Showing papers in "Journal of Neural Transmission in 1987"
TL;DR: The results support the view that the pathophysiology of Parkinson's disease may relate exclusively to the D-2 subclass of dopamine receptors.
Abstract: Preclinical evidence suggests that the D-1 dopamine receptor contributes to the generation of behaviors used as models for human extrapyramidal disorders. To evaluate the potential of D-1 receptor stimulation in neurologic disease, SKF 38393, a selective D-1 dopamine receptor agonist, was administered to seven patients with idiopathic Parkinson's disease in a double-blind, placebo controlled study. SKF 38393 was found to be rapidly absorbed when administered orally, and to occur in micromolar concentrations in spinal fluid. No change in scores of parkinsonian severity were noted when SKF 38393 was administered alone, or when the drug was combined with intravenous levodopa. The results support the view that the pathophysiology of Parkinson's disease may relate exclusively to the D-2 subclass of dopamine receptors.
126 citations
TL;DR: The muscarinic antagonist atropine 10−5 M significantly increased the3H-ACh release both in control and AD/SDAT brains, thus indicating preservation ofMuscarinic autoreceptors in the AD/ SDAT cortical tissue.
Abstract: In the presence of 9-amino-1,2,3,4-tetrahydroacridine (THA) 10(-4) M or physostigmine 10(-4) M, the in vitro 3H-Acetylcholine (3H-ACh) release from control cortical slices was significantly reduced. In contrast, THA 10(-4) M and physostigmine 10(-4) M significantly increased the release of 3H-ACh in AD/SDAT brain tissue. This facilitating effect on 3H-ACh release was partially blocked (50%) in the presence of the nicotinic antagonist d-tubocurarine 10(-6) M indicating a possible interaction via nicotinic receptors. The muscarinic antagonist atropine 10(-5) M significantly increased the 3H-ACh release both in control and AD/SDAT brains, thus indicating preservation of muscarinic autoreceptors in the AD/SDAT cortical tissue. In receptor competition studies with 3H-nicotine, 3H-ACh and 3H-quinuclidinyl benzilate (3H-QNB) as receptor ligands, THA interfered with both nicotinic and muscarinic receptor ligand binding, while physostigmine had much less effect.
102 citations
TL;DR: Preliminary results indicate that α 2-adrenoceptor density in the high affinity stateα 2H) is increased in the brain of depressed patients and add strong support to the hypothesis that endogenous depression is related to supersensitiveα 2- adrenoceptors.
Abstract: The density of brainα2-adrenoceptors, quantitated by means of the binding of the agonist [3H]clonidine, was studied in post-mortem cortical membranes of matched control subjects and depressed suicide victims. In the depressed suicide group, the specific high affinity binding of [3H]clonidine was found to be significantly increased (Bmax, 72% greater; p<0.01) without significant changes in the KD value for the radioligand. These preliminary results indicate thatα2-adrenoceptor density in the high affinity stateα2H) is increased in the brain of depressed patients and add strong support to the hypothesis that endogenous depression is related to supersensitiveα2-adrenoceptors.
91 citations
TL;DR: Findings are viewed as evidence that LY163502 can initiate sexual behavior and lower the threshold for ejaculation and as behavioral manifestations of selective dopaminergic autoreceptor activation with low doses and as the disruption of sexual behavior by induction of intense stereotypic behavior with high doses.
Abstract: The effects of selective D2-dopaminergic receptor stimulation with LY163502 on male rat copulatory behavior were evaluated. LY163502 (25 ng/kg to 25Μg/kg s. c.) produced increases in the percentage of sexually inactive rats displaying mounting behavior and ejaculating during the test period. Within this same dose range, LY163502 administration induced an increase in the percentage of non-ejaculator rats that were capable of ejaculation. These findings are viewed as evidence that LY163502 can initiate sexual behavior and lower the threshold for ejaculation. The effects of LY163502 were further evaluated in rats that were capable of ejaculation during the test period. LY163502 (25 ng/kg to 25Μg/kg s. c. or p. o.) induced significant reductions in ejaculatory latency. These effects were blocked by prior treatment with centrally active dopaminergic antagonists, RO 22-1319 and sulpiride, but not with a peripherally active antagonist, domperidone. LY163502 administration was also found to inhibit sexual behavior in low doses of 25 pg/kg −10 ng/kg s. c. and in a much larger dose of 25 mg/kg s. c. These inhibitory effects are viewed as behavioral manifestations of selective dopaminergic autoreceptor activation with low doses and as the disruption of sexual behavior by induction of intense stereotypic behavior with high doses.
