Showing papers in "Journal of Neural Transmission in 1992"

The pharmacological effect of citalopram residues in the (S)-(+)-enantiomer.

Abstract: The enantiomers of citalopram and N-demethylcitalopram have been investigated. Based on the inhibition of 5-HT uptake in vitro and the potentiation of 1-5-HTP in vivo the pharmacological activity resides in the (+)-enantiomers (the eutomers*) with the 1-(S) absolute configuration. In the 5-HT uptake test eudismic ratios of 167 and 6.6 are obtained for the enantiomers of citalopram and N-demethylcitalopram, respectively. The pharmacological profile of the eutomers of citalopram and N-demethylcitalopram very much resembles the profile of the respective racemates.

Typical and atypical neuroleptics antagonize MK-801-induced locomotion and stereotypy in rats.

Abstract: The effects of typical and atypical neuroleptics on MK-801-induced locomotor activity and stereotyped sniffing were tested. Pretreatment with the typical neuroleptic haloperidol (0.01,0.05, 0.1,0.5 mg/kg SC) and the dopamine D 2 receptor selective antagonist eticlopride (0.005, 0.01, 0.05 mg/kg SC) each resulted in significant and dose-dependent reductions of locomotor activity and sniffing. The atypical neuroleptic clozapine (1.0, 5.0, 10.0 mg/kg SC) was some-what unique in that all doses reduced locomotor activity, but only the highest dose (10.0 mg/kg) significantly reduced sniffing. The data support a functional interaction between glutamate and dopamine systems, and suggest that the behavioral activation associated with MK-801 may represent a valid model for detecting potential therapeutic agents in the treatment of schizophrenia. The data should be viewed as preliminary, however, until neuroleptics are characterized in other glutamate-based models that minimize or exclude the possible influence of nonspecific motor effects.

In vivo trapping of hydroxyl free radicals in the striatum utilizing intracranial microdialysis perfusion of salicylate: effects of MPTP, MPDP+, and MPP+.

Abstract: Increased formation of hydroxyl free radicals (·OH) reflected by ·OH adduct of salicylate in brain dialysate was demonstrated during the sustained (more than 2 hours) dopamine overflow elicited by 75 nmol of 1-methyl-4-phenyldihydropyridine (MPDP+) and 1-methyl-4-phenylpyridinium (MPP+) in the rat striatum. Owing to its weak dopamine releasing action, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) did not significantly increase the ·OH formation. This data suggests that sustained elevation of dopamine in the extracellular fluid elicited by MPTP analogues can be auto-oxidized, which in turn leads (possibly by indirect mechanisms) to the formation of cytotoxic ·OH free radicals near the nigrostriatal terminals.

Autoradiographic localization of dopamine uptake sites in the rat brain with 3H-GBR 12935.

Abstract: The regional distribution of dopamine (DA) uptake sites in the rat brain has been studied by quantitative autoradiography using [3H]GBR 12935 as a ligand. The binding of [3H]GBR 12935 to striatal sections was saturable and of high affinity (Kd = 1.6 nM); it occurred at a single population of sites and possessed the pharmacological features of the DA uptake sites. The highest densities of [3H]GBR 12935 binding sites were found in the caudate-putamen, nucleus accumbens, olfactory tubercle, ventral tegmental area and substantia nigra (especially in the pars compacta). Moderate levels of [3H]GBR 12935 binding were observed in globus pallidus, thalamus, hypothalamus, hippocampus, amygdala (basolateral nucleus) and prefrontal and cingular cortices. This regional distribution of [3H]GBR 12935 binding closely correlated with the reported distribution of dopaminergic nerve terminals. The topographical distribution of [3H]GBR 12935 has also been studied in detail in striatal subregions and this distribution was compared, using quantitative TH immunoreactivity, to the density of striatal dopaminergic nerve terminals. There is good overlapping between these two regional distributions, the highest density of both markers was found in the lateral part of the striatum and a similar rostro-caudal gradient has been observed. A dopaminergic denervation caused a complete loss of [3H]GBR 12935 in basal ganglia ipsilateral to the lesion.

The acute effect of sertindole on brain 5-HT2, D2 and alpha 1 receptors (ex vivo radioreceptor binding studies).

