Showing papers in "Journal of Neural Transmission in 1996"
TL;DR: The present contribution starts out by describing some of the clinical, pathological and neurochemical phenomena of Parkinson's disease, and hypotheses concerning the mechanisms of these neurotoxines have been related to the pathogenesis of nigral cell death in PD.
Abstract: Animal models are an important aid in experimental medical science because they enable one to study the pathogenetic mechanisms and the therapeutic principles of treating the functional disturbances (symptoms) of human diseases Once the causative mechanism is understood, animal models are also helpful in the development of therapeutic approaches exploiting this understanding On the basis of experimental and clinical findings Parkinson's disease (PD) became the first neurological disease to be treated palliatively by neurotransmitter replacement therapy The pathological hallmark of PD is a specific degeneration of nigral and other pigmented brainstem nuclei, with a characteristic inclusion, the Lewy body, in remaining nerve cells There is now a lot of evidence that degeneration of the dopaminergic nigral neurones and the resulting striatal dopamine-deficiency syndrome are responsible for its classic motor symptoms akinesia and bradykinesia PD is one of many human diseases which do not appear to have spontaneously arisen in animals The characteristic features of the disease can however be more or less faithfully imitated in animals through the administration of various neurotoxic agents and drugs disturbing the dopaminergic neurotransmission The cause of chronic nigral cell death in PD and the underlying mechanisms remain elusive The partial elucidation of the processes underlie the selective action of neurotoxic substances such as 6-hydroxydopamine (6-OHDA) or 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), has however revealed possible molecular mechanisms that give rise to neuronal death Accordingly, hypotheses concerning the mechanisms of these neurotoxines have been related to the pathogenesis of nigral cell death in PD The present contribution starts out by describing some of the clinical, pathological and neurochemical phenomena of PD The currently most important animal models (eg the reserpine model, neuroleptic-induced catalepsy, tremor models, experimentally-induced degeneration of nigro-striatal dopaminergic neurons with 6-OHDA, methamphetamine, MPTP, MPP+, tetrahydroisoquinolines, β-carbolines, and iron) critically reviewed next, and are compared with the characteristic features of the disease in man
492 citations
TL;DR: Presently available data support the view that the occurrence of additional lesions in the form of AD stage III (or more) destruction is the most common cause of intellectual decline in PD.
Abstract: Alzheimer's disease (AD) and Parkinson's disease (PD) are the most common age-related degenerative disorders of the human brain Both diseases involve multiple neuronal systems and are the consequences of cytoskeletal abnormalities which gradually develop in only a small number of neuronal types In AD, susceptible neurons produce neurofibrillary tangles (NFTs) and neuropil threads (NTs), while in PD, they develop Lewy bodies (LBs) and Lewy neurites (LNs) The specific lesional pattern of both illnesses accrues slowly over time and remains remarkably consistent across cases In AD, six developmental stages can be distinguished on account of the predictable manner in which the neurofibrillary changes spread across the cerebral cortex The pathologic process commences in the transentorhinal region (clinically silent stages I and II), then proceeds into adjoining cortical and subcortical components of the limbic system (stages III and IV - incipient AD), and eventually extends into association areas of the neocortex (stages V and VI - fully developed AD) During the course of PD, important components of the limbic system undergo specific lesions as well The predilection sites include the entorhinal region, the CA2-sector of the hippocampal formation, the limbic nuclei of the thalamus, anterior cingulate areas, agranular insular cortex (layer VI), and - within the amygdala - the accessory cortical nucleus, the ventromedial divisions both of the basal and accessory basal nuclei, and the central nucleus The amygdala not only generates important projections to the prefrontal association areas but also exerts influence upon all non-thalamic nuclei which in a non-specific manner project upon the cerebral cortex and upon the nuclei regulating endocrine and autonomic functions All these amygdala-dependent structures themselves exhibit severe PD-specific lesions In general, the extranigral destructions are in themselves not sufficient to produce overt intellectual deterioration Similarly, AD-related pathology up to stage III may be asymptomatic as well Fully developed PD with concurring incipient AD, however, is likely to cause impaired cognition Presently available data support the view that the occurrence of additional lesions in the form of AD stage III (or more) destruction is the most common cause of intellectual decline in PD
307 citations
TL;DR: No significant differences in rab3a levels were found in any brain region between AD patients possessing different numbers of the apolipoprotein E4 allele, suggesting that, although ApoE4 is a risk factor for earlier development of AD, the degree of synaptic pathology does not differ between patients with or without the ApOE4 allele.
