Showing papers in "Journal of Neural Transmission in 1997"
TL;DR: There was a significant depletion of reduced glutathione in surviving neurons in Parkinson's disease compared to nerve cell populations in control tissue and mercury orange fluorescent staining and immunostaining indicate a significant loss of neuronal reduced glutathi in surviving nigral neurons in Parkinson's disease.
Abstract: Depletion of reduced glutathione occurs in the substantia nigra in Parkinson's disease and in incidental Lewy body disease (presymptomatic Parkinson's disease) which may implicate oxidative stress in the neurode-generative process. In this study mercury orange fluorescent staining and immunostaining with an antibody to reduced glutathione have been used to determine the distribution of reduced glutathione in the substantia nigra in Parkinson's disease compared with normal individuals.
317 citations
TL;DR: The existence of a distinct biallelic variation of the 5-HTTLPR in rhesus monkeys but similar allele and genotype frequencies in this species and humans supports the notion that there may be a relationship between functional 5- HT transporter expression, anxiety-related traits, and the complexity of socialization in human and nonhuman primate populations.
Abstract: By conferring allele-specific transcriptional activity on the 5-HT transporter gene promoter in humans, the 5-HT transporter gene-linked polymorphic region (5-HTTLPR) influences a constellation of personality traits related to anxiety and increases the risk for neurodevelopmental, neurodegenerative, and psychiatric disorders. Here we have analyzed the presence and variability of the 5-HTTLPR in several species of primates including humans, and other mammals. PCR, Southern blot, and sequence analyses of the 5-HT transporter gene's 5′-flanking region in different mammalian species confirmed the presence of the 5-HTTLPR in platyrrhini and catarrhini (hominoids, cercopithecoids) but not in prosimian primates and other mammals. Since the 5-HTTLPR is unique to humans and simian primates, a progenitor 5-HTTLPR sequence may have been introduced into the genome some 40 Mio. years ago. In humans the majority of alleles are composed of either 14 or 16 repeat elements, while alleles with 18 or 20 repeat elements are rare. In contrast, great apes including orang-utan, gorilla, and chimpanzee display a high prevalence of alleles with 18 and 20 repeat elements. In hominoids all alleles originate from variation at a single locus (polymorphic locus 1). In the 5-HTTLPR of rhesus monkeys (rh5-HTTLPR) we found an alternative locus for length variation (polymorphic locus 2) generated by a 21 bp insertion/deletion event. The existence of a distinct biallelic variation of the 5-HTTLPR in rhesus monkeys but similar allele and genotype frequencies in this species and humans supports the notion that there may be a relationship between functional 5-HT transporter expression, anxiety-related traits, and the complexity of socialization in human and nonhuman primate populations.
257 citations
TL;DR: Riluzole suppressed the intracortical facilitation whereas other parameters remained unchanged, indicating that the neurotransmitter glutamate is mainly involved in facilitatory mechanisms in the motor system.
Abstract: The effect of the glutamate antagonist riluzole on excitatory and inhibitory phenomena in the human motor system was studied by transcranial magnetic stimulation (TMS) and peripheral electrical nerve stimulation. The motor threshold, the intracortical inhibition and intracortical facilitation as assessed by paired TMS, the cortical and peripheral silent periods, F wave amplitudes and F wave latencies were measured. Riluzole suppressed the intracortical facilitation whereas other parameters remained unchanged, indicating that the neurotransmitter glutamate is mainly involved in facilitatory mechanisms in the motor system.
256 citations
TL;DR: This work isolated and cloned the 5′-regulatory region of the serotonin transporter gene, which is inducible by cAMP-and PKC-dependend signal transduction pathways, and revealed a genetic polymorphism with allelic variation in transcriptional activity and protein expression.
Abstract: Mood, emotion, and cognition are modulated by the serotonergic midbrain raphe system, which seems to be involved in the pathogenesis of psychiatric disorders like those of the affective spectrum. Since a dysregulation of serotonin transporter expression might be important in the course of those disorders, we isolated and cloned the 5'-regulatory region of the serotonin transporter gene, which is inducible by cAMP- and PKC-depended signal transduction pathways. Systematic screening for length variations and functional promoter analyses revealed a genetic polymorphism with allelic variation in transcriptional activity and protein expression. This 5-HTT gene polymorphism comprises a tandemly repeated sequence in the 5'-regulatory promoter region of the serotonin transporter gene. Recent population association studies demonstrated the 5-HTT gene promoter polymorphism accounting for 4-5% of population variation of anxiety-related behavioral traits.
215 citations
TL;DR: This study demonstrates the effect of a single session of rapid TMS on tissue monoamines in rat brain and implies on a biochemical basis to the suggested ECT-like treatment potential of TMS.
Abstract: Transcranial magnetic stimulation has been suggested as a possible therapeutic tool in depression. In behavioral models of depression, magnetic stimulation induced similar effects to those of electroconvulsive shock. This study demonstrates the effect of a single session of rapid TMS on tissue monoamines in rat brain. Alterations in monoamines were selective and specific in relation to brain areas and type of monoamine. The results imply on a biochemical basis to the suggested ECT-like treatment potential of TMS.
