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Parkinson's disease (PD) is a common, late-onset neurodegenerative disorder that shows progressive extrapyramidal motor disorders (e.g., bradykinesia, resting tremors, muscle rigidity and postural instability) and various non-motor symptoms (e.g., cognitive impairment, mood disorders, autonomic dysfunction and sleep disorders). While dopaminergic agents such as l -3,4-dihydroxyphenylalanine ( l -DOPA) and dopamine D 2 agonists are widely used for the treatment of PD, there is still high clinical unmet need for novel medications that overcome the limitations of current therapies. Evidence is now accumulating that the serotonergic nervous system is involved in the pathophysiological basis of PD and can provide benefits in the treatment of PD through its diverse functions. Among 5-HT receptor subtypes, 5-HT 1A , 5-HT 2 , 5-HT 3 and 5-HT 6 receptors play an important role in modulating extrapyramidal motor disorders. In addition, 5-HT 1A , 5-HT 2 , 5-HT 3 , 5-HT 4 and 5-HT 6 receptors are implicated in modulation of cognitive impairment, mood disorders (e.g., depression and anxiety) and/or psychosis, which are frequently observed in patients with PD. Specifically, stimulation of 5-HT 1A receptors seems to be effective for multiple PD symptoms including parkinsonism, l -DOPA-induced dyskinesia, cognitive impairment, mood disorders and neurodegeneration of dopamine neurons. Blockade of 5-HT 2 receptors is also likely to improve parkinsonism, depressive mood and cognitive impairment. In addition, it was recently demonstrated that 5-HT 2A inverse agonists can alleviate PD psychosis. All these findings emphasize the therapeutic roles of the serotonergic system in PD and stimulate new insight into novel treatments by modulating 5-HT 1A and 5-HT 2 receptors. [ABSTRACT FROM AUTHOR]

Spontaneously hypertensive rats (SHR) are widely used as a rat model of attention deficit/hyperactivity disorder (AD/HD). Here, we conducted neurochemical and behavioral studies in SHR to clarify the topographical alterations in neurotransmissions linked to their behavioral abnormalities. In the open-field test, juvenile SHR showed a significant hyperactivity in ambulation and rearing as compared with Wistar Kyoto rats (WKY). Brain mapping analysis of Fos-immunoreactivity (IR) revealed that SHR showed a marked increase in Fos expression in the core part (AcC) of the nucleus accumbens (NAc). Small to moderate increases were also observed in the shell part of the NAc and some regions of the cerebral cortex (e.g., parietal association cortex). These changes in Fos expression were region-specific and the Fos-IR levels in other brain regions (e.g., hippocampus, amygdala, striatum, thalamus and hypothalamus) were unaltered. In addition, treatment of SHR with the selective D 1 antagonist SCH-23390 significantly reversed both behavioral hyperactivity and elevated Fos expression in the AcC and cerebral cortex. The present study suggests that D 1 receptor-mediated neurotransmission in the AcC is region-specifically elevated in SHR, which could be responsible for behavioral hyperactivity. [ABSTRACT FROM AUTHOR]

Abstract: Immunohistochemical studies were performed to analyze the expressional changes in hippocampal synaptic vesicle protein 2A (SV2A) following pentylenetetrazole (PTZ) kindling. Repeated treatments of mice with sub-convulsive PTZ (40mg/kg, i.p.) for 15 days progressively enhanced seizure susceptibility and induced clonic convulsions in most animals examined. Topographical analysis of hippocampal SV2A-immunoreactivity revealed that SV2A was densely expressed in the hilar region of the dentate gyrus, stratum lucidum of the CA3 field and around the periphery of CA3 pyramidal neurons. PTZ kindling region-specifically increased SV2A expression in the dentate hilus without affecting that in the stratum lucidum or the pyramidal cell layer of the CA3 field. Confocal laser microscopic analysis using PTZ-kindled mice illustrated that most SV2A was co-expressed with glutamic acid decarboxylase 67 in the cell bodies and dendrites of hilar interneurons. However, SV2A-immunoreactivity was negligibly observed in the hilar glutamatergic nerve terminals (mossy fibers) probed with the anti-vesicular glutamate transporter 1 antibody. The present study suggests that SV2A specifically regulates hilar GABAergic neurotransmission in the kindled hippocampus probably as a compensatory or prophylactic mechanism against kindling epileptogenesis. [Copyright &y& Elsevier]

