitro at 37 degrees C, 0.43 and 0.26 mumol of fatty acid were released in incubations containing synaptosomes (1.37 mumols phospholipid) or myelin (1.23 mumols phospholipid), respectively, in the presence of 0.25 mL serum. Less than 0.05 mumol of fatty acid was liberated in incubations containing only serum, synaptosomes, or myelin. For synaptosomes and serum, docosahexaenoate was the principal fatty acid released (28 mol% of total) after 3 h of incubation. This fatty acid and arachidonate made up 43 mol% of the liberated fatty acid. The presence of free docosahexaenoate was of interest, as this fatty acid is particularly enriched in phosphatidylserine and phosphatidylethanolamine, phospholipids found in the cytoplasmic half of the synaptosomal plasma membrane and in interior synaptosomal membranes. In incubations of serum and myelin, oleate was the major free fatty acid produced in 30 min to 3 h of incubation (29-35 mol% of total). After 3 h, docosahexaenoate contributed 20 mol% to the total. The release of fatty acids from the membranes may be mediated by serum phospholipase(s) or possibly by activated endogenous lipolytic activities.

Animals↗

PubMed1993

Differential effects of serum protein(s) on substrate oxidation by isolated synaptosomes and cultured rat brain astrocytes.

This report extends the finding that serum protein(s) (0.5 mg/ml) caused a 50% decrease in the rate of glucose oxidation by dissociated brain cells with only marginal effects on the oxidation of other substrates. Since dissociated cells represent a heterogeneous population, studies were initiated to determine the effect of serum on the rates of substrate oxidation by isolated synaptosomes and cultured rat brain astrocytes. Experiments revealed that the addition of 5% serum v/v to the reaction mixture resulted in a decrease in the rate of 14CO2 production from [6-14C]glucose by isolated synaptosomes by more than 70%. In contrast, the addition of 5% serum had little or no effect on the 14CO2 production from [U-14C]glutamine by the synaptosomes and only marginal effects (20-25%) on 14CO2 production from [U-14C]lactate and 3-hydroxy[3-14C]butyrate. The effect of serum on the rates of substrate oxidation were similar for synaptosomal preparations obtained from adult animal brains or 18-day-old rats, except that with the latter preparation, 14CO2 production from 3-hydroxy[3-14C]butyrate was more attenuated by the presence of serum than with the former synaptosomal preparation (50 vs. 25%). In contrast to the results with synaptosomes, the presence of 5% serum enhanced the rates of 14CO2 production from [6-14C]glucose, 3-hydroxy[3-14C]butyrate and [U-14C]lactate by 61, 35 and 69%, respectively, in cultured rat brain astrocytes. However, this enhancement did not occur when the cells were grown in chemically defined media or when dibutyryl cAMP was added to the media.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1985

Calcium transport abnormality in uremic rat brain synaptosomes.

Brain calcium is elevated in patients and laboratory animals with uremia. The significance of this finding is unclear. We evaluated calcium transport in brain of both normal and acutely uremic rats (blood urea nitrogen = 250 mg/dl) by performing studies in synaptosomes from rat brain cerebral cortex. Synaptosomes are vesicular presynaptic nerve endings from brain that contain mitochondria and are metabolically active. Two mechanisms of calcium transport were evaluated using radioactive 45Ca++ as a tracer. Both mechanisms were evaluated in the absence of exogenously administered parathyroid hormone (PTH). We first evaluated Na+-Ca++ exchange in vesicles that were loaded with NaCl in an external media containing 10 microM CaCl2. Both initial rates of calcium transport and equilibrium levels of calcium accumulation in synaptosomes prepared from uremic rats were significantly greater (P less than 0.005) than in normal. To assess calcium efflux, ATP-dependent calcium uptake (1 mM ATP) was studied in inverted plasma membrane vesicles loaded with KCl. In the uremic synaptosomes, a significant increase (P less than 0.005) in ATP-dependent calcium uptake was observed as compared with the normal. These studies show that (a) Calcium accumulation via the Na+-Ca++ exchanger is increased in synaptosomes prepared from uremic rat brain. (b) Calcium influx into inverted plasma membrane vesicles from uremic rats via the ATP-dependent calcium transport mechanism is increased when compared with normal. (c) The increased calcium accumulation in uremia by both Na+-Ca++ exchange and ATP-dependent calcium transport mechanism appears to be a result of increased synaptosomal membrane permeability to calcium. Both these abnormalities of calcium transport in uremia would tend to increase brain extracellular calcium in vivo. The defects observed in uremia do not appear to be readily reversible, and the relationship to PTH is presently unclear. These abnormalities may affect neurotransmission in the uremic state.