191 citations
TL;DR: It is concluded that 5-HT release after (+)-MDMA treatment partially contributes to (+-MDMA's effect on DA release in vivo, and the selective DA transport inhibitor GBR-12909 (1 μM), blocked (+)- MDMA’s effect onDA release.
Abstract: Acting as a substrate at the serotonin (5-HT) transporter, (+)-MDMA (3,4-methylenedioxymethamphetamine), is a potent releaser of 5-HT and causes toxicity to 5-HT neurons after repeated exposure. (+)-MDMA also releases dopamine (DA), although with less potency. Since we have shown previously that the intrastriatal application of 5-HT facilitates DA release, it was hypothesized that increased release of striatal 5-HT after MDMA may influence extracellular levels of DA. Using microdiaiysis in vivo, we found that (+)-MDMA (4.7 μmol/kg, i.v.) administration increased extracellular striatal DA levels to 501% of control (p < 0.01, n=12). However, in the presence of fluoxetine (14.4 μmol/kg, s.c.), which prevents (+)-MDMA effects on 5-HT release, the (+)-MDMA-induced increase in DA was significantly less (to 375% of control, p < 0.05, vs. no fluoxetine, n=8). In vitro studies with striatal slices, to test drug selectivity, showed that (+)-MDMA (0.3-3 μM) increased extracellular levels of both DA and 5-HT in a dose-dependent manner. Fluoxetine (3 μM) completely blocked the effects of (+)-MDMA on 5-HT release, but did not alter (+)-MDMA-induced DA release in vitro. The selective DA transport inhibitor GBR-12909 (1 μM), blocked (+)-MDMA's effect on DA release. It is concluded that 5-HT release after (+)-MDMA treatment partially contributes to (+)-MDMA's effect on DA release in vivo.
165 citations
TL;DR: The data suggested that iron may induce neuronal damage and thus excessive iron in the brain may contribute to the neuronal loss in PD and iron chelators and antioxidants may serve as potential therapeutic agents in retarding the progression of neurodegeneration.
Abstract: To elucidate the neuroprotective effects of the iron chelator desferrioxamine (DFO) and the antioxidant vitamin E on excessive iron-induced free radical damage, a chronic iron-loaded mice model was established. The relationship between striatal iron content, oxidized to reduced glutathione ratio, hydroxyl radical (.OH) levels and dopamine concentrations were observed in DFO or vitamin E pretreated iron-loaded/1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated C57BL/6 mice. The results demonstrated that both DFO and vitamin E inhibit the iron accumulation and thus reverses the increase in oxidized glutathione (GSSG), oxidized to reduced glutathione ratios, .OH and lipid peroxidation levels. The striatal dopamine concentration was elevated to normal value. Our data suggested that: (1) iron may induce neuronal damage and thus excessive iron in the brain may contribute to the neuronal loss in PD; (2) iron chelators and antioxidants may serve as potential therapeutic agents in retarding the progression of neurodegeneration.
160 citations
TL;DR: In this paper, it was shown that the degeneration of 5-HT presynapses represents only the final step in a sequence of events which compromizes the ability of 5HT terminals to maintain their functional and structural integrity.
Abstract: The massive and prolonged stimulation of serotonin (5-HT)-release and the increased dopaminergic activity are responsible for the acute psychomimetic and psychostimulatory effects of 3,4-methylenedioxy-methamphetamine (MDMA, “ecstasy”) and its congeners. In vulnerable subjects, at high doses or repeated use, and under certain unfavorable conditions (crowding, high ambient temperature), severe, in some cases fatal, averse systemic reactions (hyperthermia, serotonin-syndrome) may occur during the first few hours. Animal experiments revealed the existence of similar differences in vulnerability and similar dose- and context-related influences on a similar sequence of acute responses. The severity of these acute systemic responses is closely related to the severity of the long-term damage to 5-HT axon terminals caused by the administration of substituted amphetamines. Attempts to identify the mechanisms involved in this selective degeneration of 5-HT presynapses brought to light a multitude of different factors and conditions which either attenuate or potentiate the loss of 5-HT terminals caused by MDMA and related amphetamine derivatives. These puzzling observations suggest that the degeneration of 5-HT presynapses represents only the final step in a sequence of events which compromize the ability of 5-HT terminals to maintain their functional and structural integrity. The common feature of all these events is a profound wastage of energy. Substituted amphetamines selectively tax energy metabolism in 5-HT presynapses through their ability to exchange with 5-HT and to dissipate transmembrane ion gradients. The active carrier systems in the vesicular and presynaptic membrane operate at a permanently activated state. The resulting energy deficit can no longer adequately restored by the 5-HT presynapses when their availability of substrates for ATP production is additionally reduced by the hyperthermic and other energy consuming reactions which are elicited by the systemic administration of substituted amphetamines. The exhaustion of energy in 5-HT nerve terminals compromizes all energy-requiring endogenous mechanisms involved in the regulation of transmembrane-ion exchange, internal Ca++-homeostasis, prevention of oxidative stress, detoxification, and repair. Above a critical threshold the failure of these self-protective mechanisms will lead to the degeneration of the 5-HT axon terminals. Based on the role of 5-HT as a global modulatory transmitter-system involved in the stabilization and integration of impulse flow between distributed multifocal neuronal networks, the partial loss of 5-HT presynapses must be expected to impair the ability of these networks to maintain the integrity of signal flow pattern, and increase the likelihood of switching to unstable information processing. Behavioral responding may therefore become more dominated by activities generated in individual networks, and hitherto “buffered” personality traits and predisposition may become manifested as defined psychiatric syndromes in certain predisposed subjects.
