Search

Glial cell line-derived neurotrophic factor (GDNF) plays an important role in the pathophysiology of neuropsychiatric disorders. We examined serum GDNF levels in bipolar disorder (BD) patients and major depressive disorder (MDD) patients and their association with response to lithium therapy. We used a multicenter (six sites), exploratory, cross-sectional case-control design and recruited 448 subjects: 143 BD patients, 116 MDD patients, and 158 healthy controls (HCs). We evaluated the patients' clinical severity using the Clinical Global Impression (CGI), and responses to lithium therapy using the Alda scale. The serum GDNF levels were significantly decreased in the BD and MDD groups compared to the HCs, with no significant difference between the BD and MDD groups. After adjustment, the serum GDNF levels in the BD and MDD patients in remission or depressive states were decreased compared to the HC values. Lower serum GDNF levels in BD patients were associated with higher CGI and Alda scores (i.e., severe illness and good response to lithium therapy, respectively). Our findings suggest that the serum GDNF level may be a biomarker for both BD and MDD in remission or depressive states. The serum GDNF level may be associated with the lithium response of BD patients., (Copyright © 2021. Published by Elsevier B.V.)

This study investigated whether the longitudinal changes in symptom severity in children with autism spectrum disorder (ASD) are associated with changes in the parents׳ autistic traits. The results demonstrated two significant correlations between the changes in children׳s Social Responsiveness Scale (SRS) scores and the Social Responsiveness Scale (SRS) score changes in either the father or both parents. Autistic symptom mitigation in ASD children was associated with increased empathy levels in their parents., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

The Iowa Gambling Task (IGT) is a complex decision-making task in which monetary wins and losses guide the development of strategies. The objective of this study was to evaluate hemodynamic responses of patients with bipolar disorder (BD) during performance of the IGT using near-infrared spectroscopy (NIRS). Participants comprised 13 patients and 15 healthy control subjects who were matched for age, sex, handedness, and intelligence quotient. Relative changes in oxygenated and deoxygenated hemoglobin (oxy-Hb and deoxy-Hb) levels in the frontal region were measured using a 46-channel NIRS system. All subjects were evaluated using NIRS during a verbal fluency task (VFT) and the IGT. During performance of the IGT, BD patients showed significantly decreased oxy-Hb levels in the bilateral orbitofrontal cortex (OFC) and left prefrontal cortex (PFC) compared with normal control subjects. However, during the VFT, patients with BD showed no significant changes in oxy-Hb levels compared with control subjects. Changes in oxy-Hb levels in the bilateral OFC and the PFC during the IGT were negatively correlated with total scores on the Hamilton Rating Scale for Depression (HAM-D). Although the IGT was useful for differentiating patients with BP from control subjects, no significant differences in autonomic activity were observed., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

In this study we used near-infrared spectroscopy (NIRS) to measure relative changes in cortical hemodynamics from 19 adult and 19 preschool children (aged 3-4 years old), while they watched epochs of static and motion pictures extracted from TV programs. The spatio-temporal characteristics of oxygenated and deoxygenated hemoglobin volumes (oxy- and deoxy-Hb) of both subject groups were described and compared where appropriate for five regions of interest (ROIs). These were striate, left and right middle temporal, and left and right temporo-parietal areas. Over these areas, deoxy-Hb volumes did not differ between both groups. Preschool data showed significant increases in oxy-Hb over striate, middle temporal and temporo-parietal areas in response to visual motion stimuli. Static stimuli caused a significant oxy-Hb increase over striate and left middle temporal areas. Surprisingly, changes in adult oxy-Hb were not profound and did not show a significant oxy-Hb increase in striate and middle temporal areas in response to the motion stimuli, warranting further research. In spite of oxy-Hb volume differences, oxy-Hb recovery to baseline followed a similar pattern in both groups in response to both static and motion stimuli. Together, the results suggest that near-infrared spectroscopy is a viable method to investigate cortical development of preschool children by monitoring their hemodynamic response patterns., (Copyright © 2011 Elsevier B.V. All rights reserved.)