Abstract: The ability of sertindole to influence the ex vivo binding of3H-ketanserin,3H-prazosin and3H-spiperone to 5-HT2 receptors, α1-adrenoceptors and DA D2 receptors, respectively, in rat brain has been studied after acute treatment.

Effects of sertraline and citalopram given repeatedly on the responsiveness of 5-HT receptor subpopulations

Abstract: The effect of repeated treatment (5 and 10 mg/kg, po, twice daily, 14 days) with sertraline and citalopram (antidepressants which selectively inhibit the reuptake of 5-hydroxytryptamine (5-HT)) on the responsiveness of different 5-HT receptors to their agonists, was examined in rats and mice. Sertraline and citalopram (both at a dose 5 and 10 mg/kg) antagonized (the first one more potently) the hypothermia induced in mice by 8-OH-DPAT (a 5-HT1A agonist), but not the behavioural syndrome induced in rats by this substance. The m-chlorophenylpiperazine-induced hypothermia in mice (a 5-HT1B effect) was increased by sertraline and citalopram (only in a dose of 10 mg/kg). Both antidepressants, given repeatedly (as well acutely) attenuated exploratory hypoactivity induced in rats by m-chlorophenylpiperazine (a 5-HT1C effect). L-5-HTP-induced head twitches in mice (5-HT2 effect) were antagonized dose-dependently by both repeated sertraline and citalopram. Both antidepressants (citalopram only in higher dose) reduced the fenfluramine-induced hyperthermia in rats (5-HT2 effect). The results indicate that sertraline and citalopram given repeatedly decrease the responsiveness of 5-HT1A (presynaptic) and 5-HT2 receptors but increase the responsiveness of 5-HT1B receptors to respective agonists.

Antagonism by 8-OH-DPAT, but not ritanserin, of catalepsy induced by SCH 23390 in the rat.

Abstract: In the present experiments, it was shown that the catalepsy induced by the dopamine D1 antagonist SCH 23390 (0.2 mgkg−1 sc), was completely antagonised by the administration of 8-OH-DPAT (0.1 mg kg−1 sc) for the duration of the effect of SCH 23390 (approx. 120 min). Neither the catalepsy induced by raclopride (16 mg kg−1 sc) nor that induced by SCH 23390 (0.2 mg kg−1 sc) could be antagonised by treatment with the 5-HT2 receptor antagonist ritanserin (0.13–2.0 mg kg−1 sc). Administration of SCH 23390 (0.0125–0.2 mg kg−1 sc) produced a significant suppression of avoidance behavior at all doses, and also produced a significant decrease in the number of intertriai crosses. At the higher doses, 0.05 and 0.2 mg kg−1 sc, there were also escape failures. In contrast to the finding in our previous report that raclopride and 8-OH-DPAT in a synergistic manner produce a suppression of conditioned avoidance behavior, no such interaction was found between 8-OH-DPAT (0.1 mg kg−1 sc) and SCH 23390 (6 μg kg−1 sc) in the present study.

Serotonin-norepinephrine interactions: a voltammetric study on the effect of serotonin receptor stimulation followed in the N. raphe dorsalis and the Locus coeruleus of the rat.

Abstract: In vivo voltammetry with carbon fibre electrodes was used to study the effect of the serotoninergic (5-HT) neuronal system on the noradrenergic (NE) system in the Locus coeruleus of the rat. The voltammetric DOPAC signal in the Locus coeruleus, used as a measure of NE neuronal activity, was increased after systemic application of the 5-HT1B agonist CGS-12066B, the 5-HT2 antagonist ritanserin, and, to a lesser extent, by ipsapirone, a 5-HT1A agonist. The findings suggest that the NE neuronal system of the Locus coeruleus is stimulated by 5-HT1A and 5-HT1B receptor activation and inhibited by 5-HT2 receptors. Likewise the 5-HT releaser and uptake inhibitor fenfluramine increased the DOPAC level in the Locus coeruleus. In contrast to the 5-HT1 agonists, which reduced 5-hydroxyindoleacetic acid (5-HIAA) in the Nucleus raphe dorsalis, ritanserin increased the 5-HIAA signal in this nucleus. This finding could help to explain the action of ritanserin as sleep-modulating substance.

The contribution of the different binding sites of the N-methyl-D-aspartate (NMDA) receptor to the expression of behavior.