Abstract: Previous studies showed that 5-HT1A and 5-HT2 receptors play an important role in controlling the extrapyramidal motor disorders. However, the functions of other 5-HT receptor subtypes remain elusive. To elucidate the role of 5-HT receptors, specifically of 5-HT3∼5-HT7 subtypes, in modifying antipsychotic- induced extrapyramidal side effects (EPS), we studied the effects of the 5-HT stimulant 5-hydroxytryptophan (5-HTP) and various 5-HT receptor antagonists on haloperidol (HAL)-induced bradykinesia and catalepsy in mice and rats. Pretreatment of mice with 5-HTP (25–100mg/kg, i.p.) dose-dependently enhanced HAL (0.3mg/kg, i.p.)-induced bradykinesia and catalepsy. The potentiation of HAL-induced EPS by 5-HTP (50mg/kg, i.p.) was significantly inhibited by ritanserin (5-HT2 antagonist, 0.3-3mg/kg, i.p.), ondansetron (5-HT3 antagonist, 0.1–1mg/kg, i.p.), or SB-258585 (5-HT6 antagonist, 1–10mg/kg, i.p.) in a dose-dependent manner. However, neither WAY-100135 (5-HT1A antagonist, 1–10mg/kg, i.p.), GR-125487 (5-HT4 antagonist, 1–10mg/kg, i.p.), SB-699551 (5-HT5A antagonist, 1–10mg/kg, i.p.) nor SB-269970 (5-HT7 antagonist, 1–10mg/kg, i.p.) reduced the 5-HTP and HAL-induced bradykinesia or catalepsy. In addition, both ondansetron (0.1–1mg/kg, i.p.) and SB-258585 (3 and 10mg/kg, i.p.) also alleviated bradykinesia and catalepsy induced by HAL (0.5mg/kg, i.p.) alone in mice. Furthermore, bilateral microinjection of ondansetron (5μg (13.7nmol) per side) or SB-258585 (5μg (8.92nmol) per side) into the dorsolateral striatum (dlST) attenuated haloperidol-induced catalepsy in rats. These results suggest that serotonergic stimulation augments extrapyramidal motor disorders by activating the striatal 5-HT3 and 5-HT6 receptors and the antagonism of these receptors effectively alleviates antipsychotic-induced EPS. [Copyright &y& Elsevier]

Abstract: Blonanserin is a novel antipsychotic agent that preferentially interacts with dopamine D2 and 5-HT2A receptors. To assess the atypical properties of blonanserin, we evaluated its propensity to induce extrapyramidal side effects (EPS) and to enhance forebrain Fos expression in mice. The actions of AD-6048, a primary metabolite of blonanserin, in modulating haloperidol-induced EPS were also examined. Blonanserin (0.3–10mg/kg, p.o.) did not significantly alter the pole-descending behavior of mice in the pole test or increase the catalepsy time, while haloperidol (0.3–3mg/kg, p.o.) caused pronounced bradykinesia and catalepsy. Blonanserin and haloperidol at the above doses significantly enhanced Fos expression in the shell (AcS) region of the nucleus accumbens and dorsolateral striatum (dlST). The extent of blonanserin-induced Fos expression in the AcS was comparable to that induced by haloperidol. However, the striatal Fos expression by blonanserin was less prominent as compared to haloperidol. Furthermore, combined treatment of AD-6048 (0.1–3mg/kg, s.c.) with haloperidol (0.5mg/kg, i.p.) significantly attenuated haloperidol-induced bradykinesia and catalepsy. The present results show that blonanserin behaves as an atypical antipsychotic both in inducing EPS and enhancing forebrain Fos expression. In addition, AD-6048 seems to contribute at least partly to the atypical properties of blonanserin. [Copyright &y& Elsevier]

