Showing papers in "Journal of Neural Transmission in 1991"
TL;DR: Serotonin2 (5-HT2) receptor binding was studied, using3H-spiperone as the ligand, in post-mortem brain specimens obtained from schizophrenic patients and non-psychiatric controls, and no difference in Kd was observed between the two groups.
Abstract: Serotonin2 (5-HT2) receptor binding was studied, using3H-spiperone as the ligand, in post-mortem brain specimens obtained from schizophrenic patients (N=11) and non-psychiatric controls (N=11). The maximum number of binding sites (Bmax) was significantly decreased in schizophrenic patients as compared to normal controls. This difference did not appear to be due to neuroleptic treatment. No difference in Kd (an inverse measure of the affinity of3H-spiperone to its binding sites) was observed between the two groups. However, studies with unmedicated schizophrenic patients are needed to draw any definite conclusion. The role of serotonergic processes in the psychobiology of schizophrenia is discussed.
151 citations
TL;DR: A negative correlation between age and Bmax of 5-HT1A binding sites was found in male controls but not in female controls or suicide victims, and this relationship was less apparent among the male controls over age 60.
Abstract: The density of 5-HT1A binding using3H-8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) as binding ligand, was studied in human frontal cortex of suicide victims and normal controls who died due to medical disease or accidentally. There was no difference in the maximum number of binding site (Bmax) or Kd (an inverse measure of affinity) of 5-HT1A receptor binding sites between normal controls and the entire group of suicide victims. However, nonviolent suicides had significantly higher Bmax (22—25%) compared to both controls and violent suicides. A negative correlation between age and Bmax of 5-HT1A binding sites was found in male controls but not in female controls or suicide victims. This relationship was less apparent among the male controls over age 60.
148 citations
TL;DR: A vulnerability factor secondary to fetal developmental impairment in the entorhinal region common to both schizophrenia and MDI is suggested, suggesting a migrational malformation in the superficial layers possibly originating in the second fetal trimester.
Abstract: Both types of functional psychosis schizophrenia and manic depressive illness (MDI) share several epidemiological, clinical and genetic characteristics. Subtle morphological changes as evidenced by neuroimaging techniques have also been reported in both entities. Thus far, neuropathological changes have been described in schizophrenia only. We report four cases of MDI with neuropathological changes similar to those found in schizophrenia, i.e. definite disturbances in the cytoarchitecture within the entorhinal region indicating a migrational malformation in the superficial layers possibly originating in the second fetal trimester. A limited sector of the rostro-ventral insula showed a diminution of the nerve cell population. We suggest a vulnerability factor secondary to fetal developmental impairment in the entorhinal region common to both schizophrenia and MDI.
110 citations
TL;DR: The present findings demonstrate strong interactions between a 5-HT agonist and a DA D2 antagonist on some critical tests for antipsychotic-like actions and extrapyramidal motor effects in rats, and suggest new possibilities in the search for new antipsychotics drugs with higher clinical efficacy and less extrapYramidal side effects.
Abstract: The administration of the 5-HT1A agonist 8-OH-DPAT, 0.1 mg kg−1 sc −20 min, produced a moderate suppression of conditioned avoidance behavior (60% of controls) in the rat. This effect, however, was not seen after administration of higher doses, 0.4 and 1.6 mg kg−1 sc. The number of intertriai crosses were not affected by the lower dose but significantly increased by administration of the two higher doses of 8-OH-DPAT. The dopamine D2 receptor blocking agent raclopride, 0.05 mg kg−1, by itself did not suppress the avoidance behavior, but in combination with 8-OH-DPAT produced suppression of avoidance behavior (30% of controls) as well as intertrial crosses. Open field locomotor activity was suppressed by raclopride, 0.1 mg kg−1 sc, or by 8-OH-DPAT, 0.1 mg kg−1 sc. The combined treatment produced a further suppression of locomotor activity and a marked increase in “immobility” (stationary movements). Treadmill locomotion, however, was not affected by either compound by itself, whereas the combined treatment impaired treadmill performance. Suppression of treadmill performance by a higher dose of raclopride, 0.4 mg kg−1 sc, was not altered by the additional treatment with 8-OH-DPAT, 0.1 mg kg−1. In contrast to the additive effects of 8-OH-DPAT and raclopride on conditioned avoidance behavior, open field locomotion and treadmill performance, the catalepsy produced by raclopride, 16 mg kg−1 was completely antagonised by treatment with 8-OH-DPAT 0.1 mg kg−1. Taken together, the present findings demonstrate strong interactions between a 5-HT agonist and a DA D2 antagonist on some critical tests for antipsychotic-like actions and extrapyramidal motor effects in rats, and suggest new possibilities in the search for new antipsychotic drugs with higher clinical efficacy and less extrapyramidal side effects
107 citations
TL;DR: The stimulation of locomotor activity following D-CPPene treatment does not seem to be mediated through activation of central dopaminergic systems, however, haloperidol pretreatment antagonized this locomotor response, indicating that the dopaminaergic system plays a permissive role in this context.