Abstract: Alzheimer's disease (AD) is characterised by an increased number of senile plaques (SP) and neuroflbrillary tangles (NFT) as compared with that found in non-demented individuals of the same age, and a marked degeneration and loss of synapses. One of the main risk-factors for the disorder is inheritance of the apolipoprotein E4 (ApoE4) allele. To further study the relation between these pathogenetic substrates for AD, we quantified the synaptic vesicle membrane protein rab3a in brain tissue from 19 patients with AD and 9 age-matched control subjects. Rab3a levels were reduced in AD, both in the hippocampus (60% of control level, p < 0.0001), and in the frontal cortex (68% of control level, p < 0.01), but not in the cerebellum (92% of control level). Within the AD group, lower rab3a levels were found both with increasing duration and severity of dementia. These findings further support that synaptic pathology is closely correlated to the clinical dementia in AD. In contrast, no significant correlations were found between SP counts and duration or severity of dementia, while higher NFT counts in the frontal cortex were found with increasing severity of dementia (r=0.54, p < 0.05). There were no significant correlations between the rab3a level and SP or NFT counts, and by immunohistochemistry, reduced rab3a immunostaining was found throughout the neuropil in AD brain, without relation to SP or NFT. These findings suggest that the synaptic pathology in AD is not closely related to the presence of SP and NFT. No significant differences in rab3a levels were found in any brain region between AD patients possessing different numbers of the ApoE4 allele, suggesting that, although ApoE4 is a risk factor for earlier development of AD, the degree of synaptic pathology does not differ between patients with or without the ApoE4 allele.
190 citations
TL;DR: The results suggest that simultaneous determination of ACh and Ch concentrations in CSF may be useful for differentiating VDBt/MSID from ATD and that increasing the ACh level using cholinergic agents may be a beneficial therapeutic strategy for the treatment of ATD as well as VDBT/MSIT, and is worthy of further investigation.
Abstract: The acetylcholine (ACh) and choline (Ch) concentrations in the cerebrospinal fluid were investigated in patients with vascular dementia of the Binswanger type (VDBT) or multiple small infarct type (MSID) as compared with patients with Alzheimer-type dementia (ATD). The ACh concentration in patients with ATD was found to be significantly lower than in controls (73%, p < 0.0001), and showed a significant positive correlation with dementia scale scores (rs=0.63, p < 0.03). The Ch concentration in the CSF of ATD patients was approximately the same as in controls. In VDBT/MSID patients, the ACh concentration was significantly lower than in controls (p < 0.001), also showing a significant positive correlation with dementia scale scores (rs=0.62, p < 0.02), but was significantly higher than in ATD patients (p < 0.001). Moreover, the Ch concentration in VDBT/MSID patients was significantly higher than in controls (p < 0.001) or ATD patients (p < 0.001). These results suggest that simultaneous determination of ACh and Ch concentrations in CSF may be useful for differentiating VDBT/MSID from ATD and that increasing the ACh level using cholinergic agents may be a beneficial therapeutic strategy for the treatment of ATD as well as VDBT/MSIT, and is worthy of further investigation.
153 citations
TL;DR: The present results increase the degree of analogy between the two burst phenomena, thereby adding extra support to the contention that the cortex is involved in producing the natural bursting in DA neurons.
Abstract: Evidence suggests that the prefrontal cortex (PFC) plays an important role in the burst activity of midbrain dopaminergic (DA) neurons. In particular, electrical stimulation of the PFC elicits patterns of activity in DA neurons, closely time-locked to the stimulation, which resemble natural bursts. Given that natural bursts are produced by the activity of excitatory amino acid (EAA)-ergic afferents, if PFC-induced time-locked bursts are homologues of natural bursts, EAA antagonists should attenuate them. Hence, the NMDA (N-methy1-D-aspartate) antagonist CPP (3-((±)-2-carboxypiperazin-4-yl)propyl-1-phosphonic acid) and the AMPA (D,L-α-amino-3-hydroxy-5-methyl-4-isoxalone propionic acid)/kainate antagonist CNQX (6-cyano-7-nitroquinoxaline-2,3-dione) were applied by iontophoresis to DA neurons exhibiting time-locked bursts during PFC stimulation. CPP produced a significant reduction in time-locked bursting. In contrast, CNQX (at currents which antagonised AMPA responses) did not. These effects of CPP and CNQX on time-locked bursting mirror the effects previously reported for these drugs on natural bursting. Since natural bursting and bursting induced by PFC stimulation are both blocked selectively by CPP, the present results increase the degree of analogy between the two burst phenomena, thereby adding extra support to the contention that the cortex is involved in producing the natural bursting in DA neurons.
102 citations
TL;DR: The slight increase in the concentration of glutamate together with the reduced levels of GABA, glycine, and serine in CSF may form the neurochemical basis of the central oscillation observed in essential tremor.
Abstract: The concentrations of amino acids in the cerebrospinal fluid (CSF) (n = 20) and serum (n = 20) taken from patients with essential tremor were measured by HPLC and compared with those of controls (n = 10). Reduced concentrations of some amino acids (asparagine, glutamine, glycine, threonine, isoleucine, leucine) were observed in serum taken from patients with tremor. Significant increases were detected in the concentrations of glutamate (p < 0.001) and aspartate (p < 0.01). The general tendency of the changes in CSF and serum was similar; although the highest differences were observed in amino acid concentrations in the serum of patients with essential tremor. Opposite shifts of some amino acids were detected, in the concentrations of aspartate, serine, tyrosine, leucine, and isoleucine, which may indicate the independence of the changes in the serum from those in the CSF. This study raises the possibility that a genetically determined metabolic disorder is involved in the etiology of essential tremor that appears peripherally and, partly, centrally. The slight increase in the concentration of glutamate together with the reduced levels of GABA, glycine, and serine in CSF may form the neurochemical basis of the central oscillation observed in essential tremor.