Abstract: We studied the effects of the 5-HT1A/7 agonist 8-OH-DPAT on haloperidol-induced catalepsy and forebrain Fos expression in mice to clarify its mechanism in modulating extrapyramidal motor disorders. 8-OH-DPAT (0.1–1mg/kg, i.p.) markedly attenuated haloperidol-induced catalepsy in a dose-dependent manner with a potency greater than that of the antiparkinsonian agent trihexyphenidyl. The anticataleptic action of 8-OH-DPAT was completely antagonized by WAY-100135 (a selective 5-HT1A antagonist), but not by SB-269970 (a selective 5-HT7 antagonist). Depletion of cerebral 5-HT by p-chlorophenylalanine (300mg/kg, i.p. for 3 days) did not attenuate, but rather potentiated the action of 8-OH-DPAT. Furthermore, the anticataleptic dose of 8-OH-DPAT showed a regionally specific reduction of haloperidol-induced Fos expression in the dorsolateral striatum (dlST) and the core region of the nucleus accumbens (AcC), without affecting that in the medial prefrontal cortex, the shell region of the nucleus accumbens or the lateral septal nucleus. These results suggest that 8-OH-DPAT alleviates antipsychotic-associated extrapyramidal motor disorders by stimulating the postsynaptic 5-HT1A receptors, which specifically counteracts the D2 receptor blocking actions of antipsychotics in the dlST and AcC. [Copyright &y& Elsevier]

Abstract: To clarify the role and mechanism of the 5-HT1A receptor in modulating extrapyramidal motor disorders, we studied the actions of 5-HT1A agonists in the mouse pole test, a valid model of parkinsonian bradykinesia. Haloperidol markedly delayed pole-descending behavior of mice in the pole test, and this effect was alleviated by the antiparkinsonian agent trihexyphenidyl (a muscarinic antagonist). The selective 5-HT1A agonists, 8-hydroxydipropylaminotetraline (8-OH-DPAT) and tandospirone, significantly attenuated haloperidol-induced bradykinesia in a dose-dependent manner. The alleviation of haloperidol-induced bradykinesia by 8-OH-DPAT was completely antagonized by WAY-100135 (a selective 5-HT1A antagonist), but was unaffected by cerebral 5-HT depletion with p-chlorophenylalanine (PCPA) treatment (300 mg/kg, i.p. for 3 days). These results suggest that 5-HT1A agonists improve extrapyramidal motor disorders associated with antipsychotic treatments by stimulating the postsynaptic 5-HT1A receptor. [Copyright &y& Elsevier]

Abstract: The inwardly rectifying K+ (Kir) channel Kir4.1 is responsible for astroglial K+ buffering. We recently found that tricyclic antidepressants (TCAs) inhibit Kir4.1 channel currents, which suggests that astroglial Kir currents might be involved in the pharmacological action of antidepressants. We therefore further examined the effects of the currently most popular antidepressants, selective serotonin reuptake inhibitors (SSRIs), and other related agents on Kir4.1 channels heterologously expressed in HEK293T cells. The whole-cell patch clamp technique was used. Fluoxetine, the typical SSRI, inhibited Kir4.1 channel currents in a concentration-dependent manner with an IC50 value of 15.2 μM. The inhibitory effect of fluoxetine was reversible and essentially voltage-independent. Fluoxetine had little or no effect upon Kir1.1 (ROMK1) or Kir2.1 (IRK1) channel currents. Other SSRIs, sertraline and fluvoxamine, also inhibited Kir4.1 channel currents whereas the tetracyclic (mianserin) or the 5-HT1A receptor-related (buspirone) antidepressants did not. This study shows that SSRIs such as fluoxetine and sertraline preferentially block astroglial Kir4.1 rather than Kir1.1 or Kir2.1 channels in the brain, which may be implicated in their therapeutic and/or adverse actions. [Copyright &y& Elsevier]

Abstract: Levetiracetam (LEV) is known to inhibit convulsive seizures and is clinically used for treating both partial and generalized seizures. The study was performed to determine whether LEV possesses an inhibitory effect on absence seizures in a novel genetic animal model of absence epilepsy, Groggy (GRY) rats. Single injections of LEV at doses ranging from 20 to 160mg/kg i.p. markedly inhibited absence seizures in GRY rats. The anti-absence action of LEV was potent and the cumulative duration of spike and wave discharges (SWD) in GRY rats was almost completely suppressed even at 20mg/kg (i.p.). When the time-course of the inhibitory action of LEV (80mg/kg i.p.) was examined up to 24h after the treatment, the appearance of SWD was suppressed for over 6h after injection of LEV in contrast to the action of sodium valproate (200mg/kg i.p.) which had a very short effect (<2h). The maximum level of blood concentration of LEV was attained within 2h after administration, and the drug disappeared from the blood in 24h with T 1/2 of 2.7h. These results revealed that LEV displays potent and relatively long-lasting inhibitory effects on absence seizures in GRY rats. [Copyright &y& Elsevier]