125 citations
TL;DR: The results of the present experiments indicate that acutely administered nicotine or nicotine challenge in chronically pretreated animals with either saline or nicotine consistently increases DA release to a greater extent in the NACshell than in theNACcore, and that chronic nicotine pretreatment reduces the stimulatory action of nicotine on DA output in either the shell or the core subdivision of the Nac.
Abstract: Like several drugs of abuse, nicotine increases dopamine (DA) release in the nucleus accumbens (NAC). In the present study, the effects of acute and chronic nicotine on DA output in two subdivisions of the NAC, the core and the shell, which are largely associated with motor control and limbic functions, respectively, were examined by means of in vivo differential normal pulse voltammetry in anesthetized, pargyline-treated rats. In the first experiment, acute administration of nicotine (25, 50 and 100 μg/ kg, cumulative doses; i.v.) was found to increase DA levels in the NACshell to 163% of baseline, whereas DA output in the NACcore was not significantly affected. In the second experiment, animals were pretreated with twelve daily injections of saline or nicotine (0.5 mg/kg, i.p.); about 24 hours after the last injection, the animals were challenged with nicotine (50μg/kg and 100 μg/kg, cumulative doses; i.V.). Under these conditions, nicotine increased DA output in the NACshell in saline-pretreated animals to 248% and in nicotine-pretreated rats to 180%. Also, nicotine increased DA output in the NACcore in saline-pretreated animals to 185%, whereas no significant effect was observed in nicotine-pretreated rats. The results of the present experiments indicate (i) that acutely administered nicotine or nicotine challenge in chronically pretreated animals with either saline or nicotine consistently increases DA release to a greater extent in the NACshell than in the NACcore, and (ii) that chronic nicotine pretreatment reduces the stimulatory action of nicotine on DA output in either the shell or the core subdivision of the NAC.
107 citations
TL;DR: It is suggested that pramipexole may be cytoprotective to dopamine neurons in tissue culture through its affinity for DA receptors, its antioxidant action or its ability to enhance mesencephalic trophic activity.
Abstract: The direct-acting dopamine (DA) agonist pramipexole (2 amino-4,5,6,7-tetrahydro-6-propyl-amino-benzthiazole-dihydrocfiloride) was evaluated for its ability to attenuate levodopa-induced loss of tyrosine hydroxylase immunoreactive (THir, a marker for dopamine neurons) cells in mesencephalic cultures. Pramipexole reduced levodopa-induced THir cell loss in a dosedependent and saturable fashion (ED50=500 pM), its inactive stereoisomer was significantly less potent in this regard and pergolide and bromocriptine had negligible cytoprotective effects. Culture media from mesencephalic cultures incubated with pramipexole for 6 days increased THir cell counts in freshly harvested recipient cultures. The magnitude of this effect was directly proportional to the amount of pramipexole in the donor cultures and heatinactivation of the media abolished the growth promoting effect. The results from this exploratory set of experiments suggest that pramipexole may be cytoprotective to dopamine neurons in tissue culture. Pramipexole's affinity for DA receptors, its antioxidant action or its ability to enhance mesencephalic trophic activity could be responsible for this effect.
101 citations
TL;DR: It is suggested that iron does induce oxidative stress, but not severely injury neurons per se, which supports the hypothesis that excessive cerebral iron may contribute to the aetiology of Parkinson's disease (PD).
Abstract: In this study a chronic cerebral iron-loaded model was established by feeding mice with high iron diet. Data indicated that brain iron concentrations were significantly increased in iron-fed mice compared with those of controls. A significant increase in oxidized glutathione (GSSG), decrease in total glutathione (oxidized and reduced glutathione, GSSG + GSH), and therefore increase in the GSSG/(GSSG + GSH) ratios were observed in iron-loaded mice. Hydroxyl radical (.OH) levels in striatum and brainstem were also significantly increased. Excessive iron alone did not change either dopamine (DA) or lipid peroxidation (LPO) concentrations in striatum. However, a single injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP, 30mg/kg, i.p.) into the iron-loaded mice caused a great enhancement in all these biochemical abnormalities. These findings suggest that iron does induce oxidative stress, but not severely injury neurons per se. Excessive iron accumulation in the brain, however, is a potential risk for neuronal damage, which may promote by triggering factor(s). This supports the hypothesis that excessive cerebral iron may contribute to the aetiology of Parkinson's disease (PD).