Adenosine Triphosphate↗

PubMed1982

High affinity 3,5,3'-L-triiodothyronine binding to synaptosomes in rat cerebral cortex.

Studies were undertaken to define the existence of specific T3-binding sites in the synaptosomal fraction of rat cerebral cortex. Development-related changes of the synaptosomal T3-binding sites were compared with those of nuclear T3 receptors in rat cerebral cortex. Scatchard analysis was compatible with the existence of two sets of high affinity T3-binding sites: K1, with a mean (+/- SE) apparent dissociation constant (Kd) of 3.22 +/- 0.63 x 10(-11) M and a mean (+/- SE) maximum binding capacity (MBC) of 3.2 +/- 0.3 pg T3/mg protein, and K2, with a K4 of 2.64 +/- 0.15 x 10(-9) M and a MBC of 218.3 +/0 15.0 pg T3/mg protein. When compared to T3, 27-, 135-, 500-, and 1000-fold higher concentrations of T4, 3,5-diiodothyronine (3,5-T2), triiodothyroacetic acid, and rT3, respectively, were needed to obtain 50% depression of the synaptosomal T3 binding. Tetraiodothyroacetic acid, 3,3'-T2, 3'5'-T2, 3-monoiodothyronine (3-T1), 3'-T1, and thyronine had little effect. The MBC of T3 nuclear receptors was the highest at 2 days of age and significantly decreased thereafter, although an almost constant K4 was observed in all age groups studied. On the contrary, the MBC of the higher affinity synaptosomal T3-binding sites was low in 2-day-old rats (20.3 +/- 1.2 pg T3/g tissue) and increased thereafter to the level in young adult ras (50.4 +/- 2.2 pg T3/g tissue). However, the Kd of synaptosomal T3-binding sites was also unchanged in all age groups studied. These findings clearly indicate that there exist specific T3-binding sites in synaptosomes from rat cerebral cortex.

Aging↗

PubMed1990

Changes in the kinetics of [3H]dopamine release from median eminence and striatal synaptosomes during aging.

The release of preaccumulated tritium-labeled dopamine [( 3H]DA) was examined in isolated nerve terminals (synaptosomes) prepared from the median eminence (ME) and corpus striatum (CS) of young (2-3 months), middle-aged (11-12 months), and old (19-21 months) male rats. Fractional release of [3H]DA was measured over 1- to 10-sec time intervals under basal (5 mM K+) and depolarizing (75 mM K+) conditions in the presence of calcium. No differences in the rate of basal efflux between the age groups were observed in either ME or CS preparations. Fast-phase evoked [3H]DA release (0-1 sec) from CS synaptosomes was unchanged from young to middle-aged, but was decreased in old preparations. These data demonstrate that the nigrostriatal nerve terminal has a diminished ability to respond fully to depolarizing stimuli in advanced age. Mean serum PRL levels in old rats were 2.3-fold greater than those in both young and middle-aged rats, while serum LH levels were decreased 2.0-fold in middle-aged and old compared with those in young rats. The fact that LH levels were already decreased in middle-aged rats while PRL levels had not yet increased suggests that decreased gonadotropin titers in old rats do not result from the coincident hyperprolactinemia. In ME synaptosomes, depolarization-induced [3H]DA release was decreased at all time points in middle-aged preparations compared to that in young preparations. The reduced fractional release from the middle-aged ME synaptosomes was due to a depressed rate of release during the initial second of depolarization. Evoked release from ME terminals of old rats was comparable to that measured in the young group. Thus, there occurred an age-related biphasic change in the initial rate of evoked DA release from ME synaptosomes. Diminished response of ME dopaminergic terminals to depolarizing stimuli during middle age may be important in the later development of hyperprolactinemia in aging male rats. The increased PRL available for feedback on the tuberoinfundlbular dopaminergic neurons may, in turn, be associated with the apparent recovery of evoked [3H]DA release from ME synaptosomes of old rats.