90 citations
TL;DR: The results suggest that HVA from cortex contributes significantly to that in cisternal CSF, and raw plasma HVA measurements appear to be of limited value in gauging central dopamine metabolism and turnover.
Abstract: In a large number (91) of vervet monkeys, correlation coefficients were determined between homovanillic acid (HVA) concentrations in four brain areas. Significant correlations existed between dorsal frontal cortex and orbital frontal cortex and between putamen and caudate nucleus. However, no significant correlations existed between either cortical area and the basal ganglia areas.
90 citations
TL;DR: It is concluded that diazepam and N-desmethyldiazepam are naturally occurring compounds and may explain their occurrence in the brain and adrenals of animals.
Abstract: Benzodiazepine-binding inhibitory (BBI) activity was detected in aqueous extracts of brain and peripheral tissues of rats The BBI activity in brain and in adrenals was, at least partially, due to the presence of N-des-methyldiazepam and diazepam as shown by HPLC, UV-spectroscopy and mass spectrometry
80 citations
TL;DR: Findings are consistent with the proposal that melatonin's psychopharmacological effects are due at least in part to its ability to enhance central GABAergic transmission by modulating GABA receptor activity.
Abstract: In order to determine whether the in vitro ability of the pineal indoleamine hormone, melatonin, to modulate binding at the GABA-benzodiazepine receptor complex is operative in vivo we have examined the effects of chronic melatonin administration on3H-GABA and3H-diazepam binding in rat brain. Melatonin was injected daily in increasing doses for three weeks and animals were sacrificed at 2 or 26 hours after the final injection. A melatonin-induced enhancement of3H-GABA binding was observed in both single-point and saturation binding experiments. Scatchard analysis of3H-diazepam binding revealed a melatonin-induced increase in binding affinity at 26 hours in the forebrain and at 2 hours in the cerebellum with no significant changes in binding site concentration. These findings are consistent with the proposal that melatonin's psychopharmacological effects are due at least in part to its ability to enhance central GABAergic transmission by modulating GABA receptor activity.
78 citations
TL;DR: The dopamine content of the locus coeruleus (LC) and the uptake of tritiated DA in the presence of desmethylimipramine into fresh vibratome sections of the LC-area were determined and indicates that the DA containing afferents of theLC originate, at least partly, in the VTA.
Abstract: The dopamine (DA) content of the locus coeruleus (LC) and the uptake of tritiated DA in the presence of desmethylimipramine into fresh vibratome sections of the LC-area were determined in control rats and in rats whose ventral tegmental area (VTA) had been destroyed by local application of 6-hydroxydopamine (6-OHDA). Destruction of the VTA reduced the DA content and the number of dopaminergic fibers visualized by radioautography in the LC area. This indicates that the DA containing afferents of the LC originate, at least partly, in the VTA.
69 citations
TL;DR: Results suggest that both S- COMT and MB-COMT reside postsynaptically the nigrostriatal dopaminergic neurons.
Abstract: Activities of the two forms of catechol-O-methyltransferase (COMT), viz. the soluble (S-COMT) and the membrane-bound (MB-COMT), have been studied in the rat striatum to characterize their localization in relation to the nigrostriatal dopaminergic neurons. Selective unilateral nigrostriatal dopaminergic lesions were produced by an intranigral injection of 6-hydroxydopamine (6-OHDA; 8μg/site). 6-OHDA caused an extensive lesion of the dopaminergic neurons as revealed by non-detectable concentrations of dopamine in the striata of the lesioned sites. In spite of that neither S-COMT nor MB-COMT activities were altered in comparison with the intact control striata. The intrastriatal injection of kainic acid significantly increased S-COMT activity but to some extent decreased MB-COMT activity. Kainic acid did not alter the striatal concentration of dopamine. These results suggest that both S-COMT and MB-COMT reside postsynaptically the nigrostriatal dopaminergic neurons. S-COMT seems to be found mainly in striatal glial cells, whereas striatal MB-COMT might be located both in postsynaptic neuronal and extraneuronal cells.