TL;DR: The protective effect against L-DOPA neurotoxicity by glia conditioned medium is mediated by several compounds including neurotrophic factors and small antioxidants and is more effective than the fraction of larger molecular size, that contains large neurotrophic peptides.
Abstract: Mesencephalic glia produce soluble factors that protect dopamine neurons from L-DOPA toxicity. The chemical composition of these soluble factors is unknown. We investigated the protective effect against L-DOPA neurotoxicity in midbrain dopamine neurons of fractions of different molecular size of glia conditioned medium and candidate neuroprotective agents produced by glia including neurotrophic factors and antioxidants. Protective effects were evaluated according to the number of tyrosine hydroxylase immunoreactive cells, high affinity dopamine uptake and levels of quinones. Both fractions of glia conditioned medium, smaller and larger than 10kD, protected against L-DOPA, but the fraction of smaller molecular size, that contains small free radical scanvenger molecules, was more effective than the fraction of larger molecular size, that contains large neurotrophic peptides. Among the neurotrophic factors GDNF and BDNF totally prevented L-DOPA neurotoxicity, while NGF and bFGF were less effective. However, only NGF significantly reduced the elevation of quinones induced by L-DOPA. Ascorbic acid, at the concentration found in glia conditioned medium, provided partial protective effect against L-DOPA toxicity. Glutathione, had neurotrophic effects on untreated midbrain dopamine neurons and prevented the effect of L-DOPA. In conclusion, the protective effect against L-DOPA neurotoxicity by glia conditioned medium is mediated by several compounds including neurotrophic factors and small antioxidants.
TL;DR: It is suggested that treatment with Tolcapone, in combination with L-dopa therapy, may determine a significant improvement in cognitive resources of patients with advanced Parkinson's disease.
Abstract: The aim of this study was to evaluate the effects of Tolcapone, a reversible, selective inhibitor of catechol-O-methyltransferase, on the cognitive functions of eight patients with advanced Parkinson's disease. They underwent neuropsychological and motor assessment at baseline and were reevaluated after 6 months. During this period, they received Tolcapone three times daily, while the L-dopa dosage was progressively reduced. Significant improvements were observed in the attentional task, auditory verbal short-term memory, visuo-spatial recall, constructional praxia and motor symptoms. These data suggest that treatment with Tolcapone, in combination with L-dopa therapy, may determine a significant improvement in cognitive resources of patients with advanced Parkinson's disease.
TL;DR: The results suggest that low CSF and serum vitamin E concentrations in AD patients could be related with a deficiency of dietary intake of vitamin E.
Abstract: We compared CSF and serum levels, and the CSF/serum ratio of alpha-tocopherol (vitamin E), measured by HPLC, in 44 apparently well-nourished patients with Alzheimer's disease (AD) and 37 matched controls. CSF and serum vitamin E levels were correlated, both in AD patients and in controls. The mean CSF and serum vitamin E levels were significantly lower in AD patients, and the CSF/serum ratio of AD patients did not differ significantly between the 2 study groups. CSF vitamin E levels did not correlate with age, age at onset, duration of the disease and score of the Minimental State Examination in the AD group. Weight and body mass index were significantly lower in AD patients than in controls. These results suggest that low CSF and serum vitamin E concentrations in AD patients could be related with a deficiency of dietary intake of vitamin E.
TL;DR: Results indicate that, in the tests used, pramipexole evokes effects similar to those of typical antidepressants and, at the same time, enhances their activity (the forced swimming test in rats); therefore it may be regarded as a potential antidepressant drug.
Abstract: Pramipexole (2-amino-4,5,6,7-tetrahydro-6-propyl-amino-benzthiazole-dihydrochl oride), a new dopamine receptor agonist with preference for D3 compared to D2 and D4 receptors, was tested in rats in respect of its potential antidepressant activity. In the forced swimming test the drug under study, given three times in rats, reduced the immobility time. In the forced swimming test, joint treatment with antidepressants (imipramine, amitriptyline) and pramipexole evoked a more potent effect than any of the drugs given alone; however, the locomotor hyperactivity was weaker after joint administration. Citalopram and fluoxetine, inactive per se in the forced swimming tests, visibly enhanced the antidepressant-like effect of pramipexole but, on the other hand, they attenuated the locomotor hyperactivity evoked by the drug. Repeated treatment with pramipexole (0.3 or 1 mg/kg, twice daily for 14 days) increased the locomotor activity measured at 1 h after the last dose. Repeated administration of pramipexole (as above) potentiated the D-amphetamine- or quinpirole-induced locomotor hyperactivity. The obtained results indicate that, in the tests used, pramipexole evokes effects similar to those of typical antidepressants and, at the same time, enhances their activity (the forced swimming test in rats); therefore it may be regarded as a potential antidepressant drug.
TL;DR: In the present study alterations of EEG microstates in subjective and objective memory impairment as well as in probable Alzheimer disease compared to healthy controls were investigated and the main findings were reduced segment durations and a more anterior center of gravity of the microstate topography in DAT.
