Conditional depletion of Fus in oligodendrocytes leads to motor hyperactivity and increased myelin deposition associated with Akt and cholesterol activation.

Fused in sarcoma (FUS) is a predominantly nuclear multifunctional RNA/DNA-binding protein that regulates multiple aspects of gene expression. FUS mutations are associated with familial amyotrophic lateral sclerosis (fALS) and frontotemporal lobe degeneration (FTLD) in humans. At the molecular level, the mutated FUS protein is reduced in the nucleus but accumulates in cytoplasmic granules. Oligodendrocytes (OL) carrying clinically relevant FUS mutations contribute to non-cell autonomous motor neuron disease progression, consistent with an extrinsic mechanism of disease mediated by OL. Knocking out FUS globally or in neurons lead to behavioral abnormalities that are similar to those present in FTLD. In this study, we sought to investigate whether an extrinsic mechanism mediated by loss of FUS function in OL contributes to the behavioral phenotype. We have generated a novel conditional knockout (cKO) in which Fus is selectively depleted in OL (FusOL cKO). The FusOL cKO mice show increased novelty-induced motor activity and enhanced exploratory behavior, which are reminiscent of some manifestations of FTLD. The phenotypes are associated with greater myelin thickness, higher number of myelinated small diameter axons without an increase in the number of mature OL. The expression of the rate-limiting enzyme of cholesterol biosynthesis (HMGCR) is increased in white matter tracts of the FusOL cKO and results in higher cholesterol content. In addition, phosphorylation of Akt, an important regulator of myelination is increased in the FusOL cKO. Collectively, this work has uncovered a novel role of oligodendrocytic Fus in regulating myelin deposition through activation of Akt and cholesterol biosynthesis.

Inosine prevents hyperlocomotion in a ketamine-induced model of mania in rats.

Bipolar Disorder is a disorder characterized by alternating episodes of depression, mania or hypomania, or even mixed episodes. The treatment consists on the use of mood stabilizers, which imply serious adverse effects. Therefore, it is necessary to identify new therapeutic targets to prevent or avoid new episodes. Evidence shows that individuals in manic episodes present a purinergic system dysfunction. In this scenario, inosine is a purine nucleoside known to act as an agonist of A1 and A2A adenosine receptors. Thus, we aimed to elucidate the preventive effect of inosine on locomotor activity, changes in purine levels, and adenosine receptors density in a ketamine-induced model of mania in rats. Inosine pretreatment (25 mg/kg, oral route) prevented the hyperlocomotion induced by ketamine (25 mg/kg, intraperitoneal route) in the open-field test; however, there was no difference in hippocampal density of A1 and A2A receptors, where ketamine, as well as inosine, were not able to promote changes in immunocontent of the adenosine receptors. Likewise, no effects of inosine pretreatments or ketamine treatment were observed for purine and metabolic residue levels evaluated. In this sense, we suggest further investigation of signaling pathways involving purinergic receptors, using pharmacological strategies to better elucidate the action mechanisms of inosine on bipolar disorder. Despite the limitations, inosine administration could be a promising candidate for bipolar disorder treatment, especially by attenuating maniac phase symptoms, once it was able to prevent the hyperlocomotion induced by ketamine in rats.

Behavioral effects of psychostimulants in mutant mice with cell-type specific deletion of CB2 cannabinoid receptors in dopamine neurons.

Activation of the endocannabinoid system modulate dopaminergic pathways that are involved in the effects of psychostimulants including amphetamine, cocaine, nicotine and other drugs of abuse. Genetic deletion or pharmacological activation of CB2 cannabinoid receptor is involved in the modulation of the effects of psychostimulants and their rewarding properties. Here we report on the behavioral effects of psychostimulants in DAT-Cnr2 conditional knockout (cKO) mice with selective deletion of type 2 cannabinoid receptors in dopamine neurons. There was enhanced psychostimulant induced hyperactivity in DAT-Cnr2 cKO mice, but the psychostimulant-induced sensitization was absent in DAT-Cnr2 cKO compared to the WT mice. Intriguingly, lower doses of amphetamine reduced locomotor activity of the DAT-Cnr2 cKO mice. While cocaine, amphetamine and methamphetamine produced robust conditioned place preference (CPP) in both DAT-Cnr2 cKO and WT mice, nicotine at the dose used induced CPP only in the WT but not in the DAT-Cn2 cKO mice. However, pre-treatment with the CB2R selective agonist JWH133, blocked cocaine and nicotine induced CPP in the WT mice. The deletion of CB2Rs in dopamine neurons modified the levels of tyrosine hydroxylase, and reduced the expression of dopamine transporter gene expression in DAT-Cnr2 cKO midbrain region. Taken together, our data suggest that CB2Rs play a role in the modulation of dopamine-related effects of psychostimulants and could be exploited as therapeutic target in psychostimulant addiction and other psychiatric disorders associated with dopamine dysregulation.