Abstract: Following intraperitoneal administration of the non-competitive N-methyl-D-aspartate (NMDA) antagonist dizocilpine (MK-801), levels of the dopamine (DA) metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) increased in mouse striatum and limbic forebrain When dizocilpine was given to animals treated with NSD 1015, an inhibitor of 3,4-dihydroxyphenylalanine (DOPA) decarboxylase and monoamine oxidase, there was an increase in levels of DOPA and 3-methoxytyramine (3-MT) These findings suggest that dizocilpine stimulates DA synthesis and release in mouse brain Following dizocilpine treatment a clear-cut increase in spontaneous locomotor activity was observed, probably partly due to enhanced dopaminergic tone The competitive NMDA antagonist D-CPPene produced locomotor stimulation as well, but in contrast to following dizocilpine treatment levels of 3-MT decreased Thus the stimulation of locomotor activity following D-CPPene treatment does not seem to be mediated through activation of central dopaminergic systems However, haloperidol pretreatment antagonized this locomotor response, indicating that the dopaminergic system plays a permissive role in this context
87 citations
TL;DR: 11C-labelled L-DOPA is introduced as an alternative to the well-established L-6-[18 F]fluoro-Dopa methodology in clinical studies on brain L- DOPA uptake and dopamine synthesis, indicating competition for transport across the blood-brain barrier.
Abstract: The in vivo dopamine precursor L-3,4-dihydroxyphenylalanine (L-DOPA) labelled with 11C in the beta position has been used for positron emission tomography studies of L-DOPA utilization in the brain. The brain uptake and kinetics of L-[11C]DOPA-derived radioactivity were studied in healthy male volunteers, and the specific utilization, i.e. decarboxylation rate of L-[11C]DOPA in different brain areas, was quantified using a brain region devoid of specific L-[11C]DOPA utilization as reference. Total uptake of L-[11C]DOPA-derived radioactivity measured in the brain varied two- to three-fold between subjects, with highest radioactivity in the striatal region. Specific utilization of L-[11C]DOPA radioactivity in the striatal region and in the prefrontal cortex varied twofold between subjects. No specific utilization was observed in other regions of the brain. The uptake of radioactivity in the brain increased dose-dependently with the simultaneous administration of unlabelled L-DOPA up to 10 mg. On the other hand, a decrease in brain radioactivity uptake was measured after pretreatment with 1 mg/kg oral L-DOPA, indicating competition for transport across the blood-brain barrier. Benserazide 0.5 mg/kg orally increased somewhat the radioactivity uptake to the brain. None of these pharmacological perturbations demonstrated any clearcut effect on specific utilization of L-[11C]DOPA. Thus, 11C-labelled L-DOPA is introduced as an alternative to the well-established L-6-[18F]fluoro-DOPA methodology in clinical studies on brain L-DOPA uptake and dopamine synthesis.
67 citations
TL;DR: The data suggest that the spontaneous pattern of discharge of theSTH is probably under monoaminergic control and suggest a reciprocal interaction between dopamine and glutamatergic afferent terminals from the STH within the SNpr, but not in the pallidal complex.
Abstract: Recent neurochemical evidence suggests that chemical or electrial stimulation of the subthalamic nucleus (STH) increases dopamine release in the substantia nigra (SN) with a subsequent decrease in the striatum. In a previous paper, we reported that bicuculline-induced activation of the STH increases neuronal activity in the substantia nigra pars reticulata (SNpr) and in the pallidal complex. In order to investigate the role played by the dopaminergic system in the observed activation, the neuronal responses of subthalamic nucleus target structures were studied in amine depleted rats following subthalamic stimulation. Amine depletion was accomplished by pretreating the rats with reserpine (2 mg/kg; S.C.) and with alpha-methyl-para-tyrosine (α-mpt; 50 mg/kg; I.P.).Following this treatment, dopamine levels were reduced by 94% in the striatum as measured by HPLC. Amine depletion significantly increased the spontaneous activity of subthalamic cells by 53%. In the SNpr, no significant changes in the spontaneous neuronal activity were observed, but the excitatory responses to bicuculline-induced stimulation of the STH were potentiated as compared to non-treated animals. In the pallidial complex (GP-EP), no potentiation was found. The data suggest that the spontaneous pattern of discharge of the STH is probably under monoaminergic control. They also suggest a reciprocal interaction between dopamine and glutamatergic afferent terminals from the STH within the SNpr, but not in the pallidal complex.
57 citations
TL;DR: The functional interrelationship of 5-HT2 and Β-adrenergic receptors suggested by the present findings may provide insight into a common mechanism underlying the action of pharmacologically-distinct antidepressant drugs.