The purpose of this study was to investigate the effect of (3S)-7-chloro-3-[2-((1R)-1-carboxyethoxy)-4-aminomethylphenyl]aminocarbonylmethyl-1,3,4,5-tetrahydrobenz[c,d]indole-2-carboxylic acid hydrochloride (SM-31900), an antagonist with high selectivity and affinity for the NMDA receptor glycine-binding site, on the cerebral infarct volume in a permanent middle cerebral artery occlusion (MCAo) model, which was constructed by electrocoagulation of a unilateral middle cerebral artery distal to the olfactory tract using spontaneously hypertensive rats (SHRs). To investigate the dose-response characteristics and the therapeutic time window of SM-31900 in this MCAo model, we conducted three experiments, in which the administration of SM-31900 was started 5 min (experiment I), 30 min (experiment II), or 60 min (experiment III) after MCAo, respectively. In all the studies, SM-31900 was administered by intravenous bolus injection followed by continuous intravenous infusion to obtain a steady-state level of this compound in blood immediately after its administration. The treatment with SM-31900 was continued until 24 h after MCAo, at which time the cerebral infarct volume was measured. In experiment I, SM-31900 significantly reduced the infarct volume by 37% at a dosage of 0.38 mg/kg bolus followed by 1.5 mg/kg/h continuous infusion (0.38 mg/kg+1.5 mg/kg/h). In experiment II, the neuroprotective effect of SM-31900 was also significant, with a 25% reduction in infarct volume at a dosage of 0.38 mg/kg+1.5 mg/kg/h, and a 40% reduction at 1.5 mg/kg+6.0 mg/kg/h. Furthermore, even in experiment III, SM-31900 exerted a significant neuroprotective effect, with a 20% reduction at 1.5 mg/kg+6.0 mg/kg/h. These studies revealed that SM-31900 can exert a neuroprotective effect when it is administered up to at least 60 min after the onset of ischemia in the MCAo model, an animal model of stroke, indicating that SM-31900 is a good candidate for treating acute brain ischemia. [Copyright &y& Elsevier]

Highlights • HCN1-deficient rat strain was developed by TALEN mutagenesis. • The Hcn1 -deficient rats exhibited reduced hyperpolarization-activated currents. • The Hcn1 -deficient rats exhibited spontaneous SWDs accompanying behavioral arrest. • Both SWDs and behavioral arrest were suppressed by ethosuximide. • These findings demonstrate that deficiency of HCN1 caused absence epilepsy in rats. Abstract Hyperpolarized-activated cyclic nucleotide-gated (HCN) channels underlie hyperpolarization-activated current (I h) and are involved in controlling the excitability and electrical responsiveness of neurons. Absence epilepsy is clinically defined by a sudden, brief impairment of consciousness and behavioral arrest. Spike-and-wave discharges (SWDs) on electroencephalograms (EEG) are a diagnostic hallmark of absence epilepsy. In rat models of absence epilepsy, impaired function or expression of HCN1, a subtype of HCN channels, has been found. Here, to evaluate whether HCN1 deficiency causes absence epilepsy in rats, we developed Hcn1 -knockout rats by transcription activator-like effector nuclease mutagenesis. The cortical and hippocampal pyramidal neurons of these rats displayed a significant reduction of I h , a pronounced hyperpolarizing shift of the resting membrane potential, and increased input resistance, which indicated that the Hcn1 -knockout rats were deficient in HCN1 function. The Hcn1 -knockout rats were also more vulnerable to pentylenetetrazol-induced acute convulsions. More importantly, they exhibited spontaneous SWDs, which were accompanied by behavioral arrest, both of which were suppressed by ethosuximide. These results confirm the involvement of the HCN1 subunit in the regulation of input resistance and provide direct evidence that a deficiency of HCN1 caused absence epilepsy in rats. [ABSTRACT FROM AUTHOR]