66 citations
TL;DR: 3H-SCH 23390 is regarded as a highly selective ligand for brain dopamine D-1 receptors in vitro and correlated to the affinities to 3H-piflutixol-binding sites and to the effects on DA-sensitive adenylate cyclase.
Abstract: The binding of3H-SCH 23390 to membranes from rat and mouse brain tissue has been investigated The binding was saturable and reached equilibrium after 60 minutes Nonspecific binding was low Association and dissociation rates were Mg++-sensitive In almost all respects the binding of3H-SCH 23390 was comparable to the binding of3H-piflutixol and3H-cis(Z)-flupentixol
63 citations
TL;DR: In this article, the effect of various post-mortem storage times and temperatures on the kinetic parameters of synaptosomal high-affinity dopamine uptake was studied in rat nucleus accumbens.
Abstract: The effect of various post-mortem storage times and temperatures on the kinetic parameters of synaptosomal high-affinity dopamine (DA) uptake was studied in rat nucleus accumbens. After post-mortem storage up to 48 hours of rat headsin situ at 22 ‡C the KM data increase moderately in contrast to the Vmax data decreasing rapidly (t1/2=30 hours); at 2‡C similar changes were observed. The post-mortem changes of the kinetic parameters of noradrenaline (NA) and serotonin (5 HT) uptake were shown in this model to be similar. It is proposed to use this animal model for correcting the kinetic data of DA, NA and 5 HT uptake in human brains regarding the various post-mortem delays. Furthermore, in cryopreservation experiments using a two-step freezing procedure in liquid nitrogen of brain pieces preincubated with dimethylsulfoxide DA uptake of rat and human brain synaptosomes was unchanged after freezing-thawing. The same is true for both NA and 5 HT uptake as demonstrated in human brain tissue. Therefore, post-mortem human brain seems to be suitable for investigating synaptosomal DA, NA, and 5 HT uptake after cryopreservation and correcting for post-mortem delay, when determining kinetic parameters.
TL;DR: By postmortem analysis of the striatal tissue MPP+ was proved to cause the inhibition of monoamine oxidase (MAO), especially MAO-B and the release of DA.
Abstract: The acute effect of 1-methyl-4-phenylpyridinium ion (MPP+), a neurotoxin derived from 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP), was examined by the in vivo micro-dialysis technique. A dialysis cannula was implanted into rat striatum, and the changes in the concentrations of dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), and 5-hydroxyindoleacetic acid (5-HIAA) in the perfusate every 20 min after administration of MPP+ were determined by high-performance liquid chromatography with electrochemical detection (HPLC-ED). After MPP+ administration the levels of DOPAC, HVA and 5-HIAA were markedly decreased. On the contrary the level of DA was markedly increased and reached a maximum 40 min after beginning of the MPP+ administration. By postmortem analysis of the striatal tissue MPP+ was proved to cause the inhibition of monoamine oxidase (MAO), especially MAO-B. These results suggest that the acute biochemical changes induced by MPP+ in vivo were MAO inhibition and release of DA.
TL;DR: Preliminary data of a postmortem brain study in a single case with Rett-syndrome compared to a single control case show a severe reduction of dopamine (DA), noradrenaline (NA), and serotonin (5-HT) in most regions studied and in two regions of adrenaline (A).
Abstract: Preliminary data of a postmortem brain study in a single case with Rett-syndrome compared to a single control case show a severe reduction of dopamine (DA), noradrenaline (NA), and serotonin (5-HT) in most regions studied and in two regions of adrenaline (A). A marked increase in the 3,4-dihydroxyphenyl acetic acid (DOPAC)/DA, homovanillic acid (HVA)/ DA, and the 5-hydroxyindole acetic acid (5-HIAA)/5-HT ratios indicates increased metabolism of DA and 5-HT. Also a marked reduction of3H-spiroperidol-binding in putamen was found. This agrees with the assumption that a defect in maturation processes of central monoaminergic systems could be an underlying cause of Rett-syndrome.
