Oxytocin signal and social behaviour: comparison among adult and infant oxytocin, oxytocin receptor and CD38 gene knockout mice.

Oxytocin in the hypothalamus is the biological basis of social recognition, trust, love and bonding. Previously, we showed that CD38, a proliferation marker in leukaemia cells, plays an important role in the hypothalamus in the process of oxytocin release in adult mice. Disruption of Cd38 (Cd38 (-/-)) elicited impairment of maternal behaviour and male social recognition in adult mice, similar to the behaviour observed in Oxt and oxytocin receptor (Oxtr) gene knockout (Oxt (-/-) and Oxtr (-/-), respectively) mice. Locomotor activity induced by separation from the dam was higher and the number of ultrasonic vocalisation calls was lower in Cd38 (-/-) than Cd38( +/+) pups. However, these behavioural changes were much milder than those observed in Oxt (-/-) and Oxtr (-/-) mice, indicating less impairment of social behaviour in Cd38 (-/-) pups. These phenotypes appeared to be caused by the high plasma oxytocin levels during development from the neonatal period to 3-week-old juvenile mice. ADP-ribosyl cyclase activity was markedly lower in the knockout mice from birth, suggesting that weaning for mice is a critical time window of plasma oxytocin differentiation. Breastfeeding was an important exogenous source of plasma oxytocin regulation before weaning as a result of the presence of oxytocin in milk and the dam's mammary glands. The dissimilarity between Cd38 (-/-) infant behaviour and those of Oxt (-/-) or Oxtr (-/-) mice can be explained partly by this exogenous source of oxytocin. These results suggest that secretion of oxytocin into the brain in a CD38-dependent manner may play an important role in the development of social behaviour.

Gene expression and association analyses of LIM (PDLIM5) in bipolar disorder and schizophrenia.

We previously reported that expression level of LIM (ENH, PDLIM5) was significantly and commonly increased in the brains of patients with bipolar disorder, schizophrenia, and major depression. Expression of LIM was decreased in the lymphoblastoid cells derived from patients with bipolar disorders and schizophrenia. LIM protein reportedly plays an important role in linking protein kinase C with calcium channel. These findings suggested the role of LIM in the pathophysiology of bipolar disorder and schizophrenia. To further investigate the role of LIM in these mental disorders, we performed a replication study of gene expression analysis and performed genetic association studies. Upregulation of LIM was confirmed in the independent sample set obtained from Stanley Array Collection. No effect of sample pH or medication was observed. Genetic association study revealed the association of single nucleotide polymorphism (SNP)1 (rs10008257) with bipolar disorder. In an independent sample set, SNP2 (rs2433320) close to SNP1 was associated with bipolar disorder. In total samples, haplotype of these two SNPs was associated with bipolar disorder. No association was observed in case-control analysis and family-based association analysis in schizophrenia. These results suggest that SNPs in the upstream region of LIM may confer the genetic risk for bipolar disorder.

Poor maternal care and high maternal body mass index in pregnancy as a risk factor for schizophrenia in offspring.

OBJECTIVE: We investigated whether antenatal factors in mothers would increase the risk of schizophrenia in the offspring, and also examined any relationship between these factors and histories of obstetric complications (OCs). METHOD: Using the Mother and Child Health Handbooks of 52 patients with schizophrenia and 284 healthy subjects, we evaluated the risk-increasing effects of the frequency of antenatal care visits and mothers' body mass index (BMI) at both early and late pregnancy. RESULTS: In logistic regression analysis, there was a significant association between the number of antenatal care visits and the risk of the disorder; an increase in a unit of visits corresponds to a reduction of the risk by 12%. We also found a 24% increase in the risk with a one-unit increase of BMI at the early pregnancy, and a 19% increase at the late pregnancy. These antenatal factors were found to contribute, in part, to an excess of OCs in individuals with schizophrenia. CONCLUSION: Poor maternal care during pregnancy and comparatively high maternal BMI especially at early pregnancy may cause a predisposition to schizophrenia in the offspring.

Do olfactory reference syndrome and jiko-shu-kyofu (a subtype of taijin-kyofu) share a common entity?