Abstract: Chronic (14 day) administration of several pharmacologically-distinct antidepressant drugs resulted in marked reductions in the serotonin2 (5-HT2)-mediated quipazine-induced head shake response which were accompanied by significant reductions in the density of cortical Β-adrenergic and 5-HT2 binding sites. Noradrenergic (DSP4[N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine]-induced) and serotonergic (5,7-DHT[5,7-dihydroxytryptamine]-induced) lesions either attenuated or blocked antidepressant-induced reductions in 5-HT2-mediated behavior. DSP4- and 5,7-DHT lesions did not alter the down-regulation of 5-HT2 binding sites produced by imipramine, desipramine, phenelzine or iprindole. To a large extent, the antagonism of antidepressant-induced reductions in 5-HT2-mediated behavior was coincident with the blockade of down-regulation of Β-adrenergic binding sites by both noradrenergic and serotonergic denervation. The functional interrelationship of 5-HT2 and Β-adrenergic receptors suggested by the present findings may provide insight into a common mechanism underlying the action of pharmacologically-distinct antidepressant drugs.
53 citations
TL;DR: These findings corroborate recent reports that GC, via GC—GC receptor (GR) complex activated promotion of gene transcription, modify the expression 5- HT1A-coupled Gi (but not 5-HT2- coupled Go) resulting in altered sensitivity of5-HT 1A-mediated signal transduction and further support the hypothesis of a differential regulation of 5-TT1A and 5-ht2 receptor function and a GC—GR—G-protein—effector
Abstract: Hormonal modulation of neurotransmission emerged as a concept from the recognition that adrenocortical steroids exert profound effects at the level of receptors, G-proteins and effector units. G-proteins, a family of guanine nucleotide binding regulatory components that couple neurotransmitter receptors to various types of intracellular effector systems, appear to be a key target of glucocorticoid (GC) action in the CNS. It is thought that Gs/Gi mediates stimulation/inhibition of adenylate cyclase (AC system), which forms cyclic AMP as second messenger, while receptors stimulating phospholipase C do so through Go to produce two second messengers, inositol 1,4,5-triphosphate and diacylglycerol (PI system). Recent evidence suggests that GC increase Gsα-and decrease Giα-protein subunit expression without affecting Goα.
50 citations
TL;DR: The gender of subjects and seasonal changes, as well as height and weight of the subjects seemed to cause some variations in the levels of HVA, dopamine-Β-hydroxylase (DBH) and ACTH, which underscores the importance of standardized conditions and matched patient groups in the CSF studies.
Abstract: We have investigated neurotransmitter-related markers of the cerebrospinal fluid (CSF) in a carefully screened series of normally aging subjects in standardized conditions in order to find out the influence of age and other confounding factors on CSF measures. The levels of 3-methoxy-4-hydroxyglycol (MHPG) and the activity of acetylcholinesterase (AChE) also increased with age, while homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5 HIAA) and immunoreactivities of somatostatin (SLI), beta-endorphin (BLI) and adrenocorticotropic hormone (ACTH) were unrelated to age. The gender of subjects had no significant effect on the levels of neurotransmitter markers, while seasonal changes, as well as height and weight of the subjects seemed to cause some variations in the levels of HVA, dopamine-Β-hydroxylase (DBH) and ACTH. The study underscores the importance of standardized conditions and matched patient groups in the CSF studies.
47 citations
TL;DR: The facilitatory effect of low-dose 8-OH-DPAT seems most plausibly interpreted in terms of enhanced dopaminergic transmission, which could be brought about by 5HT1A autoreceptor-mediated inhibition of 5-HT release and consequent disinhibition of dopamine transmission.
Abstract: Two specific 5-HT1A agonists, 8-OH-DPAT (0–300 Μg/kg), and buspirone (0–3.0 mg/kg), were tested on variable-interval, threshold-current self-stimulation of rat lateral hypothalamus. Buspirone produced a prolonged monotonic depression of responding, whereas the effects of 8-OH-DPAT were biphasic: 3.0 Μg/kg produced a sustained enhancement of responding while higher doses (100–300 Μg/kg) produced a relatively short-lasting depression. This biphasic pattern parallels previously reported effects of 8-OH-DPAT on food intake and on various other behaviours. Threshold-current self-stimulation is highly sensitive to alterations in dopaminergic transmission but relatively insensitive to changes in 5-HT. Thus the facilitatory effect of low-dose 8-OH-DPAT seems most plausibly interpreted in terms of enhanced dopaminergic transmission. This could be brought about by 5HT1A autoreceptor-mediated inhibition of 5-HT release and consequent disinhibition of dopaminergic transmission. Depression of self-stimulation by higher doses of 8-OH-DPAT may reflect the activity of 8-OH-DPAT at postsynaptic 5-HT receptors, with consequent inhibition of DA transmission. Suppression of responding after buspirone at all doses tested may reflect the action of this compound as a partial agonist at postsynaptic 5-HT receptors, and/or its effects on other systems.