Tremor dominant Kyoto ( Trdk ) is an autosomal dominant mutation that appeared in F344/NSlc rats mutagenized with N -ethyl- N -nitrosourea (ENU). In this study, we characterized and genetically analyzed F344- Trdk /+ heterozygous rats. The rats exhibited a tremor that was especially evident around weaning but persisted throughout life. The tremors of F344- Trdk /+ rats were attenuated by drugs effective against essential tremor (ET) but not drugs used to treat Parkinson’s disease–related tremor, indicating that the pharmacological phenotype of F344- Trdk /+ rats was similar to human ET. Using positional candidate approach, we identified the Trdk mutation as a missense substitution (c. 866 T > A, p. I289N) in Kcnn2, which encodes the SK2 subunit of the small-conductance Ca 2+ -activated K + channel. In vitro electrophysiological studies revealed that the I289N mutation diminished SK2 channel activity. These findings demonstrate that F344- Trdk /+ rats represent a novel model of ET, and strongly suggest that Kcnn2 is the causative gene for the tremor phenotype in F344- Trdk /+ rats. [ABSTRACT FROM AUTHOR]

Nicotinic acetylcholine (nACh) receptors are implicated in the pathogenesis of movement disorders (e.g., tremor) and epilepsy. Here, we performed behavioral and immunohistochemical studies using mice and rats to elucidate the mechanisms underlying nicotine-induced tremor. Treatments of animals with nicotine (0.5–2 mg/kg, i.p.) elicited kinetic tremor, which was completely suppressed by the nACh receptor antagonist mecamylamine (MEC). The specific α7 nACh receptor antagonist methyllycaconitine (MLA) also inhibited nicotine-induced tremor, whereas the α4β2 nACh antagonist dihydro-β-erythroidine (DHβE) or the peripheral α3β4 nACh antagonist hexamethonium showed no effects. Mapping analysis of Fos protein expression, a biological marker of neural excitation, revealed that a tremorgenic dose (1 mg/kg) of nicotine region-specifically elevated Fos expression in the piriform cortex (PirC), medial habenula, solitary nucleus and inferior olive (IO) among 44 brain regions examined. In addition, similarly to the tremor responses, nicotine-induced Fos expression in the PirC and IO was selectively antagonized by MLA, but not by DHβE. Furthermore, an electrical lesioning of the IO, but not the PirC, significantly suppressed the induction of nicotine tremor. The present results suggest that nicotine elicits kinetic tremor in rodents by activating the IO neurons via α7 nACh receptors. [ABSTRACT FROM AUTHOR]

Blonanserin is a new atypical antipsychotic drug that shows high affinities to dopamine D 2 and 5-HT 2 receptors; however, the mechanisms underlying its atypicality are not fully understood. In this study, we evaluated the antipsychotic properties of AD-6048, a primary metabolite of blonanserin, to determine if it contributes to the atypicality of blonanserin. Subcutaneous administration of AD-6048 (0.3–1 mg/kg) significantly inhibited apomorphine (APO)-induced climbing behavior with an ED 50 value of 0.200 mg/kg, the potency being 1/3–1/5 times that of haloperidol (HAL). AD-6048 did not cause extrapyramidal side effects (EPS) even at high doses (up to 10 mg/kg, s.c.), whereas HAL at doses of 0.1–3 mg/kg (s.c.) significantly induced bradykinesia and catalepsy in a dose-dependent manner. Thus, the therapeutic index (potency ratios of anti-APO action to that of EPS induction) of AD-6048 was much higher than that of haloperidol, illustrating that AD-6048 per se possesses atypical antipsychotic properties. In addition, immunohistochemical analysis of Fos protein expression revealed that both AD-6048 and HAL significantly increased Fos expression in the shell part of the nucleus accumbens and the striatum. However, in contrast to HAL which preferentially enhanced striatal Fos expression, AD-6048 showed a preferential action to the nucleus accumbens. These results indicate that AD-6048 acts as an atypical antipsychotic, which seems to at least partly contribute to the atypicality of blonanserin. [ABSTRACT FROM AUTHOR]