OBJECTIVE: Olfactory reference syndrome (ORS) in the Western literature is characterized as preoccupation with the idea that the body emits a foul odor. Japanese patients with a feature similar to ORS have long been recognized as jiko-shu-kyofu, which is believed to be a culture-bound syndrome and specific to Japan. The aim of the study was to clarify the relationship between the two separate syndromes that had independently been recognized in culturally different settings. METHOD: The phenomenology and treatment of seven patients with jiko-shu-kyofu were described. A feature of jiko-shu-kyofu was then compared with that of ORS. RESULTS: In our cases, clinical characteristics of jiko-shu-kyofu such as symptomatology, insight, and pharmacotherapy response were found identical to those of ORS except for the onset at relatively younger ages. CONCLUSION: Jiko-shu-kyofu and ORS may share a common clinical entity, hence the former is not a culturally distinctive disorder.

[Schizophrenia and ocular misalignment: phenotypic and genetic association analysis].

The increased incidence of minor physical anomalies (MPAs) in schizophrenia is the fundamental basis for the neurodevelopmental hypothesis of schizophrenia etiology. Ocular misalignment falls into the category of MPAs, but this phenotype has not been assessed in schizophrenia. This study reveals that constant exotropia displays marked association with schizophrenia. To assess the genetic mechanisms, we examined the transcription factor genes ARIX and its paralogue, PMX2B. We identified frequent deletion/insertion polymorphisms in the 20-alanine homopolymer stretch of PMX2B, with a modest association between these functional polymorphisms and constant exotropia in schizophrenia. The polymorphisms were also associated with overall schizophrenia and more specifically with schizophrenia manifesting strabismus. These results suggest a possible interaction between PMX2B and other schizophrenia-precipitating factors, increasing the risk of the combined phenotypes. This study also highlights the unique nature of the polyalanine length variations found in PMX2B.

Adenosine A2A, 5-HT1A and 5-HT7 receptor in neonatally pregnenolone-treated rats.

Steroid hormones synthesized in the brain, called 'neurosteroids', modulate neuronal activity. We treated neonatal rats with a main precursor of the neurosteroidogenesis, pregnenolone, and examined adenosine A2A receptor, 5- hydroxytryptamine (5-HT)1A and 5-HT7 receptor densities in the front-parietal cortex in juvenile and adult rats. In receptor binding assay using [3H]CGS21680 and [3H]8-OH-DPAT, it was shown that neonatal pregnenolone-treatment induced a significant decrease in the adenosine A2A receptor density with no significant effects on the 5-HT1A and 5-HT7 receptor densities.

Subchronic treatment with methamphetamine and phencyclidine differentially alters the adenosine A1 and A2A receptors in the prefrontal cortex, hippocampus, and striatum of the rat.

Subchronic treatment with MAP (4.6 mg/kg, i.p., once daily for 11 days) significantly decreased the Kd, but not Bmax, values of [3H]1,3-dipropyl-8-cyclopentylxanthine ([3H]DPCPX) binding to adenosine A1 receptors in the prefrontal cortex and hippocampus, but not striatum, of rat brain. However, subchronic treatment with PCP (10 mg/kg, i.p., once daily for 11 days) did not alter the Kd and Bmax values of [3H]DPCPX binding to adenosine A1 receptors in these three regions. Subchronic treatment with MAP or PCP did not alter the Bmax and Kd values of [3H]2-p-(2-carboxyehyl)phenethylamino-5'-N-ethylcarboxyamidoadenosine ([3H]CGS21680) binding to adenosine A2A receptors in the striatum. Furthermore, subchronic treatment with MAP or PCP significantly decreased the specific binding of [3H]CGS21680 to adenosine A2A receptors in the hippocampus, but not in the prefrontal cortex. Thus, these results suggest that MAP and PCP may produce differential effects on the adenosine A2A receptors, but not adenosine A1 receptors in rat brain.

Effects of age and gender on the expression of brain-derived neurotrophic factor mRNA in rat retrosplenial cortex following administration of dizocilpine.