Abstract: The only available functional neuroimaging methods reaching the time resolution of human information processing are EEG and MEG. Since spectral analysis implies analysis of longer time epochs, the high temporal resolution of EEG is partly lost. By dividing the EEG in the time-domain into segments of similar spatial distribution on the scalp (microstates) it has been possible to assess patterns of neuronal activity representing the information process currently performed by the brain. In the present study alterations of EEG microstates in subjective (n = 31) and objective (n = 38) memory impairment as well as in probable Alzheimer disease (DAT: n = 64) compared to healthy controls (n = 21) were investigated. The main findings were reduced segment durations and a more anterior center of gravity of the microstate topography in DAT. With more pronounced cognitive dysfunction larger window sizes were found. Shorter microstates and larger windows reflect more rapidly changing spatial activation patterns, and are interpreted as an impaired capability to establish stable brain states necessary for normal brain function. The anteriorization of the microstates is consistent with results in the frequency domain and may reflect neuropathological changes in DAT.
TL;DR: Stride parameters were established in 17 patients with idiopathic Parkinson's disease and in 33 healthy age-matched controls and no stride parameter correlated with any total score of either the Hoehn-Yahr Scale, the Unified Parkinson's Disease Rating Scale Motor Examination, the Columbia Rating Scale (CURS), or the Webster Rating Scale.
Abstract: Stride parameters were established in 17 patients with idiopathic Parkinson's disease (PD; mean age 68.8 yrs.; Hoehn-Yahr stages 2 and 3) and in 33 healthy age-matched controls. Free-walking speed was lower in PD as were stride length and cadence. Impaired locomotor synergies in PD were reflected by a higher coefficient of variation of stride length; step width and its coefficient of variation (the latter related to postural imbalance in locomotion) were not changed. No stride parameter correlated with any total score of either the Hoehn-Yahr Scale, the Unified Parkinson's Disease Rating Scale Motor Examination (“UPDRS-III”), the Columbia Rating Scale (CURS) or the Webster Rating Scale. Stride length correlated with a CURS-Bradykinesia-Score, whereas gait velocity correlated with UPDRS-III-Axial-Motor-Score and with the CURS-Bradykinesia-Score. Hypokinesia of gait in moderately disabled PD patients is best assessed by combined analysis of stride parameters and locomotion-related subscores from conventional rating scales.
TL;DR: Depleted GSH following chronic administration of BSO in the rat brain does not cause damage to the nigrostriatal pathway and suggests that loss of GSH alone is not responsible for nigrostRIatal damage in PD, rather, GSH depletion may enhance the susceptibility of substantia nigra to destruction by endogenous or exogenous toxins.
Abstract: Nigral cell death in Parkinson's disease (PD) may involve oxidative stress and mitochondrial dysfunction initiated by a decrease in reduced glutathione (GSH) levels in substantia nigra. L-buthionine-(S,R)-sulphoximine (BSO; 4.8 and 9.6 mg/kg/day), an irreversible inhibitor of γ-glutamyl cysteine synthetase, was chronically infused into the left lateral ventricle of rats over a period of 28 days and markedly reduced GSH concentrations in substantia nigra (approx. 59% and 65% in 4.8 and 9.6 mg/kg/d BSO respectively) and the striatum (approx. 63% and 80% in 4.8 and 9.6 mg/kg/d BSO respectively). However, the number of tyrosine hydroxylase (TH)-positive cells in substantia nigra was not altered by BSO-treatment compared to control animals. Similarly, there was no difference in specific [3H]-mazindol binding in the striatum and nucleus accumbens of BSO-treated rats compared to control rats. In conclusion, depletion of GSH following chronic administration of BSO in the rat brain does not cause damage to the nigrostriatal pathway and suggests that loss of GSH alone is not responsible for nigrostriatal damage in PD. Rather, GSH depletion may enhance the susceptibility of substantia nigra to destruction by endogenous or exogenous toxins.
TL;DR: The dopamine agonist Pergolide is superior to L-Dopa in the treatment of RLS and NMS in patients with idiopathic restless legs syndrome.
Abstract: A double-blind randomized crossover study of 0.125 mg Pergolide (Lilly®) at bedtime versus 250 mg L-Dopa + Carbidopa (Roche®) was conducted in 16-day phases in 11 patients with idiopathic restless legs syndrome. Two patients reported a partial and 9 patients a complete relieve of motor restlessness while receiving Pergolide. Only 1 patient experienced an improvement of restlessness after L-Dopa. The patients showed polysomnographically a mean decrease in NMS cluster disturbed time by 45% from control on L-Dopa (p < 0.025) and by 79% from control on Pergolide (p < 0.001). In addition, Pergolide increased the total sleep time compared to L-Dopa (p < 0.05). In conclusion, the dopamine agonist Pergolide is superior to L-Dopa in the treatment of RLS and NMS.