Abstract: Dopamine D3 receptors are highly expressed in the cerebellum; however, their pathophysiological functions are not fully understood. Here, we conducted microinjection studies to clarify the role of cerebellar D3 receptors in modulating locomotion and cataleptogenicity in rats. Microinjection of the preferential D3 agonist 7-hydroxy-N,N-di-n-propyl-2-aminotetralin (7-OH-DPAT) into lobe 9 of the cerebellum significantly reduced spontaneous locomotor activity with a U-shaped dose–response curve. The intracerebellar microinjection of 7-OH-DPAT did not elicit catalepsy by itself, but markedly potentiated catalepsy induction with a low dose (0.3mg/kg) of haloperidol. The catalepsy enhancement by 7-OH-DPAT occurred in a dose-dependent manner and was not associated with the locomotor inhibition. U-99194A (a selective D3 antagonist) or AD-6048 (a preferential D3 vs. D2 antagonist) antagonized both the catalepsy enhancement and the locomotor inhibition with 7-OH-DPAT. In addition, U-99194A and AD-6048 per se significantly alleviated catalepsy induced by a high dose (0.5mg/kg) of haloperidol. Furthermore, microinjection of 7-OH-DPAT into the nucleus accumbens or the dorsolateral striatum neither affected spontaneous locomotor activity nor haloperidol (0.3mg/kg)-induced catalepsy. The present results illustrate for the first time the role of cerebellar D3 receptors in modulating cataleptogenicity of antipsychotic agents, implying that blockade of cerebellar D3 receptors contributes to the reduction of extrapyramidal side effects. [Copyright &y& Elsevier]

Highlights: [•] EEG Lgi1 L385R/+ rats showed patterns that corresponded to seizure behavior. [•] Neural activity is increased in the lateral temporal lobe, including auditory cortex. [•] Microarray analysis identified candidate genes responsible for audiogenic seizures. [Copyright &y& Elsevier]

Highlights: [•] Brain Fos expression was analyzed in sleep apnea (SA) model using db/db mice. [•] Intermittent hypoxia (IH) reduced Fos expression in the paralimbic cortices. [•] IH also reduced Fos expression in the amygdala, accumbens, ventral tegmental area. [•] Fos expression in the brain stem structures was relatively resistant against IH. [•] Suppression of limbic and paralimbic activities may be linked to central SA symptoms. [ABSTRACT FROM AUTHOR]

We previously demonstrated that 5-HT stimulants, including selective serotonin reuptake inhibitors (SSRIs), potentiated antipsychotic-induced extrapyramidal symptoms (EPS) by stimulating 5-HT2A/2C, 5-HT3 and 5-HT6 receptors. Here, we studied the effects of the 5-HT1A agonist (±)-8-hydroxy-2-(di-n-propylamino) tetralin ((±)-8-OH-DPAT) on the fluoxetine enhancement of EPS (i.e., bradykinesia and catalepsy) to determine if the 5-HT1A agonist can counteract the serotonergic potentiation of EPS. Fluoxetine did not induce EPS signs by itself, but significantly potentiated haloperidol-induced bradykinesia in mice. (±)-8-OH-DPAT (0.1–1mg/kg, i.p.) significantly attenuated the fluoxetine enhancement of haloperidol-induced bradykinesia in a dose-dependent manner. A selective 5-HT1A antagonist (s)-WAY-100135 completely reversed the anti-EPS action of (±)-8-OH-DPAT. Microinjection studies using rats revealed that local application of (±)-8-OH-DPAT into the dorsolateral striatum or the motor cortex significantly diminished fluoxetine-enhanced catalepsy. In contrast, (±)-8-OH-DPAT injected into the medial raphe nucleus failed to affect EPS induction. The present results illustrate that 5-HT1A agonist can alleviate the SSRI enhancement of EPS by activating postsynaptic 5-HT1A receptors in the striatum and cerebral cortex. [ABSTRACT FROM AUTHOR]

Abstract: The inwardly rectifying potassium channel subunit Kir4.1 is expressed in brain astrocytes and involved in spatial K+ buffering, regulating neural activity. To explore the pathophysiological alterations of Kir4.1 channels in epileptic disorders, we analyzed interictal expressional levels of Kir4.1 in the Noda epileptic rat (NER), a hereditary animal model for generalized tonic-clonic (GTC) seizures. Western blot analysis showed that Kir4.1 expression in NERs was significantly reduced in the occipito-temporal cortical region and thalamus. However, the expression of Kir5.1, another Kir subunit mediating spatial K+ buffering, remained unaltered in any brain regions examined. Immunohistochemical analysis revealed that Kir4.1 was primarily expressed in glial fibrillary acidic protein (GFAP)-positive astrocytes (somata) and foot processes clustered around neurons proved with anti-neuronal nuclear antigen (NeuN) antibody. In NERs, Kir4.1 expression in astrocytic processes was region-selectively diminished in the amygdaloid nuclei (i.e., medial amygdaloid nucleus and basomedial amygdaloid nucleus) while Kir4.1 expression in astrocytic somata was unchanged. Furthermore, the amygdala regions with reduced Kir4.1 expression showed a marked elevation of Fos protein expression following GTC seizures. The present results suggest that reduced activity of astrocytic Kir4.1 channels in the amygdala is involved in limbic hyperexcitability in NERs. [Copyright &y& Elsevier]