TL;DR: Cholinergic agonist binding sites in the spinal cord seem less sensitive to axonal damage than antagonist binding sites, and cholinergic and opioid receptors in peripheral nerves are transported in both anterograde and retrograde directions.
Abstract: Changes in the distribution of3H-quinuclidinylbenzilate (3 H-QNB),3 H-acetylcholine (3 H-ACh) and3 H-alpha-bungarotoxin (alpha-BTx) binding sites were studied with the use of quantitative in vitro autoradiography in the L4–L6 segments of rats 7 days after ventral L4–L6-rhizotomies and 24 hours after ligation of the dorsal roots L4–L6. The changes in the binding sites of these ligands and of3 H-etorphine binding sites were also studied in the dorsal roots of the rats operated with dorsal root ligation and in the sciatic nerves (around a ligature) in the rats operated with ventral rhizotomy. After ventral rhizotomy3 H-QNB binding sites in the ipsilateral motor neuron area were decreased by about 25% from 100±5 to 73±5 fmol/mg wet weight. After dorsal root ligation3 H-QNB binding sites in the ipsilateral posterior horn were reduced by about 30% from 91±5 to 64±7 fmol/mg wet weight. No significant changes in the binding of the other cholinergic ligands in the spinal cords were observed after the operations. In the dorsal root3 H-alpha-Btx and3 H-etorphine binding sites were higher on the distal side of the ligation (3.5±0.8 and 14±4 fmol/mg wet weight, respectively) than on the proximal side (0.7±0.5 and 2.4±1.2 fmol/mg wet weight, respectively).The same level of3 H-ACh (total, muscarinic and nicotinic) binding was observed on both sides of the ligation. In the sciatic nerve3 H-QNB and total, muscarinic and nicotinic ACh binding sites were higher on the proximal side of the ligation than on the distal side. Except for a small emergence of muscarinic-ACh binding distally to the ligation there were no changes in the number of binding sites in the sciatic nerve after the ventral rhizotomy.
TL;DR: No apparent relationship was found between the previously reported ability of these compounds to stimulate cyclic adenosine monophosphate (cAMP) production and their ability either to inhibit the firing of NAc neurons or to enable quinpirole-mediated inhibition of firing in DA-depleted rats.
Abstract: The electrophysiological effects of three selective D 1 dopamine (DA) receptor agonists, which exhibit different potencies and efficacies for stimulation of adenylate cyclase, were compared in the rat nucleus accumbens (NAc) using single unit recording and microiontophoretic techniques. The partial agonists SKF 75670 and SKF 38393, and the full agonist SKF 81297 produced nearly identical current-response curves for the inhibition of firing of NAc neurons. In rats acutely depleted of DA byα-methyl-p-tyrosine (AMPT) pretreatment, all three D 1 agonists enabled the inhibition of firing produced by the selective D 2 receptor agonist quinpirole, with SKF 38393 exerting the greatest efficacy, followed by SKF 81297 and SKF 75670. Thus, no apparent relationship was found between the previously reported ability of these compounds to stimulate cyclic adenosine monophosphate (cAMP) production and their ability either to inhibit the firing of NAc neurons or to enable quinpirole-mediated inhibition of firing in DA-depleted rats. In addition, the membrane-permeable cAMP analog 8-bromo-cAMP also caused a current-dependent inhibition of the firing of NAc neurons, but failed to enable quinpirole-mediated inhibition in AMPT-pretreated animals. These results suggest either that only a small percentage of D 1 receptors need to be stimulated to produce these electrophysiological effects, or that D 1 receptors exist within the rat NAc which are linked to transduction mechanisms other than, or in addition to, adenylate cyclase.
TL;DR: The present results clarify the topographical distribution of amygdala input to the NAS, confirm that inputs from two limbic structures are integrated within theNAS, and further illustrate the electrophysiological heterogeneity of NAS neurons.
Abstract: The nucleus accumbens septi (NAS) receives afferent input from the amygdala via the stria terminalis and from the hippocampus via the fimbria. Extracellular recordings from 196 NAS neurons in halothane-anesthetized rats revealed heterogeneous response patterns following stimulation of the amygdala. The observation that 30% of anterior NAS units but only 16% of posterior NAS units were responsive to amygdala stimulation suggested a topographical arrangement of amygdala efferents. Comparing the effects of amygdala and fimbria stimulation revealed that the two afferent pathways converge onto individual NAS neurons, but that the two sites of stimulation can differentially influence other neurons. The present results clarify the topographical distribution of amygdala input to the NAS, confirm that inputs from two limbic structures are integrated within the NAS, and further illustrate the electrophysiological heterogeneity of NAS neurons.