The present study explored minor physical anomaly items relevant to schizophrenia in order to establish a scale that can distinguish schizophrenia from controls using newly identified items along with items from the refined Waldrop scale. Seven items were significantly more frequent among schizophrenia patients (N=218) than controls (N=226). Among these seven items, two novel features, strabismus and 'cuspidal ear' showed markedly different prevalence rates between schizophrenia and control groups. A six-item scale, including the newly identified strabismus and cuspidal ear, was selected for most accurately discriminating patients with schizophrenia from controls. This scale correctly classified 59.6% of patients and 78.9% of control subjects. This new scale is procedurally more exacting and quantitative, and more relevant to schizophrenia than the original Waldrop scale. The validity of this scale should be sound since it was tested on a larger number of cohorts than used in previous research. Our scale can be used as a biomarker for predicting risk for future development of schizophrenia. The scale may also facilitate the identification of schizophrenia susceptibility genetic/environmental factors by stratifying etiologically heterogeneous patients according to physical abnormalities.

Neuronal dysfunction in the frontal cortex has been reported in the etiology of mental disorders, including schizophrenia. The adenosine A(1) receptor system, as well as the dopaminergic system, are important in the control of cortical neuronal activity. We hypothesize that neuroexcitability in early life is critical to the normal development of the brain, and neurosteroids are factors that modulate neuroexcitability during the development period. In this study, we treated neonatal rats with a neurosteroid, pregnenolone (10 microg/g) from postnatal day (PD) 3 until PD 7. In pregnenolone-treated male and female rats, adenosine A(1) receptor density, the amount of dopamine (DA), serotonin (5-HT) and their metabolites in the fronto-parietal cortex and behavioral responses in the open field were examined pre- and post-puberty. A decrease in K(d) values for the adenosine A(1) receptor binding assay using [(3)H]1,3-dipropyl-8-cyclopentylxanthine (DPCPX), increased formation of DA metabolites and hyper-locomotor activity in the open field were found in pregnenolone-treated rats compared with controls in pre- and post-puberty. An increase in 5-HT metabolites was found in the pregnenolone-treated rats in pre-puberty, but not post-puberty. These effects of pregnenolone were not different between males and females. However, correlations between horizontal and vertical activities in the open field were disrupted only in pregnenolone-treated females. The present results indicate that pregnenolone treatment during the neonatal period influences the cortical dopaminergic and adenosinergic systems as well as behavioral responses in the open field., (Copyright 2002 Elsevier Science B.V.)

Phencyclidine (PCP) has been shown to cause neurotoxicity in rat retrosplenial cortex following a single administration, although the precise mechanism underlying PCP-induced neurotoxicity is unclear. Using in situ hybridization and immunohistochemistry, we studied the effects of PCP on expression of immediate early gene zif268 mRNA and zif268 protein in the rat brain. High constitutive levels of zif268 mRNA and zif268 immunoreactivity were observed in the brain of control rats. Administration of PCP (12.5, 25 or 50 mg/kg, i.p., 6 h) caused marked induction of zif268 mRNA in the rat retrosplenial cortex, in a dose-dependent manner. However, the basal levels of zif268 mRNA in the other regions of cerebral cortex were decreased by administration of PCP. Emulsion-autoradiographical study suggested that marked expression of zif268 mRNA was observed in the layers III and IV of retrosplenial cortex where the neurotoxicity of PCP was detected. Furthermore, zif268 immunoreactivity in the layer IV of retrosplenial cortex was not changed by administration of PCP (25 mg/kg, i.p., 5 h), but that in the other layers of retrosplenial cortex was reduced by PCP. These results suggest that immediate early gene zif268 may, in part, play a role in the neurotoxicity of NMDA receptor antagonists such as PCP.