Using in situ hybridization, we studied the effects of age and gender on the expression of brain-derived neurotrophic factor (BDNF) mRNA and heat shock protein hsp-70 mRNA in the rat retrosplenial cortex following administration of the noncompetitive NMDA receptor antagonist (+)-MK-801 (dizocilpine). Male and female Sprague-Dawley rats (5 weeks, 12 weeks, or 10 months old) were given a single intraperitoneal injection of saline (1 ml/kg) or dizocilpine (0.3, 1.0, or 3.0 mg/kg). No expression of BDNF mRNA and hsp-70 mRNA was detected in the rat retrosplenial cortex after administration of saline (1 ml/kg, IP). Administration of dizocilpine (0.3, 1.0, or 3.0 mg/kg, IP) caused a marked induction of BDNF mRNA and hsp-70 mRNA in the retrosplenial cortex of male and female rats, in a dose-dependent manner. Female rats were more sensitive to the induction of BDNF mRNA and hsp-70 mRNA in the retrosplenial cortex by dizocilpine as compared to male rats. It was also found that adult (12 weeks old) and aged (10 months old) rats were more sensitive to the induction of hsp-70 mRNA and BDNF mRNA in the retrosplenial cortex by dizocilpine as compared to young (5 weeks old) rats. These results suggest that the age and gender differences observed in the expression of BDNF mRNA and hsp-70 mRNA in the retrosplenial cortex by dizocilpine may be associated with the differences in dizocilpine-induced neurotoxicity observed with gender and age within the same region.

Acute and repeated administration of the selective 5-HT(2A) receptor antagonist M100907 significantly alters the activity of midbrain dopamine neurons: an in vivo electrophysiological study.

We examined the effect of the acute and repeated administration of M100907 (formerly MDL 100907), a selective 5-HT(2A) receptor antagonist, on spontaneously active dopamine (DA) neurons in the substantia nigra pars compacta (SNC) and ventral tegmental area (VTA) of rats. This was accomplished using in vivo, extracellular single unit recording. The i.v. administration of M100907 (0.01-0.64 mg/kg) did not significantly alter the basal firing rate or pattern of spontaneously active SNC and VTA DA neurons. A single injection of either 0.01 or 0.03 mg/kg i.p. of M100907 did not significantly alter the number of spontaneously active DA neurons in either the SNC or VTA areas. However, 0.1 mg/kg i.p. of M100907 significantly increased the number of spontaneously active SNC and VTA DA neurons compared to vehicle-treated animals. A single injection of all doses of M100907 significantly decreased the degree of bursting in VTA DA neurons, whereas the 0.1 mg/kg dose increased the degree of bursting in SNC DA neurons. The repeated administration (one injection per day for 21 days) of 0.03 and 0.1 mg/kg i.p. of M100907 produced a significant decrease in the number of spontaneously active SNC and VTA DA neurons compared to vehicle-treated animals. The repeated administration of M100907 did not significantly alter the firing pattern of VTA DA neurons but significantly altered the firing pattern of SNC DA neurons. The results of this study indicate that M100907 administration alters the activity of midbrain DA neurons in anesthetized rats.

3,4-methylenedioxymethamphetamine (MDMA, ecstasy)-induced egr-1 mRNA in rat brain: pharmacological manipulation.

Using in situ hybridization and immunohistochemical techniques, we examined the expression pattern of egr-1 mRNA and Egr-1 protein in several brain regions following administration of 3, 4-methylenedioxymethamphetamine (MDMA). Furthermore, we also studied the role of N-methyl-D-aspartate (NMDA) receptor, dopamine D(1) receptor, 5-hydroxytryptamine (5-HT) transporter or 5-HT(2A) receptor in the induction of egr-1 mRNA by MDMA. Basal constitutive levels of egr-1 mRNA were detected in control rat brains. A single administration of MDMA (10 mg/kg) caused marked induction of egr-1 mRNA in the prefrontal cortex, striatum and hippocampal dentate gyrus. However, no changes in the egr-1 mRNA levels were detected in the CA1 region of hippocampus and occipital cortex after administration of MDMA (10 mg/kg). Furthermore, the expression of egr-1 mRNA in the prefrontal cortex, striatum and hippocampal dentate gyrus after administration of MDMA (10 mg/kg) was blocked significantly by pretreatment with NMDA receptor antagonist (5R, 10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,b]-cyclohepten-5, 10-imine ((+)-MK801; 1 mg/kg), dopamine D(1) receptor antagonist SCH 23390 (1 mg/kg) or 5-HT uptake inhibitor paroxetine (5 mg/kg), but not by 5-HT(2A) receptor antagonist SR46349B (5 mg/kg). However, high basal levels of Egr-1 immunoreactivity in the rat brain were not altered by administration of MDMA (10 mg/kg). These results suggest that MDMA alters the expression of egr-1 mRNA in several regions of rat brain, and that the expression of egr-1 mRNA by MDMA in the prefrontal cortex, striatum and hippocampal dentate gyrus appears to be mediated, at least in part, by NMDA receptor, dopamine D(1) receptor and 5-HT transporter.