Abstract: The effects of competitive (CGP 37849 and CGP 39551) and non-competitive (dizocilpine) N-methyl-D-aspartate (NMDA) antagonists were tested in three animal models (catalepsy, sniffing, locomotion) and, in addition, the modulation of these effects by an agonist of the strychnine-insensitive glycine binding site was investigated. Both competitive and non-competitive NMDA antagonists reduced neuroleptic-induced catalepsy. Weak sniffing was induced by the competitive antagonist but strong sniffing by the non-competitive NMDA antagonist. Due to muscle relaxation the competitive antagonist reduced locomotion, in contrast to stimulation of locomotor activity induced by the non-competitive NMDA antagonist. The glycine agonist (D-cycloserine) potentiated the effects of the non-competitive but antagonized those of the competitive NMDA antagonist.

Differential locomotor interactions between dopamine D1/D2 receptor agonists and the NMDA antagonist dizocilpine in monoamine-depleted mice

Abstract: Previous work in our laboratory has shown that the non-competitive N-methyl-D-aspartate antagonist dizocilpine (MK-801) interacts synergistically with the mixed dopamine (DA) receptor agonist apomorphine and the DA D 1 agonist SKF 38393 to promote locomotion in monoamine-depleted mice. The purpose of the present study was to compare the roles of DA D 1 and DA D 2 receptors in this interaction. To that end, dizocilpine was given in combination with either the DA D 1 receptor agonist SKF 38393 or the selective DA D 2 receptor agonist quinpirole or the preferential DA D 2 agonist bromocriptine. In general, the locomotor stimulatory effects produced by SKF 38393 were potentiated by dizocilpine, whereas the locomotor stimulation produced by quinpirole and bromocriptine was counteracted. However, baseline activity, which partly depends on how much time is allowed to elapse between administration of the DA agonist and commencement of locomotor recording, and partly on the dose of the DA agonist, seems to be an important factor that determines whether dizocilpine will have a weakening or a potentiating effect. Interestingly, the competitive NMDA antagonist D-CPPene displayed a different pattern of interaction with SKF 38393 and quinpirole in that synergistic effects were observed with both DA agonists, most conspicuously so with the DA D 2 receptor agonist. The results are interpreted in the light of present knowledge of basal ganglia neuroanatomy; they are discussed in relation to the “direct” and “indirect” pathways from the striatum to the thalamus, proposed to form part of positive and negative cortico-striato-thalamo-cortical loops, respectively, as well as to the presumed presynaptic D 2 receptors on corticostriatal glutamatergic neurons.

Blood-CSF barrier permeability and central nervous system immunoglobulin G in schizophrenia

Abstract: The ratio of albumin in cerebrospinal fluid (CSF) to serum may serve as an index of the integrity of the blood-CSF barrier, with increases in this ratio indicating increased permeability. The ratio of immunoglobulin G (IgG) in CSF to serum (divided by the albumin ratio to correct for variance in blood-CSF permeability) represents an index of the endogenous production of IgG in the central nervous system (CNS), with increases reflecting a possible infectious and/or autoimmune process stimulating central IgG synthesis. We analyzed simultaneously collected CSF and serum samples from 46 schizophrenic subjects, 8 of whom were studied both on and off neuroleptic treatment, and samples from 20 normal controls. The data indicated increases in CSF/ serum albumin ratios or CSF/serum IgG indices in 22% and 20%, respectively, of the schizophrenic patients. Only 3 patients showed elevations in both indices. Comparison of values on and off neuroleptics indicated no significant effect of neuroleptics on these indices.

Regional brain kinetics of 6-fluoro-(beta-11C)-L-dopa and (beta-11C)-L-dopa following COMT inhibition. A study in vivo using positron emission tomography.