Abstract: Antipsychotic drugs are widely used not only for schizophrenia, but also for mood disorders such as bipolar disorder and depression. To evaluate the interactions between antipsychotics and drugs for mood disorders in modulating extrapyramidal side effects (EPS), we examined the effects of antidepressants and mood-stabilizing drugs on haloperidol (HAL)-induced bradykinesia and catalepsy in mice and rats. The selective serotonin reuptake inhibitors (SSRIs), fluoxetine and paroxetine, and the tricyclic antidepressant (TCA) clomipramine, which showed no EPS by themselves, significantly potentiated HAL-induced bradykinesia and catalepsy in a dose-dependent manner. In contrast, the noradrenergic and specific serotonergic antidepressant (NaSSA) mirtazapine failed to augment, but rather attenuated HAL-induced bradykinesia and catalepsy. Mianserin also tended to reduce the EPS induction. In addition, neither treatment with lithium, sodium valproate nor carbamazepine potentiated HAL-induced EPS. Furthermore, treatment of animals with ritanserin (5-HT2A/2C antagonist), ondansetron (5-HT3 antagonist), and SB-258585 (5-HT6 antagonist) significantly antagonized the EPS augmentation by fluoxetine. Intrastriatal injection of ritanserin or SB-258585, but not ondansetron, also attenuated the EPS induction. The present study suggests that NaSSAs are superior to SSRIs or TCAs in combined therapy for mood disorders with antipsychotics in terms of EPS induction. In addition, 5-HT2A/2C, 5-HT3 and 5-HT6 receptors seem to be responsible for the augmentation of antipsychotic-induced EPS by serotonin reuptake inhibitors. [Copyright &y& Elsevier]

Abstract: Mutations in the KCNA1 gene, which encodes for the α subunit of the voltage-gated potassium channel Kv1.1, cause episodic ataxia type 1 (EA1). EA1 is a dominant human neurological disorder characterized by variable phenotypes of brief episodes of ataxia, myokymia, neuromyotonia, and associated epilepsy. Animal models for EA1 include Kcna1-deficient mice, which recessively display severe seizures and die prematurely, and V408A-knock-in mice, which dominantly exhibit stress-induced loss of motor coordination. In the present study, we have identified an N-ethyl-N-nitrosourea-mutagenized rat, named autosomal dominant myokymia and seizures (ADMS), with a missense mutation (S309T) in the voltage-sensor domain, S4, of the Kcna1 gene. ADMS rats dominantly exhibited myokymia, neuromyotonia and generalized tonic–clonic seizures. They also showed cold stress-induced tremor, neuromyotonia, and motor incoordination. Expression studies of homomeric and heteromeric Kv1.1 channels in HEK cells and Xenopus oocytes, showed that, although S309T channels are transferred to the cell membrane surface, they remained non-functional in terms of their biophysical properties, suggesting a dominant-negative effect of the S309T mutation on potassium channel function. ADMS rats provide a new model, distinct from previously reported mouse models, for studying the diverse functions of Kv1.1 in vivo, as well as for understanding the pathology of EA1. [Copyright &y& Elsevier]

Abstract: Previous studies have revealed that 5-HT1A agonists ameliorate antipsychotic-induced extrapyramidal symptoms (EPS) through postsynaptic 5-HT1A receptors. Here, we conducted an intracerebral microinjection study of (±)-8-hydroxy-2-(di-n-propylamino)-tetralin ((±)8-OH-DPAT) to determine the action site of the 5-HT1A agonist in alleviating EPS. Bilateral microinjection of(±)8-OH-DPAT (5µg/1µL per side) either into the primary motor cortex (MC) or the dorsolateral striatum (dlST) significantly attenuated haloperidol-induced catalepsy in rats. The anticataleptic action of (±)8-OH-DPAT was more prominent with the MC injection than with the dlST injection. WAY-100135 (a selective 5-HT1A antagonist) completely antagonized the reversal of haloperidol-induced catalepsy both by intracortical and intrastriatal (±)8-OH-DPAT. Furthermore, lesioning of dopamine neurons with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (30mg/kg/day, i.p., for 4days) did not alter the anti-EPS actions of (±)8-OH-DPAT in a mouse pole test. The present results strongly suggest that 5-HT1A agonist alleviates antipsychotic-induced EPS by activating postsynaptic 5-HT1A receptors in the MC and dlST, probably through non-dopaminergic mechanisms. [Copyright &y& Elsevier]