Kainic acid-induced seizures in rats represent an established animal model for human temporal lobe epilepsy. However, it is well-known that behavioral responses to the systemic administration of kainic acid are inconsistent between animals. In this study, we examined the relationship between expression of genes, neuropathological damage, and behavioral changes (seizure intensity and body temperature) in rats after systemic administration of kainic acid. The considerable differences in the response to kainic acid-induced seizures were observed in rats after a single administration of kainic acid (12 mg/kg i.p.). There was no detection of the expression of heat shock protein hsp-70 mRNA and HSP-70 protein in brain of vehicle-treated controls and in animals exhibiting weak behavioral changes (stage 1-2). A moderate expression of hsp-70 mRNA was detected throughout all regions (the pyramidal cell layers of CA1-3 and dentate gyrus) of the hippocampus, the basolateral, lateral, central and medial amygdala, the piriform cortex, and the central medial thalamic nucleus of rats that developed moderate seizures (stage 3-4). Marked expression of hsp-70 mRNA was detected in the all regions (cingulate, parietal, somatosensory, insular, entorhinal, piriform cortices) of cerebral cortex and all regions of hippocampus, and the central medial thalamic nucleus of the rats that developed severe seizures (stage 4-5). In addition, marked HSP-70 immunoreactivity was detected in the pyramidal cell layers of CA1 and CA3 regions of hippocampus, all regions (cingulate, parietal, somatosensory, insular, piriform cortices) of cerebral cortex, and the striatum of rats that developed severe seizures (stage 4-5). Furthermore, a marked expression of cyclooxygenase-2 (COX-2) mRNA and brain-derived neurotrophic factor (BDNF) mRNA levels by kainic acid-induced behavioral seizures (stage 3-4 or stage 4-5) was detected in all hippocampal pyramidal cell layers, granule layers of dentate gyrus, piriform cortex, neocortex, and amygdala. The present study suggest that the behavioral changes (seizure intensity and body temperature) and neuropathological damage after systemic administration of kainic acid are inconsistent between animals, and that these behavioral changes (severity of kainic acid-induced limbic seizures) might be correlated with gene expression of hsp-70 mRNA, COX-2 mRNA, and BDNF mRNA in rat brain., (Copyright 1998 Elsevier Science B.V.)

Epibatidine (exo-2-(6-chloro-3-pyridyl)-7-azabicyclo-[2.2.1]heptane), an extract of frog skin, is a novel and highly potent agonist for the nicotinic acetylcholine (ACh) receptor. The present study was undertaken to examine the expression of Fos protein in several rat brain regions following an acute administration of epibatidine. Furthermore, we also studied the role of the dopamine D1 and D2 receptors and the N-methyl-d-aspartate (NMDA) receptor, and nicotinic ACh receptor in the expression of Fos protein by epibatidine. A single administration of epibatidine (5, 10, 50 microgram/kg) caused a marked induction of Fos-immunoreactivity in the prefrontal cortex, medial striatum, nucleus accumbens, amygdala and superior colliculus of rat brain. In these regions, pretreatment with SCH 23390 (1.0 mg/kg), a dopamine D1 receptor antagonist, MK-801 (1.0 mg/kg), a NMDA receptor antagonist, and mecamylamine (5. 0 mg/kg), a nicotinic Ach receptor antagonist, inhibited the induction of Fos protein by epibatidine (10 microgram/kg). Pretreatment with sulpiride, a dopamine D2 receptor antagonist, blocked the induction of Fos protein in the prefrontal cortex and the core region of accumbens nucleus, but not in the medial striatum and the shell division of nucleus accumbens of rat brain. These results suggest that epibatidine induced the expression of Fos protein in several regions of rat brain, and that dopamine D1 receptor, NMDA receptor, and nicotinic ACh receptor may play a role in the expression of Fos protein by epibatidine in rat brain. Furthermore, dopamine D2 receptor may, in part, play a role in epibatidine induced expression of Fos protein in the prefrontal cortex and the core region of nucleus accumbens, but not in the medial striatum and the shell division of nucleus accumbens of rat brain., (Copyright 1998 Elsevier Science B.V. All rights reserved.)

In this study, seizures in the dentate gyrus were triggered by 2 Hz electrical stimulation while, at the same time, serial changes in paired-pulse depression was measured in free-moving rats. The perforant path was stimulated by paired pulses 25 ms apart and recordings were made in the dentate gyrus. We also observed the effect of kindling procedure on this change of evoked field potential. Paired-pulse depression started to fail following the onset of epileptic afterdischarge, both before and after kindling. As kindling progressed, paired-pulse depression increased in the initial part of the stimulus train, and also the time delay from the start of the stimulation to when paired-pulse depression started to fail increased significantly. These findings suggest that the collapse of local early, presumably GABAA-mediated, inhibition may occur after the dentate gyrus seizure onset and development of kindling epileptogenesis does not weaken but, on the contrary, enhances this local inhibitory function. Finally we propose that seizures triggered by 2 Hz electrical stimulation constitutes a useful model for examining physiological or biochemical changes during seizure initiation of awake, free-moving animals since it provides long (usually several seconds or more) latency from the start of stimulation to seizure onset.