Acute and chronic administration of the selective D(3) receptor antagonist SB-277011-A alters activity of midbrain dopamine neurons in rats: an in vivo electrophysiological study.

This study examined the effect of acute and repeated p.o. administration of the selective D(3) receptor antagonist SmithKline Beecham (SB)-277011-A (1, 3, or 10 mg/kg) on the activity of spontaneously active midbrain dopamine (DA) neurons in anesthetized, male Sprague-Dawley rats. This was accomplished with the technique of in vivo extracellular single-unit recording. A single administration of either 3 or 10 mg/kg SB-277011-A produced a significant increase in the number of spontaneously active substantia nigra pars compacta (or A9) DA neurons compared with vehicle-treated (2% methylcellulose) animals. The 10-mg/kg dose of SB-277011-A produced a significant increase in the number of spontaneously active A10 DA neurons compared with vehicle-treated animals. The acute administration of SB-277011-A produced a significantly greater alteration in the firing pattern of spontaneously active A10 DA neurons, particularly at the 3- and 10-mg/kg doses, compared with vehicle-treated animals. The i.v. administration of SB-277011-A (0.01-1.28 mg/kg) did not significantly alter the firing rate or firing pattern of either A9 or A10 DA neurons. The repeated p.o. administration of 1, 3, or 10 mg/kg SB-277011-A once a day for 21 days produced a significant decrease in the number of spontaneously active A10 DA neurons. The repeated administration of SB-277011-A produced a greater effect on the firing pattern of spontaneously active A10 DA neurons, particularly at the 3-mg/kg dose, compared with A9 DA neurons. Overall, our results indicate that SB-277011-A alters the activity of midbrain DA neurons in rats.

The effect of the acute administration of various selective 5-HT receptor antagonists on focal hippocampal seizures in freely-moving rats.

In this study, we assessed the effects of the acute administration of various 5-HT receptor antagonists on hippocampal partial seizures generated by low-frequency electrical stimulation in male Wistar rats. The seizure threshold and severity were determined by measuring the pulse number threshold and primary and secondary afterdischarges, respectively, and the latency of secondary discharge was also determined. The administration of either the selective 5-HT(1A) receptor antagonist N-[2-[4-(2-methoxyphenyl)-1-piperazineyl]ethyl]-N-(pyridinyl)-c yclohe xanecarboximimde 3 HCl (WAY 100635, 0.1-1 mg/kg i.p.), the selective 5-HT(3) receptor antagonist granisetron (0.3-3 mg/kg i.p.), the selective 5-HT(2A) receptor antagonist R-(+)-a-(2, 3-dimethoxyphenyl)-1-[2-(4-fluorophenyl) ethyl]-4-piperidine-methanol (MDL 100907, 0.3-3 mg/kg i.p.) or the 5-HT(2B,C) receptor antagonist antagonist N-(1-methyl-5-indolyl)-N'-(3-pyridyl) urea HCl (SKB 200646A, 5-50 mg/kg i.p.) did not alter the pulse number threshold compared to vehicle-treated animals. However, the acute administration of WAY 100635 (0.3 mg/kg) and M100907 (1 mg/kg) significantly increased, whereas granisetron (1 mg/kg) decreased, the primary afterdischarge duration compared to vehicle-treated animals. The latency of secondary after discharge was significantly decreased by WAY 100635 (1 mg/kg) and granisetron (3 mg/kg) compared to vehicle-treated animals. These results suggest that in this model, the antagonism of 5-HT(1A), 5-HT(2A), 5-HT(3) or 5-HT(2B,C) receptors do not lower or raise seizure threshold. However, the antagonism of 5-HT(1A) receptors may increase or augment seizure severity.

cADP-ribose potentiates cytosolic Ca2+ elevation and Ca2+ entry via L-type voltage-activated Ca2+ channels in NG108-15 neuronal cells.