Aging↗

PubMed1978

Binding of H3-imipramine, H3-dimetacrine and S35-chlorpromazine to synaptosomes.

Binding of H3-imipramine, H3-dimetacrine and S35-chlorpromazine to synaptosomes of rat cerebral cortex was studied using a centrifugation method, and kinetic analysis of the experimental data. Three psychotropic drugs were shown to be rapidly bound to synaptosomes at 2 degrees C, representing a typical binding mode with two classes of binding components, i.e., saturable and non-saturable binding. A double reciprocal plot of the saturable binding component of these drugs revealed that H3-dimetacrine and S35-chlorpromazine represented a single binding mode, whereas H3-imipramine showed a multiple one. When the synaptosomes were treated by freezing and thawing 15 times, a high affinity binding component of H3-imipramine was not observed, while the other two drugs showed a single binding mode as well as those of the undisrupted synaptosomes. To investigate the specificity of this multiple binding mode, comparative binding studies of H3-imipramine were carried out using myelin fragments of rat cerebral cortex. In the myelin fragments preparation, two typical classes of binding mode as shown in the synaptosomes were also recognized. However, a double reciprocal plot of the saturable binding component showed only a straight line, i.e., single binding mode. These findings suggest that imipramine has multiple binding sites to synaptosomes and a high affinity binding component is affected by freezing and thawing procedure.

Acridines↗

PubMed1982

Effect of morphine on the stimuli-induced calcium uptake into synaptosomes isolated from morphine-tolerant rats.

Effects of morphine on calcium uptake into synaptosomes isolated from acutely or chronically morphine-tolerant rat brain was studied. Addition of morphine inhibited the depolarization-stimulated uptake of calcium without affecting uptake under nondepolarizing conditions. This inhibition was prevented by simultaneous addition of naloxone with morphine before calcium uptake was initiated. Acute tolerance to morphine increased depolarization-stimulated synaptosomal calcium uptake. On the other hand, chronic exposure of rats to morphine to elicit tolerance to and physical dependence on morphine did not influence synaptosomal calcium uptake. However, these preparations apparently lost the ability of in vitro morphine-inhibition of calcium uptake into the synaptosomes. Our results suggested that adaptive changes of synaptosomal calcium uptake produced by exposure to morphine may be involved in tolerance and physical dependence development, but influence of morphine on calcium uptake by the synaptosomes isolated from the rats acutely tolerance to morphine was differed from that of chronic tolerant rats.

Absorption↗

PubMed2005

Mouse brain synaptosomes accumulate copper-67 efficiently by two distinct processes independent of cellular prion protein.

The prion protein (PrPC) is a copper-binding, cell-surface protein that plays an essential role in the etiology of transmissible spongiform encephalopathies. Atomic absorption spectroscopy studies have established that synaptosomal copper content is reduced in PrPC-deficient mice as compared with wild-type (WT) or PrP- overexpressing mice. To address the question of whether this is the result of a loss of function of PrPC in copper transport across the plasma membrane at the synapse, we have used synaptosomes incubated with 67Cu as a model system to characterize the mechanism of copper accumulation in nerve terminals. Our results demonstrate that mouse brain synaptosomes accumulate copper efficiently by at least two distinct mechanisms. In the presence of 1 mM EDTA, copper was taken up via a saturable high-affinity process that was moderately susceptible to competition by high concentrations of NiCl2. Uptake characteristics were clearly different in the presence of 400 microM histidine, with the most noticeable dissimilarities being considerably elevated uptake rates and moderate competition by ZnCl2 rather than NiCl2. No significant differences in copper uptake capability between WT and PrPC-knockout synaptosomes were observed under any of the experimental conditions tested in this study. Furthermore, preincubation of synaptosomes with an antibody binding to the copper-binding repeat region of the prion protein had no effect on copper uptake either. Taken together, our data indicate that synaptosomal copper uptake is independent of PrPC.