Using immunohistochemical technique, we investigated the regionally different roles of muscarinic receptors in the induction of HSP-70 by NMDA receptor antagonists. The administration of memantine and phencyclidine induced HSP-70 in the retrosplenial cortex of rat brain. Pretreatment with the muscarinic receptor antagonist scopolamine (0.1-1 mg/kg) blocked induction of HSP-70 in layer III of the retrosplenial cortex. However, induction of HSP-70 in layer V was augmented by scopolamine. These results suggest a regional difference in the mechanism of neurotoxicity induced by NMDA receptor antagonists.

The effect of NMDA receptor antagonist phencyclidine (PCP) on expression of cyclooxygenase (COX)-2 mRNA in the rat brain was studied. Administration of PCP (12.5, 25 or 50 mg/kg, i.p., 6 h) caused marked induction of COX-2 mRNA and heat shock gene hsp-70 mRNA, a marker of neuronal injury, in the retrosplenial cortex, in a dose-dependent manner. These results suggest that COX-2 may play a role in the neurotoxicity of NMDA receptor antagonists.

High-affinity N-methyl-D-aspartate (NMDA) receptor antagonists like MK-801 are known to induce the heat shock protein, HSP70, in the posterior cingulate cortex and retrosplenial cortex of rat brain. Memantine, which is a low affinity uncompetitive NMDA receptor antagonist, has been used in the treatment of Parkinson's disease in Europe. The faster kinetics of memantine in blocking and unblocking the NMDA receptor-operated ion channel as opposed to high-affinity NMDA antagonists like MK-801 has been thought to account for the safety of memantine. The present study evaluated the neurotoxic potential of memantine and amantadine using the induction of HSP70 immunoreactivity in rat brain. Memantine (25, 50, 75 mg/kg) induced HSP70 in the posterior cingulate, retrosplenial cortex and dentate gyrus of rat brain. In contrast, amantadine (50, 100, 200 mg/kg) did not induce HSP70 in the rat brain. These results suggest that memantine has an antagonistic effect at NMDA receptor in vivo, and raises the possibility that high doses of memantine may cause neuronal damage similar to those observed with other high-affinity NMDA receptor antagonists.

Using the low-frequency kindling procedure, we studied the effects of periodic 2-week stimulus-free intervals and chronic scopolamine administration on hippocampal kindling seizure development. In Experiment 1, rats were divided into two groups, interval group and no-interval group. In the interval group a 2-week stimulus interval was set after every five consecutive daily stimulations until the 21st stimulation. The number of stimulating pulses required for the triggering of epileptic afterdischarge, pulse-number threshold (PNT), was used as an indicator of the seizure threshold. PNT, afterdischarge duration (ADD) and behavioral seizure stage (BSS) of each induced seizure in the initial stage of kindling, kindling rate, seizure parameters at the completion of kindling were recorded and compared to the values of the no-interval, control group. Our result showed that PNT at the 6th stimulation, the first stimulation after the first 2-week stimulus interval increased significantly compared to control. Other seizure parameters did not differ significantly between the two groups. In Experiment 2 scopolamine hydrobromide, 0.5 and 1.0 mg/kg i.p., was administered 1 h before each electrical stimulation until each rat showed the stage-3 seizure. PNT, ADD and BSS in the initial stage of kindling, kindling rate for the stage-3 and -5 seizures, seizure parameters at the first stage-3 and -5 were recorded and compared to the values of saline-treated, control group. Although scopolamine 1.0 mg/kg increased PNT at the 5th stimulation compared to control, no other significant changes of the seizure parameters were found by scopolamine.(ABSTRACT TRUNCATED AT 250 WORDS)