82 citations
TL;DR: CSF levels of norharman and harman in PD were significantly higher compared to controls, suggesting a possible role of harman and norHarman or its N-methylated carbolinium ions in the pathophysiological processes initiating PD.
Abstract: Death of dopaminergic neurons in Parkinson's disease (PD) may partially be caused by synthesis and accumulation of endogenous and exogenous toxins. Because of structural similarity to MPTP, beta-carbolines, like norharman and harman, have been proposed as putative neurotoxins. In vivo they may easily be formed by cyclization of indoleamines with e.g. aldehydes. For further elucidation of the role of beta-carbolines in neurodegenerative disorders harman and norharman levels in cerebrospinal fluid (CSF) were measured in 14 patients with PD and compared to an age- and sex-matched control group (n = 14). CSF levels of norharman and harman in PD were significantly higher compared to controls. These results may suggest a possible role of harman and norharman or its N-methylated carbolinium ions in the pathophysiological processes initiating PD. However the origin of increased levels of these beta-carbolines remains unclear. On the one hand one may speculate, that unknown metabolic processes induce the increased synthesis of harman and norharman in PD. On the other hand a possible impact of exogenous sources may also be possible.
81 citations
TL;DR: It is suggested that IL-2 but not bFGF may relate to the compensatory response in the nigrostriatal dopaminergic regions in parkinsonian brain during progress of neurodegeneration.
Abstract: The contents of interleukin (IL)-2 and basic fibroblast growth factor (bFGF) were measured in the brain (caudate nucleus, putamen, and cerebral cortex) from control and parkinsonian patients by highly sensitive enzyme-linked immunosorbent assay (ELISA). The concentrations of IL-2 in the brain were in the order of pg/mg protein, and the values were significantly higher in the caudate and putamen from parkinsonian patients than those from control patients. However, the levels of IL-2 in the cerebral cortex showed no significant difference between parkinsonian and control patients. In contrast to IL-2, the bFGF levels in the brain were high and in the order of ng/mg protein, and there was no significant difference in the caudate and putamen between parkinsonian and control patients. Although both IL-2 and bFGF may play important roles in dopaminergic neurons as neurotrophic factors, IL-2 but not bFGF may relate to the compensatory response in the nigrostriatal dopaminergic regions in parkinsonian brain during progress of neurodegeneration.
78 citations
TL;DR: The data suggest that GDNF is probably expressed at a very low level in the adult human brain and its involvement in the pathophysiology of Parkinson's disease remains to be demonstrated, however, GDNF may represent a powerful new therapeutic agent for Parkinson's Disease.
Abstract: Glial cell line-derived neurotrophic factor (GDNF) is a potent neurotrophic factor for dopaminergic neurons. Since dopaminergic neurons degenerate in Parkinson's disease, this factor is a potential therapeutical tool that may save dopaminergic neurons during the pathological process. Moreover, a reduced GDNF expression may be involved in the pathophysiology of the disease. In this study, we tested whether altered GDNF production may participate in the mechanism of cell death in this disease. GDNF gene expression was analyzed by in situ hybridization using riboprobes corresponding to a sequence of the exon 2 human GDNF gene. Experiments were performed on tissue sections of the mesencephalon and the striatum from 8 patients with Parkinson's disease and 6 control subjects matched for age at death and for post mortem delay. No labelling was observed in either group of patients. This absence of detectable expression could not be attributed to methodological problems as a positive staining was observed using the same probes for sections of astroglioma biopsies from human adults and for sections of a newborn infant brain obtained at post-mortem. These data suggest that GDNF is probably expressed at a very low level in the adult human brain and its involvement in the pathophysiology of Parkinson's disease remains to be demonstrated. GDNF may represent a powerful new therapeutic agent for Parkinson's disease, however.
75 citations
TL;DR: The results of this study suggest that low CSF levels of HVA and a high 5-S-CyS-DA/HVA ratio together might represent useful markers for early diagnosis of Parkinson's Disease.