The effects of cADP-ribose (cADPR), a metabolite of beta-NAD(+), on the elevation of cytoplasmic free Ca(2+) concentration ([Ca(2+)](i)) and Ca(2+) influx through voltage-activated Ca(2+) channels (VACCs) were studied in NG108-15 neuroblastomaxglioma hybrid cells. NG108-15 cells were pre-loaded with fura-2 and whole-cell patch-clamped. Application of cADPR through patch pipettes did not by itself trigger any [Ca(2+)](i) rise at the resting membrane potential. A rise in [Ca(2+)](i) was evoked upon sustained membrane depolarization, and was significantly larger in cADPR-infused cells than in non-infused cells. This potentiation in the [Ca(2+)](i) elevation was reproduced by infusion of beta-NAD(+), and was blocked by 8-bromo-cADPR and antagonized by external application of ryanodine or by pretreatment of cells with FK506. Nicotinamide inhibited beta-NAD(+)-induced, but not cADPR-elicited, potentiation. [Ca(2+)](i) increases or Ca(2+) influx, measured by Mn(2+) quenching, elicited by the same protocol of depolarization was blocked completely by nifedipine but not by omega-conotoxin. Ca(2+) influx in cADPR- or beta-NAD(+)-infused cells was steeper and greater than that in control cells, and was inhibited partly by ryanodine. In contrast, ryanodine accelerated Ca(2+) influx in non-infused cells. These results show that cADPR amplifies both depolarization-induced [Ca(2+)](i) increase and Ca(2+) influx through L-type VACCs. These results suggest that cADPR functions on ryanodine receptors as a direct agonist and also interacts with L-type VACCs as an indirect agonist, i.e. via a retrograde signal.

Differences in evoked potential characteristics between DRPLA patients and patients with progressive myoclonic epilepsy: preliminary findings indicating usefulness for differential diagnosis.

The characteristics of evoked potentials in patients with dentatorubral-pallidoluysian atrophy (DRPLA) were investigated. Twelve patients with DRPLA and three patients with progressive myoclonic epilepsy (PME) attributable to other causes participated in the study. In 11 out of the 12 patients, the diagnosis of DRPLA was genetically confirmed, based on a 56-75 CAG triplet repeat expansion on chromosome 12p; in the remaining patient, the diagnosis was not genetically confirmed but the patient was clinically diagnosed as having DRPLA and was within the same pedigree as one of the 11 genetically confirmed patients. Two out of the three patients with PME, who had been tested for dodecamer repeat expansion in the cystatin B gene, were genetically confirmed as having Unverricht-Lundborg disease (UL); the remaining patient was also clinically diagnosed as having UL, but the patient did not have the aforementioned genetic abnormality. Somatosensory evoked potentials (SEPs) and brainstem auditory evoked responses (BAERs) were recorded. The amplitudes of the SEPs were determined as the peak-to-peak amplitudes between P2 and N2 deflections. The results revealed that high-amplitude SEPs were not evoked in any of the DRPLA patients; on the other hand, high-amplitude SEPs were evoked in all the patients with UL. Moreover, BAERs were absent in seven out of the 12 patients with DRPLA; on the other hand, all UL patients showed BAERs in which all peaks, from I to V, were distinguishable. These results suggest differences in pathophysiology between DRPLA, which predominantly affects the brainstem and subcortical regions, and PME, characterized by cortical hyperexcitability. Thus, evoked potential measurements may be useful to differentiate DRPLA patients from those with progressive myoclonic epilepsy.

Increased expression of zif268 mRNA in rat retrosplenial cortex following administration of phencyclidine.

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.

Acute and chronic administration of the selective sigma1 receptor agonist SA4503 significantly alters the activity of midbrain dopamine neurons in rats: An in vivo electrophysiological study.