TL;DR: The data indicate that the increase in neurotrophic factors is a possible mechanism by which (−)nicotine protects from experimental parkinsonisms, and suggest that nAChR agonists could be of potential benefit in the progression of Parkinson's disease.
Abstract: The repeated finding of an apparent protective effect of cigarette smoking on the risk of Parkinson's disease is one of the few consistent results in the epidemiology of this disorder. Among the innumerous substances that originate from tobacco smoke, nicotine is by far the most widely studied, and the most likely candidate for a protective effect against neuronal degeneration in Parkinson's disease. Nicotine is a natural alkaloid that has considerable stimulatory effects on the central nervous system (CNS). Its effects on the CNS are mediated by the activation of neuronal heteromeric acetylcholine-gated ion channel receptors (nAChR, also termed nicotinic acetylcholine receptors). In the present study, we describe the neuroprotective effects of (−)nicotine in two animal models of parkinsonism: the diethyldithiocarbamate (DDC)-induced enhancement of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) toxicity in mice, and the methamphetamine-induced neurotoxicity in rats and mice. In parallel experiments, we found that (−)nicotine induces the basic fibroblast growth factor (FGF-2) and the brain-derived neurotrophic factor (BDNF) in rat striatum. As FGF-2 and BDNF have been reported to be neuroprotective for dopaminergic cells, our data indicate that the increase in neurotrophic factors is a possible mechanism by which (−)nicotine protects from experimental parkinsonisms. Moreover, they suggest that nAChR agonists could be of potential benefit in the progression of Parkinson's disease.
TL;DR: PET was used in a multitracer protocol to evaluate D-amphetamine induced effects on dopamine biosynthesis rate and release in propofol anesthetized Rhesus monkeys and found l-[β-11C]DOPA and [11C?]raclopride suitable to indicate changes in dopamine synthesis rate andrelease respectively and can be used to mirror drug-induced changes of brain dopaminergic function.
Abstract: Positron emission tomography (PET) was used in a multitracer protocol to evaluate D-amphetamine induced effects on dopamine biosynthesis rate and release in propofol anesthetized Rhesus monkeys.l-[β-11C]DOPA was used as biochemical probe to study the brain dopamine biosynthesis rate whilst dopamine release was followed by the binding displacement of the [11C]-radiolabelled dopamine receptor antagonists, raclopride and N-methylspiperone. Studies were performed with either a constant rate intravenous infusion of D-amphetamine aiming at plasma concentrations of 0.2 to 25 ng/ml or with intravenous bolus doses of 0.1 and 0.4 mg/ kg. Decreased binding of the dopamine receptor antagonists was measured in both modes of D-amphetamine administration but notably [11C]N-methylspiperone was less able to sense D-amphetamine induced release of dopamine. At plasma concentrations aimed above 1 ng/ml a levelling off of the binding of [11C]raclopride at 68 ± 8.1% of the baseline value indicated that displacement was only possible from a fraction of the binding sites. Amphetamine was observed to increase the rate constant forl-[β-11C]DOPA utilization in the brain. This was most likely due to an acutely induced subsensitivity of presynaptic dopamine receptors.l-[β-11C]DOPA and [11C]raclopride were found suitable to indicate changes in dopamine synthesis rate and release respectively using PET and can be used to mirror drug-induced changes of brain dopaminergic function.
TL;DR: Results support the hypothesis that clozapine acts at least in part by increasing glutamatergic activity and improve improvement in negative symptoms of schizophrenia.
Abstract: To examine whether serum excitatory amino acid concentrations change with clozapine treatment and whether these changes correlate with improvement in negative symptoms, serum excitatory amino acids were measured and clinical scales administered in seven subjects with schizophrenia before and after switching from conventional neuroleptics to clozapine. Clozapine treatment was associated with increased serum glutamate and aspartate concentrations. Clinical improvement was negatively correlated with baseline glycine concentrations. These results support the hypothesis that clozapine acts at least in part by increasing glutamatergic activity.
TL;DR: Data indicate that glutamate stimulated the HPA axis via the release of ME CRH-41 into the portal circulation and this response is steroid sensitive involving type II glucocorticoid receptors.
Abstract: The effect of local administration of glutamate into the hypothalamic paraventricular nucleus (PVN) on the hypothalamo-pituitary adrenocortical (HPA) axis was studied in male rats. Glutamate caused CRH-41 depletion from the median eminence (ME) and a consequent rise in ACTH and corticosterone (CS) serum levels. In rats pretreated with systemic dexamethasone (dex) these effects were completely inhibited. The administration of the glucocorticoid receptor antagonist RU-38486 abolished the inhibitory effect of dex on the adrenocortical discharge. In addition, the depletion of hypothalamic norepinephrine (NE) and serotonin (5-HT) by specific neurotoxins administered into the ventral noradrenergic blundle or into the raphe nuclei respectively, inhibited the response of serum ACTH and CS following PVN glutamate administration. These data indicate that glutamate stimulated the HPA axis via the release of ME CRH-41 into the portal circulation. This response is steroid sensitive involving type II glucocorticoid receptors. Hypothalamic NE and 5-HT participate in the glutamate induced HPA axis activation.