In this study, the technique of extracellular single unit recording was used to examine the effect of prenatal cocaine exposure on the number of spontaneously active dopamine (DA) cells in the substantia nigra pars compacta (SNC or A9) and the ventral tegmental area (VTA or A10) of male Sprague-Dawley rats on postnatal days 56-68. In addition, the effect of the direct DA receptor agonist (+/-)-apomorphine (APO) on the basal firing rate of A10 DA cells was also determined. A significant decrease in the number of spontaneously active A10 DA cells was observed in offspring whose dams were treated with 40 mg/kg/day of cocaine s.c. from gestational days 8-20 when compared with offspring of pair-fed and non-treated control dams. The number of spontaneously active A9 DA cells was significantly decreased in the offspring of cocaine-exposed dams when compared to pair-fed offspring. In contrast, there were no significant differences among the three prenatal groups regarding the sensitivity of spontaneously active A10 DA cells to APO (2-64 micrograms/kg, i.v.). Overall, our results suggest that in utero cocaine exposure may alter presynaptic DA activity in offspring long after their exposure has been terminated.

Using the low-frequency kindling technique, we studied the effects of chronic MK-801 and chronic methamphetamine (MAP) administration on hippocampal kindling seizure development. In experiment 1, MK-801 (0.05, 0.1 mg/kg i.p.) was administered 2 h before each electrical stimulation until kindling developed into stage-3 seizure. In experiment 2, we started daily electrical stimulations two weeks after the last injection of chronic MAP administration (6 mg/kg/day, 14 days). The number of stimulating pulses required for the triggering of epileptic afterdischarge (pulse-number threshold, PNT) was used as an indicator of the seizure threshold. PNT, afterdischarge duration (ADD) and behavioral seizure stage (BSS) of each induced seizure in the initial stage of kindling; the kindling rates for stage 3 and stage 5 seizures; seizure parameters at the completion of kindling of the drug-treated groups were recorded and compared to the values of each saline-treated control group. Our result showed that MK-801 administration prior to each electrical stimulation selectively and significantly increased PNT in the initial stage of kindling without affecting other seizure parameters. Chronic pretreatment of MAP caused a selective and significant decrease of PNT of the first two stimulations in the kindling process. Taken together with the previous studies, these results suggest that long-term potentiation plays an important role in the development of the excitability of seizure focus but not of the induced seizure's propagation in the hippocampal kindling phenomenon. Clinically MK-801 seems to be a more efficacious drug in preventing the induction of seizures than in suppressing the acquired seizures.

We stimulated the dorsal hippocampus of the rat with 2 Hz electrical stimulation to induce kindling seizures. As we reported previously using cats, pulse-number threshold (PNT), the number of stimulating-pulses required for the triggering of epileptic afterdischarge, decreased profoundly in the initial stage of the kindling process and the behavioral seizure stage (BSS) developed in the later stage. After the completion of kindling, a 4 week interval elevated PNT significantly compared to the value at the completion of kindling, whereas BSS showed no regression. These results suggest that there are two types of neuroplasticities which are independent of each other in the kindling phenomenon, one is the early-short type which is involved in the susceptibility of epileptic focus in hippocampus and the other is the late-long type which is involved in the full propagation of kindled seizures to the extra-limbic area.

In this study, we have identified and characterized 5-HT3-like receptors in the rat medial prefrontal cortex (mPFc), an area with a moderate density of 5-HT3 binding sites, using the techniques of single unit recording and microiontophoresis. The microiontophoresis of the 5-HT3 receptor agonist 2-methylserotonin (2-Me-5HT), similar to the action of 5-HT, produced a current-dependent (10-80 nA) suppression of the firing rate of both spontaneously active and glutamate (GLU)-activated (quiescent) mPFc cells. Phenylbiguanide (PBG), another 5-HT3 receptor agonist, suppressed the firing rate of mPFc cells but was less effective compared to 2-Me-5HT. The continuous iontophoresis (10-20 min) of 1 M magnesium chloride markedly attenuated the suppressant effect produced by electrical stimulation of the ascending 5-HT pathway, but did not alter 2-Me-5HT's action, suggesting that the action of 2-Me-5HT is a direct one. The suppressant action of 2-Me-5HT on mPFc cells was blocked by a number of structurally diverse and selective 5-HT3 antagonists, with a rank order of effectiveness as follows: ICS 205930 = (+/-)-zacopride greater than granisetron = ondansetron = LY 278584 greater than MDL 72222. Furthermore, the intravenous administration of (+/-)-zacopride antagonized the action of 2-Me-5HT and PBG on mPFc cells. In contrast to the effects of the 5-HT3 receptors antagonists, other receptor antagonists such as metergoline (5-HT1A,1B,1C.2), (+/-)-pindolol (5-HT1A,1B, beta), SCH 23390 (5-HT1C.2, D1), l-sulpiride (D2) or SR 95103 (GABAA) failed to block 2-Me-5HT's action. These results combined suggest that 2-Me-5HT's suppressive action on mPFc cells is mediated directly by 5-HT3-like receptors.