Abstract: High-performance liquid chromatography with electrochemical detection has been employed to analyze ultrafiltrates of cerebrospinal fluid of Parkinson's Disease (PD) patients and age-matched controls for the dopamine (DA) metabolites homovanillic acid (HVA) and 5-S-cysteinyldopamine (5-S-CyS-DA). The mean level of HVA in the CSF of PD patients, measured 5 days after withdrawal from L-DOPA therapy, was significantly lower than that measured in controls. By contrast, mean levels of 5-S-CyS-DA were not significantly different in the CSF of PD patients taking L-DOPA (PD-LT patients) the same patients 5 days after discontinuing this drug (PD-LW patients) or controls. However, the mean 5-S-CyS-DA/HVA concentration ratio was significantly (p < 0.05) higher in the CSF of PD-LW patients compared to controls. Although the PD patient population employed in this study had been diagnosed with the disease several years previously and had been treated with L-DOPA for prolonged periods of time the results of this study suggest that low CSF levels of HVA and a high 5-S-CyS-DA/HVA ratio together might represent useful markers for early diagnosis of PD. The high 5-S-CyS-DA/HVA ratio observed in the CSF of PD-LW patients also provides support for the hypothesis that the translocation of glutathione or L-cysteine into neuromelanin-pigmented dopaminergic cell bodies in the substantia nigra might represent an early event in the pathogenesis of PD.
65 citations
TL;DR: Repeated TMS (9 days) reduced β-adrenergic receptor binding in cortex, as does electroconvulsive shock (ECS) and other antidepressant treatments, and TMS appears to be a potential antidepressive treatment.
Abstract: Recently, a method for transcranial magnetic stimulation (TMS) of the brain has been developed. Thus, it is possible to explore neurochemical and behavioral effects of TMS in rats. Repeated TMS (9 days) reduced β-adrenergic receptor binding in cortex, as does electroconvulsive shock (ECS) and other antidepressant treatments. Thus TMS appears to be a potential antidepressive treatment.
TL;DR: Evidence is provided that 5-HT release in the dorsal raphé is dependent on the opening of fast activated sodium channels and that dorsal rapho-HT1a receptors control somatodendritic and hippocampal 5- HT release.
Abstract: Somatodendritic and terminal release of serotonin (5-HT) was investigated by simultaneously measuring extracellular concentrations of 5-HT, 5-hydroxyindole-3-acetic acid (5-HIAA) and homovanillic acid (HVA) in the dorsal raphe and ventral hippocampus in freely moving rats. Perfusion of tetrodotoxin (TTX, 1μM and 10μM) into the dorsal raphe simultaneously decreased dorsal raphe and hippocampal 5-HT release. However, following TTX perfusion into the hippocampus (10μM), hippocampal 5-HT release was profoundly reduced but dorsal raphe 5-HT remained unchanged.
TL;DR: Partial substitution of levodopa by bromocriptine (>30%) as first-line treatment of Parkinson's disease proves active in the prophylaxis oflevodopa associated motor side effects.
Abstract: Long-term levodopa treatment in Parkinson's disease is typically associated with “motor side effects” consisting in dyskinesias and/or fluctuations in motility referred to as the on-off phenomena. The main objective of this prospective, randomized, multi-centre study was to determine to what extent the development of such complications could be prevented by partial substitution of levodopa monotherapy (L-DOPA/benserazide) by bromocriptine in patients with early symptoms of the disease. The basic trial population included 674 newly diagnosed Parkinsonian patients that were randomly allocated to monotherapy with levodopa or a combination therapy based upon a nearly 40% replacement of levodopa by bromocriptine. The two target regimens had to be consistently maintained for 42 months. Parkinsonian symptoms were assessed by means of the Webster rating scale, the Hoehn and Yahr scale, and the Zung Self-Rating Depression scale. Motor side effects and adverse events were recorded at each regular clinic visit. Neurological symptoms improved and stabilized in a similar manner during treatment with both regimens throughout the study period. Motor side effects were observed in more patients on levodopa alone than on combination therapy (28.8 vs 20%; p=0.008). According to Kaplan-Meier estimates the cumulative probability of experiencing motor side effects was 0.43 on monotherapy, compared to 0.28 on combination therapy, which was equal to a one third reduction of risk (p=0.025). In regard to motor side effects, the degree of substitution of levodopa proved relevant: patients with >50% substitution by bromocriptine exhibited half the risk observed in those with 30%) as first-line treatment of Parkinson's disease proves active in the prophylaxis of levodopa associated motor side effects. Early combination therapy therefore extends the period of optimal disease control.
TL;DR: Monoamine (norepinephrine, dopamine, serotonin) and metabolite endogenous levels were determined in the rat medial vestibular nucleus (MVN) using HPLC with electrochemical detection to suggest the presence of non precursor specific dopaminergic pools.
Abstract: Monoamine (norepinephrine, dopamine, serotonin) and metabolite endogenous levels were determined in the rat medial vestibular nucleus (MVN) using HPLC with electrochemical detection. As a comparison, the locus cœruleus (LC) and dorsal raphe nucleus (RD) which contain the cell bodies of MVN noradrenergic and serotoninergic neurons respectively were also analyzed. Norepinephrine (NE) and serotonin (5-HT) basal levels of MVN were high (33.8 and 39.2pmol/mg protein respectively) but lesser than in LC or RD. Great amounts of MHPG and 5-HIAA were also present in the MVN. The turnover of NE assessed both from the ratio MHPG/NE and by the decrease in the NE content after treatment with α-methylparatyrosine was faster in the MVN (half-life∶ 1.5h) than in LC (half-life∶ 3.6h). On the other hand, the ratio 5-HIAA/5-HT was lower in the MVN (0.58) than in the RD (0.85) indicating a smaller 5-HT turnover in the MVN. In addition, like LC and RD, the MVN contained meaningful amounts of dopamine (DA) and DOPAC. The high ratio DA/NE (0.27) suggests the presence of non precursor specific dopaminergic pools. However, individualized dopaminergic neurons have not yet been demonstrated. The data are discussed in line with the possible neurotransmitter function of monoamines in the MVN.