TL;DR: It was found by experimental manipulations that CGRPI fibers in the stomach were exclusively extrinsic in origin; some of such fiber in the duodenum were intrinsic in origin, though most were supplied by C GRPI cells outside the duODenum.
Abstract: We studied the three-dimensional distribution of structures with calcitonin gene-related peptide-like immunoreactivity (CGRPI) in the rat stomach and duodenum, including the origins of these structures, using indirect immunofluorescence in both muscle strips and frozen sections. There was a very dense meshwork of CGRPI fibers in the circular and longitudinal muscle layers, and also in the myenteric and submucous plexuses of the stomach and duodenum. No CGRPI neurons were seen in the stomach, even in rats treated with colchicine; in the duodenum, there was a group of CGRPI cells in the myenteric and submucous ganglia. No regional differences were seen in the stomach and duodenum. We found by experimental manipulations that CGRPI fibers in the stomach were exclusively extrinsic in origin; some of such fibers in the duodenum were intrinsic in origin, though most were supplied by CGRPI cells outside the duodenum.
TL;DR: In this paper, the effect of various post-mortem storage times and temperatures on the kinetic parameters of synaptosomal high-affinity dopamine uptake was studied in rat nucleus accumbens.
Abstract: The effect of various post-mortem storage times and temperatures on the kinetic parameters of synaptosomal high-affinity dopamine (DA) uptake was studied in rat nucleus accumbens. After post-mortem storage up to 48 hours of rat heads in situ at 22 degrees C the KM data increase moderately in contrast to the Vmax data decreasing rapidly (t1/2 = 30 hours); at 2 degrees C similar changes were observed. The post-mortem changes of the kinetic parameters of noradrenaline (NA) and serotonin (5 HT) uptake were shown in this model to be similar. It is proposed to use this animal model for correcting the kinetic data of DA, NA and 5 HT uptake in human brains regarding the various post-mortem delays. Furthermore, in cryopreservation experiments using a two-step freezing procedure in liquid nitrogen of brain pieces preincubated with dimethylsulfoxide DA uptake of rat and human brain synaptosomes was unchanged after freezing-thawing. The same is true for both NA and 5 HT uptake as demonstrated in human brain tissue. Therefore, post-mortem human brain seems to be suitable for investigating synaptosomal DA, NA, and 5 HT uptake after cryopreservation and correcting for post-mortem delay, when determining kinetic parameters.
TL;DR: It was found that ipsapirone inhibits induced by 8-OH-DPAT and 5-methoxy-dimethyltryptamine behavioural effects (flat body posture and forepaw treading) in normal and reserpinized rats.
Abstract: Ipsapirone (TVX Q 7821, 2-(4-(4-(2-pyrimidinyl)-1-piperazinyl)butyl)-1,2-benzisothiazol-3-(2H)one-1,1-dioxidehydrochloride), a new anxiolytic drug in respect of the evaluation of its effect on central 5-hydroxy-tryptamine (5-HT), noradrenaline and dopamine functions was studied. It was found that ipsapirone inhibits induced by 8-OH-DPAT and 5-methoxy-dimethyltryptamine (agonists of 5-HT1A receptors) behavioural effects (flat body posture and forepaw treading) in normal and reserpinized rats. Ipsapirone partly inhibited in rats but not in mice the 8-OH-DPAT-induced hypothermia. Ipsapirone, administered at high doses, decreased the body temperature in rats and mice, inhibited the 5-hydroxytryptophan-induced head twitches in mice and the tryptamine-induced convulsions and tremor in rats. In the hind limb flexor reflex preparation of the spinal rat only high doses of the drug inhibited stimulation induced by quipazine, m-chlorphenylpiperazine, 8-OH-DPAT and St 587 (an agonist ofα1-adrenoceptors). Ipsapirone did not block the fenfluramine- and m-chlorphenylpiperazine-induced hyperthermia in rats at an ambient temperature of 28‡C. The drug did not affect clonidine-induced sedation and inconsiderably attenuated clonidine-induced hypothermia in mice. It attenuated the d-amphetamine-induced locomotor hyperactivity in mice and rats but, given alone, decreased the locomotor activity.