In this study, we examined the effects of the cholecystokinin-A (CCK-A) antagonist devazepide (MK 329) and the CCK-B antagonist L-365,260 to reverse the decrease in the number of spontaneously active dopamine (DA) cells in the ventral tegmental area and substantia nigra pars compacta after chronic haloperidol (HAL) or clozapine (CLOZ) treatment. The intravenous administration of devazepide (2 micrograms/kg) but not L-365,260 (2 micrograms/kg) reversed the reduction in the number of spontaneously active A9 and A10 DA cells produced by chronic HAL. Furthermore, devazepide also reversed the decrease in the number of spontaneously active A10 DA cells produced by chronic CLOZ administration. Overall, these results suggest that CCK-A but not CCK-B receptors play an important role in mediating or maintaining the chronic antipsychotic drug-induced effect on midbrain DA cells.

Acute effects of 4 anticonvulsants on hippocampal kindled seizures induced with about 3 Hz electrical stimulations were assessed in cats. The number of stimulating pulses required for the triggering of epileptic afterdischarge (pulse-number threshold, PNT) was used as the indicator for the seizure threshold. Duration of afterdischarge (ADD), ictal and interictal behaviors and serum drug levels were also recorded. PB produced a PNT-increase more prominently than an ADD-decrease with seizure stage regression. PHT produced only a proconvulsive effect by decreasing PNT. CBZ also produced a proconvulsive effect by decreasing PNT at a low dose, and decreased PNT and ADD simultaneously at a high dose. Conversely VPA increased PNT and ADD simultaneously. These results were discussed comparing mainly with a previous study of amygdala-generating seizures.

Cats were stimulated in the ventral hippocampus with low-frequency (about 3 Hz) square wave pulses. All subjects were kindled until generalized convulsion occurred. During the kindling process, the number of stimulating pulses required for the provocation of afterdischarge (AD), which was used as an indicator of AD threshold, decreased suddenly in the initial stage and increased gradually in the late stage. We consider this phenomenon to be important in deepening the understanding of seizure generation.

Cats were stimulated in the dorsal hippocampus with low-frequency square wave pulses. All subjects were kindled until generalized convulsion occurred. In the early stage of the kindling process, an increase in the interpulse interval and a decrease in the number of stimulating pulses required for the provocation of epileptic afterdischarge were observed, but in the late stage a decrease in the former and an increase in the latter were observed. It appears from these data that completion of hippocampal kindling is accompanied by a decrease in excitability at the site of stimulation subsequent to an increase in the same.

We assessed the post-seizure effects on the seizure threshold and the seizure duration using low-frequency kindling technique. The number of stimulating pulses required for a triggering of epileptic afterdischarge (pulse-number threshold; PNT) was used for the indicator of seizure threshold. PNT increased significantly at 2 and 4 h inter-stimulation intervals, whereas it decreased significantly with an increase of seizure duration at 16 and 24 h intervals. It appears from these data that a post-seizure excitation occurs after a post-seizure inhibition.

Cats were stimulated in the lateral amygdala with low-frequency square-wave pulses. All subjects were kindled until generalized convulsion occurred. During the kindling process, a prolongation of the interpulse interval and a reduction of the number of pulses required for the provocation of afterdischarges were observed. We refer to this phenomenon as the 'saving-effect' of stimulating pulses to provoke afterdischarges.