TL;DR: Significant and positive correlations are found between UFC on the one hand, and the 24 hr urine excretion of noradrenaline, dopamine, and adrenaline, on the other, and significant relationships between those catecholamines and the postdexamethasone UFC and plasma cortisol values are established.
Abstract: In order to delineate putatively coexisting dysregulations between sympathoadrenal system and hypothalamic-pituitary-adrenal (HPA)-axis during depression, the authors measured the following: the pre and postdexamethasone (1 mg) 24 hr urine excretion of noradrenaline, dopamine, adrenaline, 3-methoxy-4-hydroxyphenylglycol (MHPG), free cortisol (UFC), and plasma cortisol. Melancholic patients were characterized by a significantly higher excretion of noradrenaline, dopamine and adrenaline, combined with significantly increased UFC, postdexamethasone plasma cortisol, and UFC values. We found significant and positive correlations between UFC on the one hand, and the 24hr urine excretion of noradrenaline, dopamine, and adrenaline, on the other. By the same token, we established significant relationships between the 24 hr urine excretion of those catecholamines and the postdexamethasone UFC and plasma cortisol values. Cortisol nonsuppressors exhibited a significantly higher excretion of noradrenaline, dopamine and adrenaline, as compared with cortisol suppressors. Dexamethasone administration did not have a significant effect on the urinary output of noradrenaline, dopamine, adrenaline or MHPG.
TL;DR: Present data indicate that serotonergic postsynaptic receptors mediate both the inhibitory and the facilitatory actions of TFMPP or 8-OH-DPAT in copulation, which further support the idea that endogenous serotonin acts via the stimulation of 5-HT1B receptors to induce its inhibitory effects on masculine sexual behaviour.
Abstract: In order to establish whether the 5-HT1A or the 5HT1B agonists, 8-OH-DPAT or TFMPP, produce their facilitatory or inhibitory actions on masculine sexual behaviour via a mechanism involving: (a) the serotonin synthesis or release; (b) the stimulation of presynaptic receptors, or (c) the stimulation of somatodendritic receptors, three series of experiments were performed. The administration of the serotonin synthesis inhibitor, p-chlorophenylalanine (p-CPA, 300mg/kg×3 days), facilitated sexual behaviour but does not interfere neither with the inhibitory nor with the facilitatory effects of TFMPP (0.5mg/kg) or 8-OH-DPAT (0.5 mg/kg), respectively. The icv or the intraraphe administration of the serotonergic neurotoxin, 5,7-dihydroxytryptamine (5,7-DHT), slightly stimulated masculine sexual behaviour and produced a decrease in serotonin and its metabolite levels. In lesioned animals TFMPP (0.5 mg/kg) resulted in an inhibitory effect reflected as a prolongation of the ejaculation latency. The inhibitory effect of this drug on mounting behaviour was not observed in 5,7-DHT treated rats. In lesioned animals 8-OH-DPAT (0.5 mg/kg) produced the same facilitatory effect. Present data indicate that serotonergic postsynaptic receptors mediate both the inhibitory and the facilitatory actions of TFMPP or 8-OH-DPAT in copulation. All data further support the idea that endogenous serotonin acts via the stimulation of 5-HT1B receptors to induce its inhibitory effects on masculine sexual behaviour.
TL;DR: In adult rats, the neuro-degenerative effects following the intrastriatal infusions of NMDA or quinolinate, but not kainate, were prevented by LY 274614 and is a promising therapeutic agent for conditions where glutamate plays a role in the pathology of neuronal degeneration.
Abstract: Antagonists for the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor may have therapeutic potential as neuroprotectant agents in conditions of neuronal degeneration that include brain ischemia, Huntington's chorea, and Alzheimer's disease. Here we have investigated the pharmacological actions of LY274614, a structurally novel competitive NMDA receptor antagonist, for pharmacological selectivity and neuroprotectant effects following systemic administration. LY274614 potently displaced NMDA receptor ([3H]CGS19755) binding (IC50 = 58.8 +/- 10.3 nM), but had no appreciable affinity at [3H]AMPA or [3H]kainate receptor sites at up to 10,000 nM. NMDA-induced convulsions in neonatal rats or NMDA-induced lethality in mice are potently and selectively antagonized by i.p. or p.o. LY274614. Oral doses showed a delayed but prolonged duration of effect. In adult rats, the neurodegenerative effects (loss of choline acetyltransferase activity) following the intrastriatal infusions of NMDA or quinolinate, but not kainate, were prevented by LY274614 (2.5 to 20 mg/kg i.p.). LY274614 is an effective neuroprotectant agent against NMDA receptor-induced toxicity when administered systemically and is a promising therapeutic agent for conditions where glutamate plays a role in the pathology of neuronal degeneration.