TL;DR: It was found that only the PMS/PD group of patients had improved significantly with appropriate treatment, and improved motor function in PD patients is associated with decreased PMS, regardless of wether the patients are treated with dopaminergic or anticholinergic agents.
Abstract: Muscle activity during sleep is a new area of interest in sleep research. No precise brain structures are known to be involved in sleep movement. The etiology of periodic movements during sleep is unknown. The present study was dedicated to evaluate involvement of basal ganglia in periodic movements of the legs during sleep (PMS) in Parkinson's diseased patients. Sleep was monitored in 3 patients suffering from Parkinson's disease and PMS (PMS/PD) and in 3 patients suffering from restless legs syndrome and PMS (PMS/non PD). Following treatment, the six patients were monitored again during sleep. It was found that only the PMS/PD group of patients had improved significantly with appropriate treatment. Improved motor function in PD patients is associated with decreased PMS, regardless of wether the patients are treated with dopaminergic or anticholinergic agents. This is consistent with our previous data. It may be suggested that the striopallidal system is involved in periodic sleep movements of Parkinson's diseased patients.
TL;DR: Ability to produce a short-lived increase in PRL secretion in the rat appears to be common to the atypicl neuroleptic drugs, as evidenced by an enhanced accumulation of dihydroxyphenylalanine in the median eminence after the inhibition of DOPA decarboxylase.
Abstract: Two atypical neuroleptic agents, clozapine and fluperlapine, produced rapid elevations in plasma PRL concentrations that were similar in magnitude to those produced by haloperidol. However, the PRL response to clozapine or fluperlapine was of much shorter duration than that elicited by haloperidol. Clozapine, but neither fluperlapine nor haloperidol, produced a rapid increase in the activity of tuberoinfundibular dopamine (TIDA) neurons, as evidenced by an enhanced accumulation of dihydroxyphenylalanine (DOPA) in the median eminence after the inhibition of DOPA decarboxylase. The clozapine-induced increase in DOPA accumulation was evident within 30 minutes after its administration and persisted for at least 4 hours. The clozapine-induced increase in the activity of TIDA neurons may account, in part, for the abbreviated PRL response to this neuroleptic. In addition, ability to produce a short-lived increase in PRL secretion in the rat appears to be common to the atypical neuroleptic drugs.
TL;DR: The results seem to indicate that following fluvoxamine intake at night, the early morning decline of melatonin is delayed, and it is suggested that the underlying mechanism leading to a rise in morning melatonin levels cannot be explained solely on the basis of an inhibition of 5-HT reuptake and that other pharmacological properties of flu voxamine may be involved.
Abstract: The influence of various antidepressants on the morning levels of plasma melatonin was studied in human volunteers after acute and subchronic administration in weekly increasing doses over a period of three weeks. Two monoamine oxidase (MAO) inhibitors (tranylcypromine: irreversible type A and B; pirlindole: reversible type A), two reuptake inhibitors (maprotiline: selective for noradrenaline; fluvoxamine: selective for serotonin) and an alpha 1/alpha 2-adrenergic and serotonin S2-receptor antagonist (mianserin) were administered to groups of 4 to 7 healthy volunteers each. Two hours after a single oral dose at 9 a.m., at the end of each week and one week after the last dose, morning levels of melatonin were measured using a radioimmunological method. In addition, platelet MAO activity and the uptake of 14C-5-HT into platelets were determined. Plasma melatonin concentrations at 9 a.m. were significantly increased after the intake of 150 mg fluvoxamine the night before; whereas, administration of the same dose in the morning did not lead to increases in melatonin during the day. Following subchronic administration, plasma melatonin levels were significantly increased after the 1st (50 mg/day), 2nd (100 mg/day) and 3rd (150 mg/day) week of fluvoxamine intake in comparison to pre-drug levels. No changes in early morning levels of plasma melatonin were measured in the subjects receiving the other antidepressants, after acute as well as after subchronic administration. The results seem to indicate that following fluvoxamine intake at night, the early morning decline of melatonin is delayed. It is suggested that the underlying mechanism leading to a rise in morning melatonin levels cannot be explained solely on the basis of an inhibition of 5-HT reuptake and that other pharmacological properties of fluvoxamine may be involved.