Abstract: We examined the effects of JP-1302 (a selective α2C antagonist), BRL-44408 (a selective α2A antagonist) and yohimbine (a non-selective α2 antagonist) on haloperidol-induced bradykinesia and catalepsy in mice to elucidate the role of α2 adrenoceptor subtypes in modifying extrapyramidal motor disorders. JP-1302 (0.1–1mg/kg, s.c.) dose-dependently ameliorated haloperidol-induced bradykinesia in the pole-test and reversed the catalepsy time increased by haloperidol. Antibradykinetic and anticataleptic actions of JP-1302 were statistically significant at 0.3 and 1mg/kg, and these doses did not alter the ambulatory distance, rearing or center–perimeter residence time in the open-field test. BRL-44408 (1–10mg/kg, s.c.) and yohimbine (0.3–3mg/kg, i.p.) also ameliorated haloperidol-induced bradykinesia and catalepsy. However, both agents significantly decreased ambulatory distance and rearing in the open-field test, possibly reflecting their anxiogenic actions associated with α2A antagonism. The present study shows for the first time that blockade of α2C receptors can alleviate antipsychotic-induced extrapyramidal motor disorders without affecting gross behaviors. [Copyright &y& Elsevier]

Abstract: NADPH oxidase plays an important role in vascular oxidative stress in hypertensive diseases. We evaluated whether NADPH oxidase-dependent superoxide (O2 −) production is involved in the deoxycorticosterone acetate (DOCA)-salt-induced hypertension, using mice which are genetically deficient in gp91phox, an NADPH oxidase subunit protein (gp91−/− mice). Two weeks after the DOCA-salt treatment, systolic blood pressure was significantly elevated in wild-type mice, but not in gp91−/− mice. After a 5-week treatment period, wild-type mice developed high blood pressure, with a systolic blood pressure of 127±3 mm Hg, compared with 107±4 mm Hg in gp91−/− mice. Aortic O2 − production in wild-type DOCA-salt-treated mice was significantly higher than that in wild-type sham mice, whereas there were no significant differences in aortic O2 − production between gp91−/− DOCA-salt-treated and sham mice. These findings suggest that vascular O2 − overproduction via gp91phox-containing NADPH oxidase is one of the crucial factors in the development of DOCA-salt-induced hypertension. [Copyright &y& Elsevier]

• Phf24-null rats were highly sensitive to chemically-induced seizures. • Kindling with pentylenetetrazol was also facilitated in Phf24-null rats. • Phf24-null rats showed defects in emotional responses and spatial learning. • Phf24 is important in modulating epileptogenesis, emotion and cognition. Phf24 is known as Gαi-interacting protein (GINIP) and is associated with the GABA B receptor. To study the function of Phf24 protein in the central nervous system (CNS), we have newly developed Phf24-null rats and investigated their behavioral phenotypes, especially changes in seizure sensitivity, emotional responses and cognitive functions. Phf24-null rats did not exhibit any spontaneous seizures. However, they showed a higher sensitivity to pentylenetetrazol (PTZ)- or pilocarpine-induced convulsive seizures. Phf24-null rats also showed an elevated susceptibility to kindling development with repeated PTZ treatments, suggesting that Phf24 acts as an inhibitory modulator in epileptogenesis. Although young Phf24-null rats showed normal gross behaviors, elevated spontaneous locomotor activity, especially in terms of the circadian dark period, emotional hyper-reactivity, reduced anxiety behaviors in the elevated plus-maze (EPM) test, and cognitive deficits in the Morris water maze test were explicitly observed at older age (20-week-old). The present results suggest that Phf24 is essential for proper functioning of the CNS, especially in preventing epileptogenesis and controlling emotional and cognitive functions. [ABSTRACT FROM AUTHOR]