Abstract: The regional brain kinetics of (β-11C)-L-dopa and 6-fluoro-(β-11C)-L-dopa was measured in six Rhesus monkeys using positron emission tomography (PET). Radioactivity accumulated specifically in the striatal region and the increase in L-dopa-derived radioactivity utilization with time was calculated using surrounding brain as a reference area, this being devoid of dopaminergic activity. The rate constant for selective striatal utilization i.e. grossly decarboxylation was 0.0110 ± 0.0007 (S.D) and 0.0057 ± 0.0006 min1 for (β-11C)-L-dopa and 6-fluoro-(β-11C)-L-dopa, respectively. After pre-treatment of the monkeys with the peripherally and centrally active catecholamine-O-methyl transferase (COMT) inhibitor Ro 40-7592 10 mg/kg, the decarboxylation rate remained unchanged (0.0112 ± 0.0015 min-1) for (β11C)-L-dopa, whereas an increase in rate was measured for 6-fluoro-(β-11C)L-dopa (0.0092 ± 0.0015 min−1). Differences in the distribution of radiolabelled metabolites i.e. the corresponding O-methyl-L-dopa in the reference area is most probably the reason for the difference in calculated decarboxylation rate seen between the radiotracers. The higher decarboxylation rate measured for 6-fluoro-(β-11C)-L-dopa after blockade of COMT shows that the radiolabelled metabolites i.e. 6-fluoro-O-methyl-(β-11C)-L-dopa significantly contributes to background radioactivity.

Interaction between glutamatergic and dopaminergic tone in the nucleus accumbens of mice: evidence for a dual glutamatergic function with respect to psychomotor control.

Abstract: The rotation induced by a unilateral injection of the competitive NMDA receptor antagonist AP-5 was studied in mice with different tone in the central dopaminergic systems. AP-5 induced contralateral rotation in monoamine-depleted mice and in monoamine-depleted mice treated with a dopamine D-1 receptor agonist. In contrast, AP-5 induced predominantly ipsilateral rotation in monoamine-depleted mice treated with a mixed D-1/D-2 or a D-2 selective dopamine agonist and in mice with intact monoaminergic systems.

Pharmacologic properties of (-)-3PPP (preclamol) in man.

Abstract: The dopamine (DA) autoreceptor agonist (−)-3PPP (preclamol) was tested in male schizophrenic volunteers for safety. The drug was administered intramuscularly in a single rising dose design, crossed with a similar “rising dose” placebo period; all evaluations and raters were blind to drug or placebo administration. Pharmacokinetic, endocrine, safety, and mental status outcome measures were completed before and after each single dose of drug or placebo. Pharmacokinetic analysis showed blood levels between 200–500 pmoles/ml after the intramuscular drug doses of 30–40 mg. Drug half life is 2–2.5 hrs. Growth hormone (GH) levels were elevated in a linear fashion to the 30 mg dose; whereafter, the drug failed to affect GH at all. All safety evaluations were negative, including any untoward effects on the major organ systems. After single dose drug administration, evidence of antipsychotic action occurred in two of the four subjects. This study suggests that (−)-3PPP/preclamol is a safe drug for study in the treatment of schizophrenia and may have antipsychotic efficacy.

Brain kinetics of 11 C-labelled L-tryptophan and 5-hydroxy-L-tryptophan in the rhesus monkey. A study using positron emission tomography.

Abstract: 5-Hydroxy-L-tryptophan labelled with 11 C is introduced as a tracer for the in vivo assessment of brain serotonin synthesis in the Rhesus monkey using positron emission tomography, PET. Increasing radioactivities were seen in the striatal area in contrast to that seen in other brain regions. Following 11 C-labelled L-tryptophan an even spread of brain radioactivity was seen. This selective increase most probably results from the decarboxylation of tracer and retention of formed products since no striatal increase of radioactivity was seen when 5-hydroxy-L-tryptophan labelled with 11 C in the carboxy-position was administered. Furthermore, pretreatment of the monkey with a centrally active decarboxylase inhibitor (NSD 1015, 10 mg/kg) did not lead to increased striatal radioactivities after the administration of 5-hydroxy-(beta-11 C)-L-tryptophan. The selective utilization of the radiotracer in the striatal area increased with a rate constant calculated to be 0.0055 +/- 0.0015 min-1 (n = 5) using the surrounding brain as reference area. A non-significant influence of radiolabelled metabolites to the rate constants measured was shown after pretreatment of the monkeys with selective and non-selective monoamine oxidase inhibitors, respectively. These results may give a basis for the use of the new tracer 5-hydroxy-(beta-11 C)-L-tryptophan in PET-studies of brain serotonin metabolism in health and disease.

Neurotransmitter-mediated inhibition of post-mortem human brain adenylyl cyclase.