TL;DR: Investigating if it is possible to strengthen NMDA receptor-mediated neurotransmission by modulating the associated glycine site found it to be possible, and the effects of systemic and intraventricular administration of glycine, D-Serine and L-serine on the hyperactivity induced in mice by the uncompetitiveNMDA receptor antagonist MK-801 were tested.
Abstract: It is well known that the un-competitive N-methyl-D-aspartate (NMDA) receptor antagonist phencyclidine can induce a syndrome in humans that mimics both positive and negative symptoms of schizophrenia. In the light of this observation, it has been hypothesised that schizophrenia might be due to a hypofunction of central glutamate systems. A glycine agonist, by strengthening glutamatergic transmission, has been suggested to be useful as treatment. A crucial issue is the uncertainty regarding the degree of saturation of the glycine site associated with the NMDA receptor. The purpose of this study was to investigate if it is possible to strengthen NMDA receptor-mediated neurotransmission by modulating the associated glycine site. The effects of systemic and intraventricular administration of glycine, D-serine and L-serine on the hyperactivity induced in mice by the uncompetitive NMDA receptor antagonist MK-801 were tested. Systemically administered glycine and D-serine were found to decrease MK-801-induced hyperactivity. Intraventricularly administered D-serine in doses of 50 or 100μg/side was found to decrease MK-801-induced hyperactivity during the second half hour of registration; L-serine given in the same doses did not affect the MK-801-induced hyperactivity during this period. These data may suggest that the NMDA receptor-associated glycine site is not saturated in vivo.
TL;DR: The notion that complex functional interactions between D1 and D2 receptor families occur within the central nervous system is extended and suggested that novel effects might be derived from combined administration of receptor selective agonists and antagonists are suggested.
Abstract: Functional interactions between dopamine receptor subtypes may affect behavioral and biochemical responses which serve as models for neuropsychiatric illnesses and the clinical effects of drug therapy. We evaluated the effects of chronic exposure to the selective D1 receptor antagonist SCH 23390, and the selective D2 receptor antagonist metoclopramide, on spontaneous and drug-induced behavior and receptor density in rats, and then determined how these effects would be modified by concurrent administration of antagonists or agonists [SKF 38393, LY 171555 (quinpirole)] selective for the complementary receptor subtype. Administered alone, both the D1 and D2 antagonists had acute cataleptic effects to which animals became tolerant following chronic treatment, but the selective antagonists had opposing effects on spontaneous locomotor activity. Both antagonists produced equivalent, supersensitive behavioral responses to apomorphine, and resulted in an increase in D2 receptor density. Coadministration of the D1 and D2 antagonists had a synergistic effect on catalepsy, attenuated the effects on spontaneous locomotor activity observed with either drug alone, and had an additive effect on both apomorphine-induced stereotypic behavior and D2 receptor proliferation. On the other hand, when either selective antagonist was combined with the agonist selective for the complementary receptor subtype, both D2 receptor proliferation and behavioral supersensitivity were completely blocked. Combined antagonist-agonist treatments had opposing effects on the development of tolerance to antagonist-induced catalepsy. D2 - but not D1 - receptor densities were correlated with animals' behavioral responses to apomorphine. There results support and extend the notion that complex functional interactions between D1 and D2 receptor families occur within the central nervous system, and suggest that novel effects might be derived from combined administration of receptor selective agonists and antagonists.
TL;DR: The results suggest that homozygosity for thermolabile MTHFR is a risk factor for schizophrenia-like psychosis and this risk may be reduced by folate supplementation.
Abstract: The gene for methylenetetrahydrofolate reductase (MTHFR) has shown polymorphism in the general human population. In its homozygous form, a C677T mutation occurs in more than 5% of the grown-up population and produces a thermolabile variant which reduces the overall enzyme activity to less than 30% of normal. We investigated patients with schizophrenia-like psychosis. If hyperhomocysteinemic, their DNA-genotype for thermolabile C677T mutation was determined. Seven of 11 patients, six males and one female, were homozygous for thermolabile MTHFR. One male patient was heterozygous and all three normal homozygotes were females. In the patients who were homozygous for the C677T mutation, the homocysteine concentrations did not respond to vitamin B12 but were normalized by folate supplementation. In the normal homozygotes, however, the homocysteine concentrations were reduced by vitamin B12 alone. Our results suggest that homozygosity for thermolabile MTHFR is a risk factor for schizophrenia-like psychosis. Possibly, this risk may be reduced by folate supplementation.
TL;DR: Fluoxetine's action leading to an increase in extracellular norepinephrine was not occurring in the terminal areas of the hypothalamus but elsewhere in the brain, possibly cell bodies in the locus coeruleus.