In this study, we examined the effect of the acute and repeated administration of the selective sigma (sigma)1 receptor agonist 1-(3, 4-dimethoxyphenethyl)-4-(3-phenylpropyl)piperazine dihydrochloride (SA4503) on the number and firing pattern of spontaneously active dopamine (DA) neurons in substantia nigra pars compacta (SNC) and ventral tegmental area (VTA) in anesthetized, male Sprague-Dawley rats. This was accomplished using the technique of in vivo extracellular single unit recording. The intravenous administration of SA4503 (0.01-1.28 mg/kg) did not significantly alter the firing rate or pattern of spontaneously active DA neurons in either the SNC or VTA. A single injection of either 0.1 or 0.3 mg/kg i.p. of SA4503 did not alter the number of spontaneously active SNC and VTA DA neurons. In contrast, a single injection of 1 mg/kg i.p. of SA4503 produced a significant decrease and increase in the number of spontaneously active SNC and VTA DA neurons, respectively. Overall, the firing pattern parameters of spontaneously active SNC DA neurons were altered more significantly than those of spontaneously active VTA DA neurons following the acute administration of SA4503. The repeated administration (one injection per day for 21 days) of 0.3 and 1 mg/kg i.p. of SA4503 produced a significant increase in the number of spontaneously active VTA DA neurons. In addition, the repeated administration of SA4503 produced a greater alteration of the firing pattern of spontaneously active VTA compared to SNC DA neurons. Our results suggest that the administration of SA4503 significantly alters the activity of spontaneously active midbrain DA neurons, particularly those in the VTA following repeated administration.

Behavioral changes and expression of heat shock protein hsp-70 mRNA, brain-derived neurotrophic factor mRNA, and cyclooxygenase-2 mRNA in rat brain following seizures induced by systemic administration of kainic acid.

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.

Effect of acute administration of various 5-HT receptor agonists on focal hippocampal seizures in freely moving rats.

In this study, we assessed the effects of the acute administration of various 5-HT receptor agonists on hippocampal partial seizures generated by low-frequency electrical stimulation in male Wistar rats. The seizure threshold and severity were determined by measuring the pulse number threshold and primary and secondary afterdischarges and the latency of secondary discharge was also determined. The administration (0.1-1 mg/kg, i.p.) of either the 5-HT1A receptor agonist, 8-hydroxy-2-(di-n-aminopropyl)tetralin (8-OH-DPAT), or the selective 5-HT3 receptor agonist, 4-amino-(6-chloro-2-pyridyl)-1-piperidine (SR 57227A, 0.3-3 mg/kg, i.p.), did not alter any of the seizure parameters compared to those in vehicle-treated animals. Similarly, the administration of 0.3 and 1 mg/kg, i.p., of the 5-HT2A,C receptor agonist, (+/-)-2,5-dimethoxy-4-iodophenyl-2-aminopropane (DOI), did not alter any of the seizure parameters, whereas 3 mg/kg significantly decreased the latency of the secondary afterdischarge compared to that in vehicle-treated animals. The selective serotonin reuptake inhibitor, (+/-)-fluoxetine (2 mg/kg, i.p.), significantly increased the pulse number threshold and decreased the primary afterdischarge duration compared to those in vehicle-treated animals. In contrast, higher doses (6 or 20 mg/kg, i.p.) of fluoxetine did not significantly alter any of the seizure parameters measured. These results suggest that, in this model, stimulation of 5-HT1A, 5-HT2A,C and 5-HT3 receptors does not alter seizure threshold or severity and that the blockade of 5-HT uptake produced by a low dose of fluoxetine appears to increase seizure threshold and decrease seizure severity.

Acute and chronic administration of clozapine produces greater proconvulsant actions than haloperidol on focal hippocampal seizures in freely moving rats.

In this study, we assessed the effects of the acute (a single injection) and repeated (once daily injections for 21 days) administration of the atypical antipsychotic drug clozapine (1.5, 5, or 15 mg/kg i.p.) and the typical antipsychotic drug haloperidol (0.15, 0.5, and 1.5 mg/kg, i.p.) on hippocampal partial seizures generated by low-frequency electrical stimulation in male Wistar rats. The seizure threshold and severity were determined by measuring the pulse number threshold (PNT) and the primary afterdischarge duration (ADD), respectively. A single injection of either 5 or 15 mg/kg of clozapine significantly decreased the PNT and significantly increased the primary ADD, indicating a proconvulsant action. The repeated administration of clozapine (1.5, 5, or 15 mg/kg, i.p.) produced dose-dependent, proconvulsant effects by significantly decreasing the PNT and by significantly increasing the primary ADD. In contrast to clozapine, the acute administration of haloperidol did not significantly alter the PNT or the primary ADD. The repeated administration of haloperidol (0.5 and 1.5 mg/kg, i.p.), unlike clozapine, significantly decreased the primary ADD, but did not alter the PNT. Overall, clozapine produces a greater proconvulsant action than haloperidol in an animal model of hippocampal seizures.