Abstract: The effects of a range of neurotransmitter agonists showing selectivity for receptor types inhibitorily coupled to adenylyl cyclase were compared in membrane preparations of hippocampus, frontal cortex and caudate nucleus/ striatum from previously frozen post-mortem human and rat brain. Agonists were tested against basal and forskolin stimulated activities, forskolin being a potent activator of the catalytic sub-unit of the enzyme. Of those agonists tested, only somatostatin (100 μM) and neuropeptide Y (10 μM) gave consistent inhibitions of basal and forskolin stimulated enzyme activities in all three regions of both human and rat brain. Somatostatin-mediated inhibition of human brain adenylyl cyclase was reduced in the absence of GTP and in the presence of the guanine nucleotide partial agonist, guanosine 5′-O-thiodiphosphate, consistent with a G-protein-linked receptor. No such GTP-dependence was found for the neuropeptide Y-mediated adenylyl cyclase inhibition. GTP-dependent somatostatin mediated inhibitions of human brain adenylyl cyclase activity were of highest magnitude in the thalamus, intermediate magnitude in the hippocampus and caudate nucleus and lowest magnitude in the frontal cortex. It is concluded that of a range of neurotransmitter receptor agonists tested, only somatostatin gives robust, GTP-dependent responses that are reproducible enough to be used with post-mortem tissue for the comparison of receptor function in human brain disorders.

Long latency event related potentials in rats: The effects of changes in stimulus parameters and neurochemical lesions

Abstract: Animal models of event related potentials (ERPs) have recently been developed in order to gain further understanding of the psychobiological variables which may underlie these brain potentials. In the present study, unanaesthetized rats were utilized in order to evaluate the effects on rat ERP morphology of changes in the auditory stimulus parameters used to elicit these potentials such as tone probability and intensity. In addition, the consequences of reductions in norepinephrine (NE) produced by six-hydroxydopamine (6-OHDA) lesions to the area of the dorsal noradrenergic bundle in ERP wave forms were evaluated. Forty, experimentally naive, male rats chronically implanted with electrodes were used in this study. The results of these studies showed that in all electrode sites (frontal cortex, ventral thalamus, dorsal hippocampus, locus coeruleus) a series of large amplitude potentials in the 10–200 msec latency range could be recorded, some of which were sensitive to changes in the auditory stimulus parameters such as probability and tone intensity. Late positive potentials in the 300–400 msec range could be identified in recordings from the dorsal hippocampus and were found to be sensitive to probability independent of tone intensity. Dorsal noradrenergic bundle lesions were also found to produce significant changes in these rat ERP components. Lesioned animals were found to have increases in amplitude to the early negative potentials (in the 50–100 msec range) in response to frequent tones in cortical leads and decreases in the amplitude of the late positive potentials (in the 300–400 msec range) recorded in hippocampal leads in response to infrequent tones. These findings are consistent with a role for NE in the forebrain in the processing of novel or “selective” stimuli.

Cholinergic mechanisms in physical dependence on barbiturates, ethanol and benzodiazepines

Abstract: The aim of this review is to summarize the effects of acute and chronic treatment with barbiturates, ethanol and benzodiazepines on cholinergic mechanisms in the brains of experimental animals. A single dose of each of these substances reduces the turnover of ACh in the brain. Long-term treatment has the opposite effect; complicated interactions including decreased content of ACh are induced. Barbiturates have been shown to bind stereospecifically to muscarinic and nicotinic receptors in the brain, but this has not been observed for ethanol or the benzodiazepines. The effects on the cholinergic system are affected by the length of treatment and choice of treatment regimen. No effect on cholinergic parameters, such as muscarinic receptors, in the brain is observed on withdrawal of ethanol or barbiturate treatment when the animals are still tolerant towards the substances. The increase in the number of muscarinic receptors observed in several brain regions on withdrawal is seen as a sign of cholinergic supersensitivity. The number of receptors returns to normal when abstinence convulsions have occurred. The assumption of a cholinergic influence is supported by the finding that atropine, given as a single dose on the day of withdrawal of barbital, can prevent the muscarinic receptor changes. Furthermore, long-term barbital or ethanol treatment can induce permanent persistent changes in the cholinergic system in the brain. Cognitive defects and a significant permanent reduction in the content of ACh can be measured in rats which have had long-term barbital treatment. Similarly, a reduced number of muscarinic receptors has been measured in different brain regions of chronic alcoholics. Accumulating data support the role of the cholinergic system in expressing symptoms of physical dependence on barbiturates, ethanol and benzodiazepines as well as in the permanent long-term effects observed after end of treatment.