TL;DR: It is suggested that in SHR the LC system, in spite of a reduced basal activity, displays increased responsiveness to sensory stimuli, a phenomenon that may contribute to the development of hypertension.
Abstract: Previous studies have indicated that brain noradrenaline (NA) neurons in spontaneously (genetically) hypertensive rats (SHR) are implicated in the development of hypertension. Thus, a number of biochemical aberrations in the metabolism of NA in the SHR brain have been detected although the data are not in total agreement. We report here experiments utilizing single cell recording techniques which show directly a reduction in neuronal activity of brain NA neurons in the locus coeruleus (LC) of SHR. This reduction develops gradually with age and in parellel with the increased blood pressure (BP), but is not altered by acute alterations in BP. The SHR were found to display an increased intraneuronal monoamine oxidase (MAO) activity as well as a specifically reduced sensitivity of inhibitory alpha2-receptors within the LC. It is suggested that in SHR the LC system, in spite of a reduced basal activity, displays increased responsiveness to sensory stimuli, a phenomenon that may contribute to the development of hypertension.
TL;DR: The data indicate that the locomotor stimulant effects of bromocriptine are modulated by D1 receptors and this effect is blocked by their pretreatment with the selective D-1 antagonist, SCH 23390.
Abstract: Mice were pretreated with reserpine plusα-methyl-p-tyrosine (10 mg/ kg plus 200 mg/kg). One hour later they were administered the selective dopamine D-2 agonist bromocriptine or vehicle. Three hours after the bromocriptine, mice were challenged with the selective D-1 agonist SKF 38393, and locomotor activity was measured each 5 min for three hours. Neither bromocriptine nor SKF 38393 produced significant stimulation. The combination, however, produced a dose-dependent and coordinated increase in activity. If the bromocriptine was given only one hour before the SKF 38393 challenge (i.e., three hours after the reserpine plusα-methyl-p-tyrosine), no interaction was seen. In naive mice, when SKF 38393 and bromocriptine were administered together, the locomotor response to bromocriptine was quantitatively and qualitatively altered. The initial depressant response to bromocriptine was shortened, producing a more rapid onset of the stimulant response. In one experiment, the maximal activity induced by bromocriptine was increased by SKF 38393. The ability of SKF 38393 to alter the locomotor stimulant effect of bromocriptine in naive mice was blocked by their pretreatment with the selective D-1 antagonist, SCH 23390. The data indicate that the locomotor stimulant effects of bromocriptine are modulated by D1 receptors.
TL;DR: GABA can enhance 3H-NA release not only through GABA-A receptors but also by penetrating into NA terminals through a GABA uptake system, which implies coexistence of carriers for NA and GABA uptake on a same nerve terminal.
Abstract: γ-Aminobutyric acid (GABA) increased in a concentration-dependent way (3–300ΜM) the basal release of tritium from rat cerebral cortex and hippocampus synaptosomes, prelabelled with3H-noradrenaline (3H-NA); however, GABA was ineffective on hypothalamic nerve endings. The effect displayed by low concentrations (<10ΜM) of GABA was largely bicuculline-sensitive. Muscimol mimicked GABA, while (−)baclofen was inactive. The releasing effects produced by concentrations of GABA higher than 10ΜM were largely prevented by SK&F89976A, SK&F 100330A and SK&F 100561, three novel GABA uptake inhibitors. When present together, GABA uptake blocker and bicuculline counteracted entirely the GABA effects. The basal release of3H-5-hydroxytryptamine (3H-5-HT) in synaptosomes from various CNS regions was not affected by GABA. In conclusion: GABA can enhance3H-NA release not only through GABA-A receptors but also by penetrating into NA terminals through a GABA uptake system. This implies coexistence of carriers for NA and GABA uptake on a same nerve terminal. The carrier coexistence occurs in selective CNS areas. The phenomenon appears to be transmitter-selective.