TL;DR: The data are supportive of the view that MDMA-induced toxicity of 5-HT neurons may be related to the production of free radicals and subsequent oxidative damage.
Abstract: The extent of long-term depletion of serotonin (5-HT) produced by 3, 4-methylenedioxymethamphetmaine (MDMA) was assessd in rats treated with the antioxidants sodium ascorbate or L-cysteine. There was a 30–35% reduction in the striatal concentration of 5-HT 7 days following a single injection of MDMA (20mg/kg, sc). MDMA had no significant effect on striatal concentrations of 5-HT in rats that had been treated with ascorbate (250mg/kg, ip) or cysteine (500mg/kg, ip) 30 min prior to and 5hrs following the administration of MDMA. Treatment with ascorbate or cysteine did not alter the accumulation of MDMA in brain as determined by in vivo microdialysis. Moreover, neither ascorbate nor cysteine altered the stimulation of dopamine release elicited by MDMA. These data are supportive of the view that MDMA-induced toxicity of 5-HT neurons may be related to the production of free radicals and subsequent oxidative damage.
TL;DR: It is speculated that the clinical expression of “stable” or “wearing-off” depends on the absorption of levodopa as well as the presynaptic terminal and post synaptic receptors.
Abstract: Effects of the chronic administration of levodopa on its peripheral pharmacokinetics and the contribution of the pharmacokinetics to the pathogenesis of the wearing-off phenomenon are re-evaluated. The concentration of plasma levodopa and clinical symptoms were determined 4 hours after oral levodopa (levodopa 100 mg + benserazide 25 mg) administration on 55 parkinsonian patients. Long-term levodopa therapy markedly increased the peak levodopa concentration (Cmax) and the area under the time-concentration curve (AUC); whereas, it decreased time to the peak concentration (Tmax) and the elimination half-life (T1/2). These results suggest that long-term levodopa therapy accelerates the absorption of levodopa. The wearing-off group (n = 23), however, had a markedly higher Cmax and AUC, and a shorter Tmax and T1/2 than the stable group (n = 32). We speculate that the clinical expression of "stable" or "wearing-off" depends on the absorption of levodopa as well as the presynaptic terminal and post synaptic receptors.
TL;DR: It is suggested that biochemical markers of depression in CSF of PD may be influenced by antiparkinsonian therapy and that depression in PD may respond to serotonin reuptake inhibitors mainly in later stages of PD.
Abstract: Introduction. Etiology of depression in Parkinsons disease (PD) is associated with serotonergic dysfunction. Previous studies, supporting this hypothesis, were performed on patients treated with antiparkinsonian drugs. To eliminate the influence of parkinsonian drug therapy and to elucidate significance of different biochemical pathways in PD associated with depression we determined levels of biogenic amines in cerebrospinal fluid (CSF) of 26 untreated “de novo” Parkinsonian patients.Material and methods. Patients were scored with the Hamilton depression scale (HD) and subdivided into groups with HD score ≥ 18 and HD score <18. Diagnosis of depression was made according to DSM III R. Both groups were matched for age and motor disability.Results. In both groups no significant differences appeared between CSF levels of dopamine, noradrenaline, 3,4-dihydroxyphenylacetic acid, homovanillic acid, 3-methoxy-4-hydroxyphenylglycol and 5-hydroxyindole acetic acid, determined by high-performance liquid chromatography.Discussion. In contrast to previous studies on treated Parkinsonian patients no sign of altered serotonin metabolism especially in context with severity of depression in early stages of PD was found. Due to our results, we suggest, that biochemical markers of depression in CSF of PD may be influenced by antiparkinsonian therapy and that depression in PD may respond to serotonin reuptake inhibitors mainly in later stages of PD.
TL;DR: Impaired aiming may be explained by diminished ability for complex, semivoluntary movements in depressive Parkinsonian patients, as determined by the subtest aiming of the Motor Performance Test Series.
Abstract: The Motor Performance Test Series (MPTS) is widely used for treatment control in Parkinson's disease (PD). To elucidate the possible influence of depression on the fine motor skills in PD, 54 patients with idiopathic PD were investigated with the MPTS. 27 patients with major intensity of depression were compared to 27 age and motor disability matched patients with minor symptoms of depression, evaluated by the Zung depression scale. As determined by the subtest aiming, a significant lower ability for precise, quick complex arm-hand movements in depressed Parkinsonian patients was found. This result may be explained partly by motivation deficits in depressed patients with PD. On the other hand impairment of special motor loops including frontal lobe projections to specific thalamic subnuclei or to the caudate nucleus may cause disturbances of the subtest aiming in depressed Parkinsonian patients. On the basis of these findings impaired aiming may be explained by diminished ability for complex, semivoluntary movements in depressive Parkinsonian patients. The influence of psychiatric comorbidity on MPTS subtest aiming has to be considered in further therapy studies using evaluation of motor deficits by MPTS.