Increased binding of 3H-L-deprenyl in spinal cords from patients with amyotrophic lateral sclerosis as demonstrated by autoradiography.

Abstract: The present investigation has applied quantitative autoradiography and histochemistry to study the regional distribution of MAO-B and its relation to the number of cells in respective regions. L-deprenyl binds irreversibly and quantitatively to the B-form of monoamine oxidase, MAO, and is an ideal3H-ligand to measure the MAO-B enzyme protein in tissues by means of in vitro autoradiography. The investigation is performed on spinal sections from five controls and five cases with amyotrophic lateral sclerosis (ALS) on cervical, thoracic and lumbar level. The highest density of3H-L-deprenyl binding was found around the central canal (lamina X). MAO-B was markedly increased (up to 2.5 times of values in controls) specifically in regions of neurodegeneration e.g. motor neuron laminae and corticospinal tracts. There was a high correlation between glial cell count and3H-L-deprenyl binding with a relation indicating enhanced MAO-B protein in glial cells within areas of neurodegeneration. In contrast the increased microglial cell number in ALS did not show any correlation with3H-L-deprenyl binding.

Opposite effects of rough and gentle handling with repeated saline administration on c-fos mRNA expression in the rat brain.

Abstract: The rough handling with repeated saline administration (1.2 ml/kg s.c. for 7 days) enhanced cortical c-fos mRNA expression in the rat brain after a single saline stimulation (1.2 ml/kg s.c.) due to increasing baseline c-fos mRNA levels, whereas the gentle handling with repeated saline administration declined c-fos mRNA expression after a single injection due to decreasing the baseline of c-fos mRNA levels. These two types of handling with the repeated injection led to diametrically opposite results on c-fos mRNA expression after a single stimulation. Neither two types of handling with repeated saline injections affected the net increment of c-fos mRNA induction after a single stimulation, therefore, the effects of handling with repeated treatment on c-fos mRNA expression might be independent of the effects of a single saline stimulation. The present study suggests that c-fos mRNA induction after a single stimulation might be affected by the types or intensities of handling and that care must be taken to estimate c-fos mRNA induction.

Transient reduction of cerebral blood flow leads to longlasting increase in GABA content in vulnerable structures and decreased susceptibility to bicuculline induced seizures.

Abstract: Rats were exposed for 24 min to bilateral clamping of the common carotid arteries (BCCA) in pentobarbital anaesthesia. The GABA content was measured 24 hours, 48 hours, 4 days, 14 days and 3 months after BCCA. In other groups of rats seizures were elicited by i.p. injection of (+)-bicuculline (3 mg/kg) 24 hours, 48 hours, 4 days, 14 days and 3 months after BCCA. Analysis of the GABA content revealed significant increase compared with controls in the hippocampus, frontal cortex and substantia nigra from 24 hours up to 3 months. Bicuculline treatment induced tonic/clonic seizures and status epilepticus in sham operated animals; these effects were drastically diminished at various time points after BCCA. The present results suggest that BCCA produces a longlasting increase in GABA content and as a consequence protection from bicuculline-induced seizures.

A rapid assay for neurotransmitter amino acids, aspartate, glutamate, glycine, taurine and γ-aminobutyric acid in the brain by high-performance liquid chromatography with electrochemical detection

Abstract: For simultaneous assay of the five neurotransmitter amino acids, Asp, Glu, Gly, Tau, and GABA in brain tissues, a very rapid and simple chromatographic method using high-performance liquid chromatography with electrochemical detection in combination with o-phthalaldehyde derivatization is described. Because the present method permits the determination of these five amino acids within less than five minutes in one chromatographic run, up to 100 samples a working day can be analyzed using an autosampler. Withinrun coefficients of variation for these five amino acids were less than 2% (n=20). The quantitative detection limit was 2.5 pmol for the 5 amino acids. The present method has been applied to the measurement of the five amino acid neurotransmitter levels in several discrete brain regions of mice treated with and without electroconvulsive shock.