TL;DR: The selective effect of haloperidol, but not sulpiride or clozapine, treatment on striatal GAD activity parallels the ability of hal operidol to induce striatal dopamine receptor supersensitivity in the same animals.
Abstract: Rats were treated continuously for 12 months with therapeutically equivalent doses of haloperidol (1.4–1.6 mg/kg/day), sulpiride (102–109 mg/kg/day) or clozapine (24–27 mg/kg/day) and examined for alterations in brain glutamic acid decarboxylase (GAD) and3H-flunitrazepam binding.
TL;DR: Although no sex differences were found in the in vitro measured characteristics of both enzymes involved in GABA metabolism, the turnover of GABA was greater in males, consistent with previous reports showing the greater resistance of male rats to GABA-related convulsions.
Abstract: The turnover of GABA (estimated from the post-mortem accumulation of GABA), and the activity of glutamic acid decarboxylase and GABA transaminase, along with the saturation of both enzymes by cofactor pyridoxal phosphate, were studied in the substantia nigra of rats of both sexes. Although no sex differences were found in the in vitro measured characteristics of both enzymes involved in GABA metabolism, the turnover of GABA was greater in males. This finding is consistent with our previous reports showing the greater resistance of male rats to GABA-related convulsions.
TL;DR: The data indicate that amineptine inhibits DA uptake and is virtually devoid of DA releasing effects, and displays a relatively low affinity for the NE uptake system.
Abstract: The effects of amineptine on 3H-dopamine uptake and 14C-dopamine release have been studied simultaneously in double labelling test performed on rat striatal synaptosomes. 3H-dopamine uptake was completely inhibited at 10 microM amineptine, a concentration which produced only a weak 14C-DA release (13% of the 14C-radioactivity stored). The IC 50 for the inhibition of 3H-DA uptake was not modified by a previous treatment with reserpine whereas the IC 50 of (+) amphetamine and the IC 50 of clomipramine were decreased 9 fold and increased two fold, respectively. In binding studies on rat striatal membranes amineptine displaces in vitro the 3H-GBR 12783, bound specifically to a component of the neuronal DA uptake complex. The apparent affinity of amineptine for this binding site was more than 150 times higher than its affinity for the binding site of 3H-desipramine on rat cortical membranes. In mice, increasing doses of amineptine injected i.p. reduced in a dose dependent manner the specific retention of radioactivity in the striatum after an i.v. injection of a tracer dose of 3H-GBR 12783. These data indicate that amineptine inhibits DA uptake and is virtually devoid of DA releasing effects. It displays a relatively low affinity for the NE uptake system. Its neurochemical profile in the double labelling test clearly differs from that of (+) amphetamine and from that of classical tricyclic anti-depressants.
TL;DR: Competition experiments clearly showed two pharmacologically distinct sites, but question the relative specificity of some of the adrenergic drugs.
Abstract: The tritiated adrenergic antagonists prazosin ([3H]PRZ) and idazoxan ([3H]IDA, or RX-781094) bind specifically and with high affinity in membrane preparations from cerebral cortex to alpha-1- and alpha-2-adrenoceptors respectively. Saturation experiments, performed to determine the density of receptors (Bmax; maximum binding capacity) and the dissociation constant (Kd 25 °C), were analyzed by the methods of Eadie and Hofstee, iterative modelling, and the procedure of Hill. The pharmacologic properties and specificity of the labelling was verified by displacement experiments using alpha-adrenergic antagonists and agonists. The antagonist drugs showed the following order of potency to displace [3H]prazosin: prazosin ≫ phentolamine ≫ corynanthine > pyrextramine ≫ yohimbine ≫ piperoxan > benextramine > idazoxan; for the agonists: clonidine ≫ (−)-noradrenaline ≫ (−)-adrenaline ≫ phenylephrine, while other drugs, such as (−)-propranolol, dopamine, (−)-isoproterenol and serotonin only competed with the alpha-1-ligand at concentrations above 20 μM. The alpha2-sites labelled by [3H]idazoxan were characterized by the antagonist displacement sequence idazoxan ≫ phentolamine > yohimbine = > piperoxan ≫ pyrextramine ≫ benextramine ≫ prazosin ≫ corynanthine. The agonists order of potency to compete with [3H]idazoxan was clonidine ≫ phenylephrine = > (−)-adrenaline > (−)-noradrenaline, and for other related drugs it was (−)-propranolol ≫ dopamine ≫ serotonin > (−)-isoproterenol. These competition experiments clearly showed two pharmacologically distinct sites, but question the relative specificity of some of the adrenergic drugs.