TL;DR: The results indicate that the behaviourally depressive and DA increasing effects of GHBA and baclofen are mediated by activation of GABAB-receptors.
Abstract: Previous studies have shown that administration of γ-hydroxybutyric acid (GHBA) or baclofen is associated with a decrease in locomotor activity as well as an increase of dopamine (DA) in brain. In the present study we analyse whether these actions are related to activation of GABA B -receptors utilising a GABA B -receptor antagonist, CGP 35348. Administration of GHBA (200 or 800 mg/kg, i.p.) or baclofen (4 or 16 mg/kg, i.p.) induced a marked and dose-dependent decrease in locomotor activity in mice, that was antagonised by pretreatment with CGP 35348 (400 mg/kg, i.p.). Treatment with the highest doses of GHBA and baclofen produced clear-cut increases in forebrain DA concentration. Also these effects were effectively antagonised by pretreatment with CGP 35348. Treatment with the GABA B -receptor antagonist alone did not influence the locomotor activity or brain DA concentration. These results indicate that the behaviourally depressive and DA increasing effects of GHBA and baclofen are mediated by activation of GABA B -receptors.
TL;DR: Reductions in the initial inhibition were not systematically related to reductions in time-locked bursting, and the phenomena do not appear to be causally related.
Abstract: Electrical stimulation of the prefrontal cortex produces an inhibition-excitation (IE) activity pattern in the majority of responsive midbrain dopaminergic neurons. The excitatory phase often contains events, time-locked to the stimulation, which resemble natural bursts. The present study investigated the relationship between the inhibition and time-locked bursts by reducing the impact of the inhibition through membrane hyperpolarisation with the dopamine agonist apomorphine (i.v.) or antagonism with the GABAA antagonist picrotoxin (i.v. and iontophoretic). Apomorphine abolished or reduced time-locked bursting in all IE cells. Picrotoxin reduced the initial inhibition in the majority of IE cells, and abolished or reduced time-locked bursting at the highest intravenous dose. However, reductions in the initial inhibition were not systematically related to reductions in time-locked bursting. Hence, the phenomena do not appear to be causally related. Instead, time-locked bursts appear to be based on a straightforward excitation, which makes them closely analogous to natural bursts.
TL;DR: The data indicate that some dopamine antagonists behave as inverse agonists, and thus appear to inhibit an agonist-independent activity of the D3 receptor on [3H]thymidine incorporation pathway, but not on the cAMP pathway.
Abstract: In NG 108-15 cells expressing the recombinant human D3 receptor, dopamine agonists enhance [3H]thymidine incorporation and decrease cAMP accumulation. In these cells, but not in wild type cells, haloperidol, fluphenazine, and various other antipsychotics inhibited basal [3H]thymidine incorporation in a concentration-dependent manner. In contrast, other dopamine antagonists such as nafadotride or (+)AJ 76, two D3-preferring antagonists, were without effect. The concentration-response curve of haloperidol was shifted to the right in presence of nafadotride, with a potency compatible with its nanomolar apparent affinity as neutral antagonist. Pertussis toxin treatment abolished or markedly reduced the responses to haloperidol or fluphenazine. In contrast, no significant enhancement of cAMP accumulation could be observed, under the influence of haloperidol or eticlopride. These data indicate that some dopamine antagonists behave as inverse agonists, and thus appear to inhibit an agonist-independent activity of the D3 receptor on [3H]thymidine incorporation pathway, but not on the cAMP pathway.
TL;DR: The number of serotonin transporter sites is not altered in Brodmann area 9 in suicide, and that fewer3H-paroxetine and 3H-imipramine binding sites found in this region of cerebral cortex of suicides may be explained by a reduction in the nontransporter binding sites.
Abstract: Suicide has been associated with decreased serotonin transmission Measurement of concentrations of serotonin, its precursors tryptophan (TRY) and 5-hydroxytryptophan (5-HTP) and its metabolite 5-hydroxyindoleacetic acid (5-HIAA), have been used as indices of serotonin activity, and with serotonin transporter binding, are indices of the integrity of serotonin nerve terminals Most previous studies have not distinguished high affinity transporter binding from a very similar nontransporter binding site, where binding is not dependent on Na+ or Cl- and that does not have a known functional role We therefore, assayed binding kinetics in prefrontal (PFC) and temporal cortex (TC) in matched pairs of suicide victims and controls using the selective ligand 3H-paroxetine, and employing 1 microM sertraline to define specific binding to the transporter and 10 microM sertraline which also displaces binding to the high affinity, nontransporter site In addition, we measured concentrations of TRY, 5-HTP, serotonin and 5-HIAA in the same brain areas The total number of 3H-paroxetine transporter and nontransporter binding sites (Bmax), was lower in the suicide group compared to controls in both Brodmann area 9 (prefrontal cortex; p = 002) and in Brodmann area 38 (temporal cortex, p = 001) In contrast, no differences were found in the number of high affinity transporter binding sites and concentrations of serotonin, 5-HIAA, 5-HTP or TRY (p > 005) We conclude that the number of serotonin transporter sites is not altered in Brodmann area 9 in suicide, and that fewer 3H-paroxetine and 3H-imipramine binding sites found in this region of cerebral cortex of suicides may be explained by a reduction in the nontransporter binding sites
TL;DR: The data suggest that genetically determined structural variation of the A2aAR does not play a major role in the development of schizophrenia, and further investigation of the patient's family revealed independent segregation between the Ser-340 variant and psychiatric illness.