TL;DR: (−)-Deprenyl (0.25 or 2mg/kg) or saline was injected daily into male Wistar rats for 3 weeks and induced a significant increase in the soluble but not the particulate form of the enzyme.
Abstract: (−)-Deprenyl (0.25 or 2mg/kg) or saline was injected daily into male Wistar rats for 3 weeks. The striata were dissected out and soluble and particulate Superoxide dismutase activity measured. (−)-Deprenyl at 2mg/kg induced a significant increase in the soluble but not the particulate form of the enzyme. The possibility that this action contributes to the ability of (−)-deprenyl to retard nigral degeneration in man and prolong life in rats is discussed.
TL;DR: A simple, sensitive, reliable and reproducible isocratic HPLC technique for the measurement of OPA/sulphite derivatives of human brain amino acid neurotransmitters is described, applied to the determination of GABA and glutamate in brain tissue taken post-mortem from patients with Huntington's disease and control subjects.
Abstract: A simple, sensitive, reliable and reproducible isocratic HPLC technique for the measurement of OPA/sulphite derivatives of human brain amino acid neurotransmitters is described. This employs a sample preparation that is also compatible with the concurrent determination of monoamines and their metabolites on a separate HPLC system. The method has been applied to the determination of GABA and glutamate in brain tissue taken post-mortem from patients with Huntington's disease and control subjects.
TL;DR: The study shows for the first time in humans that striatal MSP binding reflects the different D2 dopamine receptor affinities of clozapine and haloperidol.
Abstract: Four schizophrenic patients were investigated with dynamic positron emission tomography (PET) using (18F)fluorodeoxyglucose (FDG) and (18F)methylspiperone (MSP) as tracers. Two schizophrenics were on haloperidol therapy at the time of MSP PET. The other two schizophrenics were treated with clozapine, in one of them MSP PET was carried out twice with different daily doses (100 mg and 450 mg respectively). Neuroleptic serum levels were measured in all patients. Results were compared with MSP PET of two drug-free male control subjects and with a previous fluoroethylspiperone (FESP) study of normals. Three hours after tracer injection specific binding of MSP was observed in the striatum in all cases. The striatum to cerebellum ratio was used to estimate the degree of neuroleptic-caused striatal D2 dopamine receptor occupancy. In the haloperidol treated patients MSP binding was significantly decreased, whereas in the clozapine treated patients striatum to cerebellum ratio was normal. Even the increase of clozapine dose in the same patient had no influence on this ratio. Despite the smaller number of patients the study shows for the first time in humans that striatal MSP binding reflects the different D2 dopamine receptor affinities of clozapine and haloperidol.
TL;DR: Changes in aspartic acid, glutamic acid, serine, glutamine, glycine and GABA concentrations with ageing were determined in the same brain structures and were in good agreement with those previously reported.
Abstract: Concentrations of the sulfur-containing amino acids methionine, homocysteic acid, cysteic acid and taurine were measured in brain structures of young and old Wistar rats in an attempt to establish a possible link between the increase in oxidative stress with ageing and changes in tissue levels of these amino acids. Contrary to data reported by others, in all brain structures of young and old rats homocysteic acid levels could not be quantified. Compared with young rats, in old animals taurine and methionine concentrations significantly decreased in striatum and cortex; decreased taurine levels were also found in nucleus accumbens and cerebellum and lower concentrations of methionine were found in midbrain, hippocampus and pons-medulla. Cysteic acid levels either did not change or significantly increased in cortex and hippocampus. These results are discussed taking into account the biosynthesis of sulfur-containing amino acids in rat brain and the decrease in glutathione in relation to oxidative stress with ageing. Changes in aspartic acid, glutamic acid, serine, glutamine, glycine and GABA concentrations with ageing were also determined in the same brain structures and were in good agreement with those previously reported (Strolin Benedetti et al., 1990 a, b).
TL;DR: This hypothesis offers a framework in which winter-induced retinal dopamine deficiency or retinal melatonin overactivity may cause SAD and by which light reverses this syndrome.
Abstract: The author describes how phototherapy may treat seasonal affective disorder (SAD) by stimulating the production of retinal dopamine and suppressing the production of retinal melatonin. This hypothesis offers a framework in which winter-induced retinal dopamine deficiency or retinal melatonin overactivity may cause SAD and by which light reverses this syndrome. This hypothesis is consistent with recent data indicating that phototherapy in SAD acts specifically through the eyes.
TL;DR: The results indicate the existence of physiological changes in the functional state of both dopaminergic systems during the ovarian cycle, which are partially different for each neuronal pathway, and supports the exist of a specific regulation, and not indiscriminate effects, by the hormones involved in this cycle.