TL;DR: The results on REM sleep confirm earlier results involving serotonin uptake inhibitors and serotonin precursor loading and indicate that increased synaptic serotonin concentrations suppress REM sleep.
Abstract: Sleep and waking in cats and rats were studied 6–10 hours following acute administration of zimeldine, alaproclate or saline. The effects on slow wave sleep of the two compounds markedly differed in the cats. Following zimeldine, sleep with a high amount of synchronized slow waves (SWS-2) was increased, and total sleep was unchanged. Following alaproclate, SWS-2 did not increase, and total sleep was reduced. In the rats, zimeldine increased SWS-2 during the first 4 hours after administration, while there was no change in SWS following alaproclate. Both zimeldine and alaproclate increased REM latency and reduced REM sleep in both species with somewhat more pronounced effects in cats than in rats.
TL;DR: None of the compounds used affected either DOPAC and HVA concentrations or the rate of utilisation of DA in the substantia nigra, however, Sulpiride and remoxipride produced a modest rise in nigral DA synthesis.
Abstract: The effects of dopamine (DA) antagonists upon DA synthesis and utilisation in the rat striatum, olfactory tubercle and substantia nigra have been studied. The concentrations of dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), the rate of depletion of DA afterin vivo inhibition of tyrosine hydroxylase by H 44/68, and the accumulation of L-DOPA afterin vivo inhibition of 1-aromatic amino acid decarboxylase by NSD 1015 were measured in the study. Haloperidol (0.23μmol/kg i. p.), sulpiride (293μmol/kg i. p.) and remoxipride (5.6μmol/kg i. p.) increased both DA synthesis and utilisation in the striatum and olfactory tubercle. A lower dose of sulpiride (45μmol/kg i. p.) increased DA synthesis and utilisation in the olfactory tubercle alone. None of the compounds, at the doses used, affected either DOPAC and HVA concentrations or the rate of utilisation of DA in the substantia nigra. Sulpiride (293μmol/kg i. p.) and remoxipride, however, produced a modest rise in nigral DA synthesis. The dopamine D 1-selective antagonist SCH 23390 had only modest effects on striatal, limbic and nigral DA synthesis and utilisation at the doses tested (0.078 and 0.36μmol/kg i. p.).
TL;DR: Pineal substances as well as some of their analogues showed an inhibitory effect only at non-physiologically high concentrations, however, crude pineal extracts were more active than the synthetic pineal substances tested.
Abstract: The effect was studied of a number of synthetic indoleamines, pteridines,β-carbolines, of AVT and of crude extracts from rat and ovine pineal glands on human melanoma cellsin vitro. The identified pineal substances as well as some of their analogues showed an inhibitory effect only at non-physiologically high concentrations. However, crude pineal extracts were more active than the synthetic pineal substances tested. They contain a compound which may have a tumor-inhibiting potency comparable to that of methotrexate but a different mechanism of action.
TL;DR: In general rodents need 60 times as much aspartame, on a mg/kg basis, as humans to obtain comparable elevations in phenylalanine with respect to tyrosine.
Abstract: All aspartame does given to humans cause greater elevations in plasma (and, presumably, brain) phenylalanine than in plasma tyrosine. In contrast, doses of aspartame usually used in experiments on rodents preferentially elevate tyrosine. Since phenylalanine can inhibit brain catecholamine synthesis while tyrosine is the antidote for this effect, we determined the aspartame dose that would be needed to elevate phenylalanine more than tyrosine in rodents, using published data. In general rodents need 60 times as much aspartame, on a mg/kg basis, as humans to obtain comparable elevations in phenylalanine with respect to tyrosine.