Erythrocyte membrane sodium — potassium adenosine triphosphatase activity in affective disorders

Abstract: Erythrocyte membrane Na+,K+-ATPase activity was studied in drug naive patients with bipolar (BP) mania (n=62) and unipolar (UP) depression (n=60) and normal controls (n=66). Compared to controls there was a significantly decreased Na+,K+-ATPase activity in UP depressives but no change in BP manics. However, lithium treatment caused a significant increase in Na+,K+-ATPase activity although there was no correlation between plasma lithium levels and enzyme activity. Plasma cortisol correlated inversely with Na+,K+-ATPase in UP depressives. Interestingly, the lithium responders [ 50% BRMS score). These observations indicate that monitoring of Na+,K+-ATPase activity during lithium therapy is useful to predict a therapeutic response.

The mechanism of perturbation in monoamine metabolism by L-DOPA therapy: in vivo and in vitro studies

Abstract: In the cerebrospinal fluid of the patients with Parkinson's disease treated with L-DOPA, L-3-O-methyldopa was the major metabolite of administered L-DOPA. Using a dopaminergic cell model, clonal rat phenochromocytoma PC 12h cells, and by microdialysis of the rat striatum it was proved that L-3-O-methyldopa was taken up into monoamine neurons by transport system specific for aromatic L-amino acids and inhibited transport of L-DOPA and other amino acids competitively. L-3-O-Methyldopa depleted allosteric regulation of the biopterin cofactor on activity of tyrosine hydroxylase, the rate-limiting enzyme of catecholamine synthesis. Depletion of the allostery may perturb the buffer action of endogenous L-DOPA synthesis that stabilizes dopamine level in the brain. By these mechanisms L-3-O-methyldopa may reduce clinical effectiveness of administrated L-DOPA and be involved in wearing-off phenomenon. L-DOPA inhibited the activity of tryptophan hydroxylase and thus serotonin synthesis, which may be related to psychiatric side-effects in the patients under L-DOPA therapy.

Heterologous supersensitization between serotonin2 and alpha2-adrenergic receptor-mediated intracellular calcium mobilization in human platelets

Abstract: Recent reports suggest that serotonin (5-HT)2 receptor-mediated second messenger systems are enhanced in platelets of affective disorders. To make the mechanism of the enhanced response clear, we investigated 5-HT2 and alpha (α)2-adrenergic receptor-induced intracellular calcium (Ca2+) mobilization in platelets of healthy volunteers, using fura-2. 5-HT2 and α2-adrenergic receptor-mediated Ca2+ mobilization was enhanced by prior exposure to the other type of agonist, so called “heterologous supersensitization”. The supersensitization was due to the enhancement of maximal response without change in agonist affinity. Chelating extracellular Ca2+ did not diminish the supersensitization. This enhancement of Ca2+ mobilization was not inhibited by H-7, an inhibitor of protein kinase C. However, this supersensitization was inhibited by pretreatment with sodium fluoride which directly activates guanine nucleotide binding regulatory proteins (G proteins). These results suggest that the supersensitization was caused from intracellular Ca2+ storage sites through a G protein-coupled pathway.

Effects of subacute exposure to noise on the noradrenergic innervation of the cardiovascular system in young and aged rats: a morphofunctional study.

Abstract: The effects of subacute noise stress on the noradrenergic pattern and receptor-mediated responses were examined in aorta and atria of young and aged rats. Noise exposure increased the density of noradrenergic fibres and responses to the β-adrenergic agonist isoprenaline in the cardiac tissue of young animals. In aged rats, the stressing stimulus markedly increased the maximal response to the α-agonist on the aortic musculature; on the contrary, a reduced responsiveness to the β-agonist was observed at the cardiac level, without any noteworthy changes in the noradrenergic pattern in comparison to aged controls. The present results indicate that subacute noise stress induces both morphological and functional modifications of the noradrenergic nervous system and also that after subacute noise stress, morphological changes do not necessarily correspond exactly to functional data; the latter show responses that are more widely differentiated than the morphological ones.

On central muscle relaxants, strychnine-insensitive glycine receptors and two old drugs: zoxazolamine and HA-966.