Abstract: Several lines of evidence suggest an involvement of adenosine A2a receptor (A2aAR) mediated adenosinergic neuromodulation in the etiopathogenesis of schizophrenia We therefore perfomed a systematic mutation scan of the complete coding region of the human A2aAR gene in a sample of 42 schizophrenic patients We detected one rare naturally occurring receptor variant (Gly-340-Ser) and two silent mutations (405C/T and 1083C/T) To our knowledge the Gly-340-Ser substitution is the first naturally occurring molecular variant of the A2aAR identified Determining the frequency of the three variants in 42 unrelated healthy controls, we observed a significant trend towards an overrepresentation of the 1083T variant in patients when compared to controls (p=0041) This trend was followed up in a large independent replication sample However, we were not able to confirm the original trend in the second sample (p=0367) The Ser-340 variant was found in a single schizophrenic individual Investigation of the patient's family revealed independent segregation between the Ser-340 variant and psychiatric illness Our data suggest that genetically determined structural variation of the A2aAR does not play a major role in the development of schizophrenia
TL;DR: It would seem that the changes in the affinity of [3H]paroxetine binding to the hippocampus of schizophrenic subjects are not likely to be due to neuroleptic drug treatment but may be involved in the pathology of the illness.
Abstract: [3H]paroxetine binding to membrane from hippocampus, obtained at autopsy, from 24 schizophrenic and 24 non-schizophrenic subjects has been measured. The affinity of [3H]paroxetine binding to hippocampal membrane was decreased in subjects with schizophrenia (Kd=0.50 ± 0.04 vs. 0.24 ± 0.02nM; mean ± S.E.M. p < 0.001) but was not different in schizophrenic subjects who had or had not committed suicide (Kd=0.50 ± 0.07 vs. 0.50 ± 0.04nM). The density of [3H]paroxetine binding sites did not differ between the schizophrenic and non-schizophrenic subjects. For the schizophrenic subjects, there was no relationship between ante-mortem neuroleptic drug treatment and [3H]paroxetine binding to the hippocampal membrane. Finally, this study has shown that neuroleptic drug treatment of rats does not alter [3H]paroxetine binding to the hippocampal membranes. Thus, it would seem that the changes in the affinity of [3H]paroxetine binding to the hippocampus of schizophrenic subjects are not likely to be due to neuroleptic drug treatment but may be involved in the pathology of the illness.
TL;DR: Investigation of whether or not adrenalectomy (ADX) and glucocorticoid substitution influence the pathway of both glucose and glycogen metabolism in cerebral parietotemporal cortex and hippocampus found that the effect of ADX on enzyme activities was reversed.
Abstract: In non-nervous tissues, glucocorticoids (GCs) counteract the effects of insulin and stimulate gluconeogenesis. The present study was designed to investigate whether or not adrenalectomy (ADX) and glucocorticoid substitution influence the pathway of both glucose and glycogen metabolism in cerebral parietotemporal cortex and hippocampus, and if so how. The activities of respective key enzymes, such as hexokinase (HK), phosphofructokinase (PFK), pyruvate kinase (PK), glucose-6-phosphatase (G6Pase) and phosphorylase a (PLa), and the concentrations of the intermediates, such as glucose (Glu), glucose-6-phosphate (G6P), fructose-6-phosphate (F6P), fructose-1,6-bisphosphate (F16PP), pyruvate (Pyr), lactate (Lac), glycogen (Glyc) and glucose-1-phosphate (G1F), were measured in the brains of 1-year-old male Wistar rats under controlled conditions 3 days after ADX or sham operation and in a pilot study after ADX and substitution with corticosterone (CST) suspended in sesame oil or after ADX and subcutaneous administration of the vehicle only. An increase in both glycolytic flux and glycogen breakdown and a decrease in gluconeogenesis in cerebral cortex but not in hippocampus were observed after ADX. After substitution with CST in adrenalectomized rats the effect of ADX on enzyme activities was reversed: significant differences from adrenalectomized rats that received vehicle only was shown for PK and G6Pase activities in both areas of the rat brain investigated.
TL;DR: Evidence is given of the participation of the peptidergic systems in the aging process and the involvement of the monoaminergic system in several functional abnormalities appearing in senescence.