Animals↗

PubMedDate not supplied

[Use of electron microscopy for study of animal brain synaptosomes].

Studies were carried out on the fraction of animal brain synaptosomes obtained by the method of differential centrifugation. We studied the possibility of using electron microscopy of ultrathin section and freeze-etching for assessment of the state of synaptosomal membranes and functional state of synaptosomes. The method of freeze-etching proved to be the most informative. In order to assess the state of synaptosomes, the following characteristics were used: coefficient of lateral diffusion and asymmetric distribution of intramembrane particles. It was also possible to identify mitochondria in the synaptosomal fraction using freeze-etching, which is an important criterion of purity of the suspension of synaptosomes.

Animals↗

PubMed1998

[Regulation of ACTH4-9 analogue on the Ca2+ level of mouse hippocampal synaptosomes].

The effect of ACTH4-9 analogue Org2766 on the [Ca2+]i level of mouse hippocampal synaptosomes was studied. Synaptosomal free calcium concentration ([Ca2+]i) and 45Ca2+ uptake were measured respectively by spex cation measurement system and Beckman LS-9800 liquid scintillation spectrometer. Low dose of Org2766 did not change synaptosomal [Ca2+]i level, but decreased 45Ca2+ uptake. High dose of Org2766 increased [Ca2+]i without affecting 45Ca2+ uptake. Low dose of Org2766 inhibited the anisomysin-induced increase of synaptosomal [Ca2+]i while high dose had no effect. These results suggest that the regulation of Org2766 on hippocampal synaptosomal Ca2+ level may be achieved by inhibiting the Ca2+ influx and increasing the release of synaptosomal calcium pool.

Adrenocorticotropic Hormone↗

PubMed1992

A spin probe study of the effects of chlorpromazine and its derivatives on lipid-protein interactions in synaptosomal membranes.

The electron spin resonance spectra of 16-doxyl stearic acid (16-SA) incorporated into synaptosomes mostly showed a fluid lipid component and a minor motionally-restricted component (MRC) of the molar fraction of 10-20%, measured at 0 degree C. At 10 mmol/l concentration, thioridazine (TRZ), chlorpromazine (CPZ), chlorprothixene (CPT), perphenazine (PFZ) and levopromazine (LPZ) raised the MRC molar fraction in the synaptosomes to 100, 92, 65, 41 and 39%, respectively (as detected by the spin probe at 0 degrees C). At 4% concentration, TRZ, CPZ, CPT, PFZ, and LPZ the respective MRC percentages were 100, 75, 41, 24 and 17%. In synaptosomal membranes, AMRC splitting values of MRC, induced by TRZ and CPZ, were similar to those of the probe in human serum albumin. MRC induced by CPZ and TRZ was constant (+/- 15%) within the temperature range from 0 to 30 degrees C. At drug/lipid ratios > or = 2 : 1, TRZ and CPZ formed rigid complexes with total lipids isolated from the rat brain. The complexes melted upon increasing the temperature of the samples over 10-20 degrees C. The drugs decreased the lipid concentrations in synaptosomes in the order of potency TRZ > CPZ > CPT > PFZ > or = LPZ; this was similar to their effect on MRC increase. The drugs tested increased the membrane dynamics/disordering, and their potency fairly correlated with their MRC increasing effects. It is supposed that the drug-induced 16-SA probe MRC increase in synaptosomes was a result of mainly decreased lipid/protein ratio in the synaptosomal membranes, which in turn probably is connected with perturbation of lipid-protein interactions and/or membrane proteins. The perturbation of lipid-protein interactions and/or membrane proteins may be connected with the drug perturbation effect on the bulk lipid membrane part.

Animals↗