Abstract: In this work, we have studied the changes in the functional state of nigrostriatal (NSDA) and mesolimbic (MLDA) dopaminergic neurons during the estrous cycle of the female rat. The activity of tyrosine hydroxylase (TH), the turnover rate (Kt) after inhibition of dopamine (DA) synthesis and the ratio between the contents of this amine and its metabolite, L-3,4 dihydroxyphenylacetic acid (DOPAC), were used as indices of neuronal activity. The neuronal activity of NSDA neurons rose during estrous and declined during proestrous, as reflected by the values of Kt and DOPAC/DA ratio measured during both phases. Interestingly, the course of variations in striatal TH activity was similar, although retarded in relation to the changes in neuronal activity. Thus, TH activity was high during diestrous, whereas it was low during estrous. The activity of MLDA neurons was reduced during proestrous. This can be concluded from the decreased Kt and DOPAC/DA ratio measured in this phase and it was accompanied by a low TH activity. Thereupon, both Kt and TH activity increased during estrous. These results indicate the existence of physiological changes in the functional state of both dopaminergic systems during the ovarian cycle, which are partially different for each neuronal pathway. This supports the existence of a specific regulation, and not indiscriminate effects, by the hormones involved in this cycle, mainly estradiol and progesterone.
TL;DR: Results show that carnitine and acetylcarnitine are stereospecific neuroactive compounds with a cholinomimetic activity and may play a role in a modulatory system for the cholinoceptive cortical neuron.
Abstract: Carnitine and acetylcarnitine have been demonstrated to be present in the CNS and to be involved in cholinergic mechanisms, even if their exact role in neurotransmission is still unknown. This microiontophoretic study was carried out on single cholinoceptive neurons of the somatosensory cortex in the rat in order to analyze the effects of L- and D-carnitine and L-acetylcarnitine on the spontaneous firing and the neuronal responses to some putative transmitters. L-carnitine and L-acetylcarnitine increased the spontaneous discharge rate, while D-carnitine was found to be ineffective. L-acetylcarnitine clearly potentiated the cholinergic excitatory responses. On the contrary, L-carnitine was found to reduce cholinergic responses in a great percentage of units and to inhibit L-acetylcarnitine-induced excitatory responses. Atropine blocked the increase in firing rate induced by L-carnitine and L-acetylcarnitine, thus suggesting for both of them a muscarinic activity. No interactions were observed between carnitines and GABA and glutamate. These results show that carnitine and acetylcarnitine are stereospecific neuroactive compounds with a cholinomimetic activity. They may play a role in a modulatory system for the cholinoceptive cortical neuron.
TL;DR: The concentration of the tripeptide glutathione was measured in primary cultures of neurons and astroglial cells from rat cerebral cortex and brain stem and in the cultured astrocytes γ-GC produced a dose-dependent increase in GSH, but this effect failed to reach statistical significance.
Abstract: The concentration of the tripeptide glutathione (GSH) was measured in primary cultures of neurons and astroglial cells from rat cerebral cortex and brain stem The concentration of GSH was found to be approximately 20 nmol/ mg protein in the neuronal culture from the cerebral cortex and ca 40 nmol/ mg protein in the neuronal brain stem cultures A GSH concentration of approximately 20 nmol/mg was observed in the astrocyte cultures from both brain regions The possibility to increase the GSH concentration was tested by incubating the cultures in the presence of the GSH precursor γ-glutamylcysteine (γ-GC) In the cultured astrocytes γ-GC produced a dose-dependent increase in GSH A similar increase was observed in the neuronal cultures, but this effect failed to reach statistical significance
TL;DR: The results indicate that concomitant blockade of NMDA-receptors and activation of dopamine receptors results in synergistic or at least additive motor stimulatory effects.
Abstract: The competitive NMDA-antagonists SDZ EAA-494 and CGP 37849 and the mixed D-1/D-2 dopamine agonists CI 201-678 and SDZ 205-152 reverse akinesia in monoamine-depleted mice in a dose dependent manner. Combination of threshold doses of NMDA-antagonists with dopamine agonists markedly enhances anti-akinetic effects. CI 201-678 which in addition to D-1 and D-2 receptors stimulates alpha-2 receptors produces a stronger effect than SDZ 205-152 which is devoid of alpha-2 agonist activity. The results indicate that concomitant blockade of NMDA-receptors and activation of dopamine receptors results in synergistic or at least additive motor stimulatory effects.
TL;DR: Results indicate that plasma AO is encoded by gene(s) independent of those for MAO-A andMAO-B, and raise the possibility that plasmaAO, and perhaps the closely related tissue AO, benzylamine oxidase, as well as other atypical AOs or MAOs encoded independently from MAO to contribute to the oxidative deamination of dopamine and 5-HT in humans.