Abstract: The effect of age on the monoamines 5-hydroxytryptamine (5-HT), noradrenaline (NA) and dopamine (DA), their metabolites 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA), 3,4-dihydroxphenylacetic acid (DOPAC), and the 5-HT precursor 5-hydroxy-L-tryptophan (5-HTP), together with the peptides neuropeptide Y (NPY), somatostatin (SOM), and corticotropin-releasing factor (CRF), was studied in frontal cortex, gyrus cinguli and hypothalamus from 23 healthy control subjects, aged 16-75 years. After correcting for postmortem interval, significant decreases in gyrus cinguli NA, NPY and CRF, and hypothalamic DA, HVA, and 5-HIAA concentrations were obtained with advancing age. The involvement of the monoaminergic system in several functional abnormalities appearing in senescence is suggested. Furthermore, evidence is given of the participation of the peptidergic systems in the aging process.
TL;DR: Gluatamtergic fibers have been immunocytochemically localized in the entorhinal cortex of postmortem schizophrenic brains and it is proposed that increases in glutamaters from the amygdala may be responsible for these changes and that they may play a central role in the pathophysiology of schizophrenia.
Abstract: Gluatamtergic fibers have been immunocytochemically localized in the entorhinal cortex of postmortem schizophrenic brains. The density of small caliber vertical fibers was higher in schizophrenics than controls, with no significant increase in the number of large caliber fibers. Increased glutamatergic fiber density has been previously reported in the cingulate cortex. It is proposed that increases in glutamatergic fibers from the amygdala may be responsible for these changes and that they may play a central role in the pathophysiology of schizophrenia.
TL;DR: The results suggest that N-methyl(R)salsolinol synthesis may not depend on dopamine level, but on the activity of enzymes related to its synthesis and/or catabolism.
Abstract: N-Methyl(R)salsolinol, an endogenous neurotoxin, has been proposed to be closely involved in the pathogenesis of Parkinson's disease. The selective toxicity to dopaminergic neurons was strictly limited for (R)-enantiomer of N-methylsalsolinol. Its precursor, (R)salsolinol was enzymatically synthesized from dopamine and acetaldehyde in human. However, it has never been examined whether a non-enzymatic reaction produces racemic salsolinol derivatives from dopamine especially in patients under L-DOPA therapy. To clarify the point, their contents were examined in intraventricular fluid from parkinsonian patients administrated with L-DOPA. Only (R)-enantiomer of N-methylsalsolinol and very low concentration of salsolinol could be detected. The results suggest that N-methyl(R)salsolinol synthesis may not depend on dopamine level, but on the activity of enzymes related to its synthesis and/or catabolism. The results are discussed in relation to pathogenesis Parkinson's disease.
TL;DR: The results strongly suggest that the CYPIA1 might be one of the susceptibility genes for PD, which is a multifactorial neurodegenerative disorder resulting from environmental factors acting on genetically susceptible individuals with normal aging.
Abstract: Idiopathic Parkinson's disease (PD) is a multifactorial neurodegenerative disorder resulting from environmental factors acting on genetically susceptible individuals with normal aging Cytochrome P450IA1 is a dioxin-inducible enzyme which is responsible for the activation of procarcinogens and environmental pollutants, such as benzo[α]pyrene and other aromatic hydrocarbons The frequencies of polymorphic alleles of cytochrome P450IA1 gene (CYPIA1) were studied in 126 unrelated patients with PD in comparison with 176 healthy Japanese The frequency of the Msp I polymorphic allele, a variant of CYPIA1 (m2), was significantly higher in patients with PD (0444) than in controls (0349) The risk of PD in homozygotes for m2 was 234-fold greater than homozygotes for the wild-type, ml The relative risk for PD in homozygotes for CYPIA1Val was 654-fold higher than in homozygotes for the wild type (CYPIA1Ile)(p < 0001) These results strongly suggest that the CYPIA1 might be one of the susceptibility genes for PD
TL;DR: The findings suggest that the MA-induced dopaminergic, but not serotonergic neurotoxicity, may be related to the neural process such as NO· formation caused by the activation of postsynaptic DA receptor.
Abstract: We examined effects of nitric oxide (NO·) synthesis inhibition on methamphetamine (MA)-induced dopaminergic and serotonergic neurotoxicity. The toxic dose of MA (5 mg/kg, sc, X4) significantly decreased contents of dopamine (DA), dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the striatum (ST), and significantly decreased contents of serotonin (5-HT) in the ST, nucleus accumbens (NA) and medial frontal contex (MFC). Coadministration with a NO· synthase inhibitor, Nω-nitro-L-arginine methyl ester (LNAME) (30 mg/kg, ip, X2), reduced the MA-induced decreases in contents of DA, DOPAC and HVA in the ST, but not reduced the MA-induced decreases in contents of 5-HT in the ST, NA and MFC. These findings suggest that the MA-induced dopaminergic, but not serotonergic neurotoxicity, may be related to the neural process such as NO· formation caused by the activation of postsynaptic DA receptor.