Abstract: The selective serotonin uptake inhibitor fluoxetine (10mg/kg i.p.) increased tissue levels of the norepinephrine metabolite 3-methoxy-4-hydroxyphenylethylene glycol sulfate (MHPG-SO4) in rat hypothalamus, indicating an increased release of norepinephrine. Microdialysis studies in conscious rats showed that fluoxetine (10 mg/kg i.p.) increased extracellular concentrations of norepinephrine as well as serotonin in the hypothalamus. In contrast, desipramine (10mg/kg i.p.) increased extracellular concentration of norepinephrine but not serotonin in the hypothalamus. Consistent with its mechanism of being a selective serotonin uptake inhibitor, local perfusion of fluoxetine (10μM) caused a 7-fold increase in hypothalamic extracellular serotonin and a small non-significant increase in extracellular norepinephrine. The subsequent systemic injection of fluoxetine (10mg/kg s.c.) after local perfusion caused a 3-fold increase in extracellular norepinephrine, indicating that fluoxetine's action leading to an increase in extracellular norepinephrine was not occurring in the terminal areas of the hypothalamus but elsewhere in the brain, possibly cell bodies in the locus coeruleus.
TL;DR: The allele frequency for −108Val was higher in PD patients compared with controls, although the differences did not reach the statistical significance, and COMT gene polymorphism may constitute a genetic risk factor for PD among Japanese.
Abstract: We report −108Met/Val polymorphism of the COMT gene in Japanese patients with Parkinson's disease (PD). The allele frequency for −108Val was higher in PD patients compared with controls, although the differences did not reach the statistical significance. However, the frequency of -108Val homozygotes was significantly higher in PD patients (56.8%) than in control subjects (44.2%), and heterozygotes of −108Met/Val were less in PD. COMT gene polymorphism may constitute a genetic risk factor for PD among Japanese.
TL;DR: The results obtained in this study indicate that the levels of mRNA coding for dopamine D1 and D2 receptors are regulated by the antidepressant drugs.
Abstract: The present study examined the effects of acute and repeated administration of three antidepressant drugs (imipramine, citalopram and (+)-oxaprotiline) on the levels of mRNA coding for dopamine D1 and D2 receptors in the rat brain. Quantitive in situ hybridization with 35S-labelled oligonucleotide probes has been utilised. The level of mRNA coding for dopamine D1 receptor (D1 mRNA) is decreased following repeated administration of imipramine, both in the nucleus accumbens and in the striatum. On the other hand, the repeated administration of citalopram, the selective inhibitor of serotonin reuptake, resulted in an increase in the level of D1 mRNA in the striatum and in the core region of nucleus accumbens. A similar tendency, i.e.: an increase in the level of D1 mRNA was observed after repeated administration of (+)-oxaprotiline, a selective inhibitor of noradrenaline reuptake. The level of mRNA coding for dopamine D2 receptors (D2 mRNA) was increased in all the brain regions studied, both after administration of imipramine and citalopram. (+)-Oxaprotiline did not produce any statistically significant changes in the level of D2 mRNA. The results obtained in this study indicate that the levels of mRNA coding for dopamine D1 and D2 receptors are regulated by the antidepressant drugs. The changes concerning the dopamine D2 receptors are more consistent and fit in with the previously described binding and behavioral effects and seem to be important for the mechanism of action of antidepressant drugs.
TL;DR: The results suggest that moderate-to-high doses of PBN whether injected in a single dose prior to MPTP or subchronically following MPTP injections may afford protective effects against both the functional changes and DA-loss caused by MPTP treatment, possibly through an antioxidant mechanism.
Abstract: In Experiment 1, groups of mice were administered either saline or MPTP (2 × 30mg/kg, s.c., separated by a 24-hr interval) 30min after being injected either PBN (15, 50 or 150mg/kg, s.c., low, medium and high doses, respectively) or L-Deprenyl (0.25 or 10.0mg/kg, s.c., low and high doses, respectively), the reference compound used, or saline. Tests of spontaneous motor activity 14 days later indicated that the MPTP-induced hypokinesia for locomotion and rearing was alleviated by prior administration with PBN (50 or 150mg/kg) or L-Deprenyl (10.0mg/kg); lower doses of PBN (15mg/kg) and L-Deprenyl (0.25mg/kg) did not affect the MPTP-induced deficits. Dopamine (DA) concentrations in the striatum confirmed a more severe loss of DA in the MPTP, PBN(15) + MPTP and Deprenyl(0.25) + MPTP groups than in the control group. Significant protection of DA was observed in the PBN(50) + MPTP, PBN(150) + MPTP and Deprenyl(10) + MPTP groups that did not exhibit an hypokinetic behaviour. In Experiment 2, the effects of repeated treatment with PBN (50mg/kg, s.c. over 12 days), post-MPTP, were studied in aged (15-month-old) and young (3-month-old) mice. Subchronic administration of PBN increased substantially the motor activity of old and young mice that had received MPTP. Aged control (saline) mice showed an activity deficit compared to young control mice; this deficit was abolished by repeated PBN treatment. The results suggest that moderate-to-high doses of PBN whether injected in a single dose prior to MPTP or subchronically following MPTP injections may afford protective effects against both the functional changes and DA-loss caused by MPTP treatment, possibly through an antioxidant mechanism.