Abstract: Two individuals with an X-chromosomal deletion were recently found to lack the genes encoding monoamine oxidase type A (MAO-A) and MAO-B. This abnormality was associated with almost total (90%) reductions in the oxidatively deaminated urinary metabolites of the MAO-A substrate, norepinephrine, and with marked (100-fold) increases in an MAO-B substrate, phenylethylamine, confirming systemic functional consequences of the genetic enzyme deficiency. However, urinary concentrations of the deaminated metabolites of dopamine and serotonin (5-HT) were essentially normal. To investigate other deaminating systems besides MAO-A and MAO-B that might produce these metabolites of dopamine and 5-HT, we examined plasma amine oxidase (AO) activity in these two patients and two additional patients with the same X-chromosomal deletion. Normal plasma AO activity was found in all four Norrie disease-deletion patients, in four patients with classic Norrie disease without a chromosomal deletion, and in family members of patients from both groups. Marked plasma amine metabolite abnormalities and essentially absent platelet MAO-B activity were found in all four Norrie disease-deletion patients, but in none of the other subjects in the two comparison groups. These results indicate that plasma AO is encoded by gene(s) independent of those for MAO-A and MAO-B, and raise the possibility that plasma AO, and perhaps the closely related tissue AO, benzylamine oxidase, as well as other atypical AOs or MAOs encoded independently from MAO-A and MAO-B may contribute to the oxidative deamination of dopamine and 5-HT in humans.
TL;DR: It is of importance to measure kinetics of ligand-receptor binding in vivo rather than static analysis to reveal functional roles of dopamine receptor in vivo, especially in the study of the human brain with positron emission tomography (PET).
Abstract: The in vivo binding of [3 H]N-methylspiperone (NMSP) and [3 H]raclopride was compared in mice treated with reserpine (5 mg/kg, 24 hr prior to the tracer injection). With both radioligands, selective accumulation of radioactivity in the striatum following intravenous injection was observed, whereas a relatively low accumulation and a rapid decline in radioactivity in the cerebellum was seen. Reserpine significantly decreased [3 H]NMSP binding in vivo, however it increased [3 H]raclopride binding. By compartment model analysis, it was found that the decrease in [3 H]NMSP binding was primarily due to the decrease in the association rate (K3) and the increase in [3 H]raclopride was due to the decrease in the dissociation rate (K4) in vivo. As both Kd and Bmax of dopamine D2 receptors have been reported to be unaltered by reserpine, these results suggested that some unknown factors except Kd and Bmax which influence on in vivo binding of receptors might be changed by reserpine. These results revealed that it is of importance to measure kinetics of ligand-receptor binding in vivo rather than static analysis. These two different types of radioligands can be combined to reveal functional roles of dopamine receptor in vivo, especially in the study of the human brain with positron emission tomography (PET).
TL;DR: Results indicate that the dopamine system may be involved, at least in part, in the potentiating effect of the combined treatment with AD + MK-801, and this effect was completely blocked by haloperidol and only partly by prazosin.
Abstract: MK-801, a non-competitive NMDA receptor antagonist, induced the locomotor hyperactivity in rats. Imipramine (IMI), amitriptyline (AMI), citalopram (CIT) given acutely increased the MK-801-induced locomotor hyperactivity. Mianserin (MIA) showed a similar but weaker effect. Haloperidol completely blocked the hyperactivity induced by the antidepressant drug (AD) + MK-801. Prazosin had an only weak antagonistic effect. Repeated treatment with AD increased the MK-801 locomotor hyperactivity to a greater extent than acute treatment. This effect was completely blocked by haloperidol and only partly by prazosin. The obtained results indicate that the dopamine system may be involved, at least in part, in the potentiating effect of the combined treatment with AD + MK-801.
TL;DR: The present results show that there is no general age-related decrease in the level of monoamines and of their metabolites in the rat cerebral cortex and that the changes display a complex, area-specific pattern.
Abstract: Age-related changes in the levels of dopamine (DA) and its metabolites were measured in seven cerebral cortical areas and in the striatum of 3, 10 and 27 month-old Sprague-Dawley rats. An age-related increase in DA levels was observed in the somatomotor (SM) cortex. In contrast, a decrease was observed in the temporal (T) cortex. Decreases in homovanillic acid (HVA) levels were observed in prelimbic (PL), pyriform (PY) and T cortex of aged rats, whereas significant increases in the levels of 3-methoxytyramine (3-MT) were observed in PL, prefrontal (PF), cingulate (C) as well as in T cortex. In the striatum, DA and HVA were decreased but the level of 3-MT remained unchanged. Norepinephrine (NE) levels increased in rats from 3 to 27 months in all the cortical areas. The increase in the levels of the DA extraneuronal metabolite, 3-MT, confirms our previous results showing that the release of DA might be increased with age in some cortical areas. The present results show that there is no general age-related decrease in the level of monoamines and of their metabolites in the rat cerebral cortex and that the changes display a complex, area-specific pattern.