Abstract: Zoxazolamine is in the centrally-acting muscle relaxant class of drugs, which reportedly act by decreasing CNS interneuronal activity. These drugs, but not anxiolytics, decrease dopaminergic turnover and induce a pacemakerlike discharge pattern in dopaminergic neurons. A mechanism for these effects was not found in previous reports. We observed that (+)-HA-966, an inhibitor of the glycine modulatory site on the NMDA receptor, has a similar effect on dopaminergic impulse flow, which suggested that this may be the possible site of action of classical muscle relaxants. However, a competitive antagonist of NMDA receptors, NPC-12626, had little effect on impulse flow. Binding of 20 nM [3H]-glycine to cortical synaptosomal membranes was inhibited by (+)-HA-966, IC 50=3.16 μM, but only poorly by zoxazolamine, IC 50=474 μM, and chlorzoxazone, a related drug, caused no displacement. The drugs were then tested for protection from amphetamine neurotoxicity. Neither 50 mg/kg zoxazolamine nor 30 mg/kg (+)-HA-966 prevented (+)-amphetamine (0.1 mmol/kg plus 10 mg/kg iprindole) depletion of striatal dopamine (DA), but 3.0 mg/kg of MK-801, a non-competitive NMDA receptor antagonist, did protect DA content. Since baclofen induces a regular firing rate in DA neurons, zoxazolamine and (+)-HA-966 were tested for displacement of 10 nM [3H]-1-baclofen from cortical synaptosomal GABAb receptors, but were ineffective. Thus, the effects of these muscle relaxants on DA neurons are mediated by a mechanism other than strychnine-insensitive glycine or GABAb receptors.

Benzodiazepine receptor recruitment after acute stress in synaptosomal membranes from forebrain of young chicks: action of Triton X-100.

Abstract: In young chicks submitted to acute stress by forced swimming there was a significant increase in the number of the measurable [3 H]-flunitrazepam receptors in synaptosomal membranes from forebrain. In addition, low sub-solubilizing concentrations of Triton X-100 caused a significant increase in the measurable [3H]-flunitrazepam receptor number in synaptosomal membranes from non-stressed chicks. However, this Triton X-100 stimulatory effect was not observed when tested in synaptosomal membranes from stressed chicks. In all cases the affinity remained unchanged. This result suggest that: (i) acute stress and Triton X-100 induce receptor recruitment by enhancing [3 H]-flunitrazepam accessibility to a pool of receptors which is unmeasurable either before stress or in absence of detergent; (ii) neither recruitment types are additive and they involve receptors coming from the same nonmeasurable pool; (iii) stress induces a maximal recruitment of existing benzodiazepine receptors; (iiii) the pool of nonmeasurable receptors represents about a quarter of the total in control chicks. The recruitment at a short time of stress could be interpreted in terms involving internalization; recycling or modulation of receptors but not its biosynthesis or degradation.

Pergolide can induce soluble superoxide dismutase in rat striata.

Abstract: Pergolide, a dopamine receptor agonist, given daily i.p. for three weeks at 0.04mg/kg and 0.4mg/kg, significantly induced soluble (Cu-Zn) superoxide dismutase in the rat striatum, while having no effect on the mitochondrial (Mn) form of the enzyme. Such induction, which can also be effected by (–)-deprenyl, may help to protect against nigrostriatal degeneration.

Muscarinic cholinergic receptor-mediated modulation on striatal c-fos mRNA expression induced by levodopa in rat brain.

Abstract: To clarify the interactions between dopamine receptors and muscarinic cholinergic receptors by which neurotransmitters may affect genetic responses, we studied the effects of the muscarinic cholinergic agonist, carbachol, and the muscarinic cholinergic antagonist, trihexyphenidyl, on levodopa-induced c-fos messenger RNA (mRNA) expression in rat striatum. Animals were administered levodopa (levodopa with one-tenth dosage of carbidopa), carbachol or thrihexyphenidyl alone or administered in combination as levodopa (100 mg/kg) + carbachol, or levodopa + trihexyphenidyl given as a single bolus. Levodopa given alone increase the expression of c-fos mRNA. Although carbachol or trihexyphenidyl alone was ineffective in inducing c-fos mRNA, the combination of levodopa and carbachol (⩾ 0.1 mg/kg) significantly suppressed the induction of c-fos mRNA as compared with levodopa given alone. The combined administration of levodopa and trihexyphenidyl showed a trend toward an additive effect on the induction of c-fos mRNA vs levodopa alone. These findings suggest that the muscarinic cholinergic system may modulate the levodopa-induced c-fos mRNA expression which then regulates the expression of other mRNAs.