Hyperactivity and memory/learning deficits evoked by developmental exposure to nicotine and/or ethanol are mitigated by cAMP and cGMP signaling cascades activation.

Pregnant smoking women are frequently episodic drinkers. Here, we investigated whether ethanol exposure restricted to the brain growth spurt period when combined with chronic developmental exposure to nicotine aggravates memory/learning deficits and hyperactivity, and associated cAMP and cGMP signaling disruption. To further investigate the role of these signaling cascades, we verified whether vinpocetine (a phosphodiesterase inhibitor) ameliorates the neurochemical and behavioral outcomes. Swiss mice had free access to nicotine (NIC, 50 µg/ml) or water to drink during gestation and until the 8th postnatal day (PN8). Ethanol (ETOH, 5 g/kg, i.p.) or saline were injected in the pups every other day from PN2 to PN8. At PN30, animals either received vinpocetine (20 mg/kg, i.p.) or vehicle before being tested in the step-down passive avoidance or open field. Memory/learning was impaired in NIC, ETOH and NIC + ETOH mice, and vinpocetine mitigated ETOH- and NIC + ETOH-induced deficits. Locomotor hyperactivity identified in ETOH and NIC + ETOH mice was ameliorated by vinpocetine. While cyclic nucleotides levels in cerebral cortex and hippocampus were reduced by NIC, ETOH and NIC + ETOH, this outcome was more consistent in the latter group. As observed for behavior, vinpocetine normalized NIC + ETOH nucleotides levels. pCREB levels were also increased in response to vinpocetine, with stronger effects in the NIC + ETOH group. Exposure to both drugs of abuse worsens behavioral and neurochemical disruption. These findings and the amelioration of deleterious effects by vinpocetine support the idea that cAMP and cGMP signaling contribute to nicotine- and ethanol-induced hyperactivity and memory/learning deficits.

Conditional inactivation of Npy1r gene in mice induces behavioural inflexibility and orbitofrontal cortex hyperactivity that are reversed by escitalopram.

Cognitive flexibility is the ability to rapidly adapt established patterns of behaviour in the face of changing circumstance and depends critically on the orbitofrontal cortex (OFC). Impaired flexibility also results from altered serotonin transmission in the OFC. The Y1 (Y1R) and Y5 (Y5R) receptors for neuropeptide Y (NPY) colocalize in several brain regions and have overlapping functions in regulating cognition and emotional behaviour. The targeted disruption of gene encoding Y1R (Npy1r gene) in Y5R containing neurons (Npy1rY5R-/- mice) increases anxiety-like behaviour and spatial reference memory. Here we used the same conditional system to analyse whether the coordinated expression of the Y1R and Y5R might be required for behavioural flexibility in reversal learning tasks, OFC serotoninergic tone and OFC neural activity, as detected by immunohistochemical quantification of the immediate-early gene, c-Fos. In addition, we investigated whether the acute treatment of Npy1rY5R-/- mice with the selective serotonin reuptake inhibitor escitalopram affected behavioural flexibility and OFC c-Fos expression. Npy1rY5R-/- male mice exhibit an impairment in performing the reversal task of the Morris water maze and the water T-maze but normal spatial learning, working memory and sociability, compared to their control siblings. Furthermore, Npy1rY5R-/- male mice display decreased 5-hydroxytriptamine (5-HT) positive fibres and increased baseline neural activity in OFC. Importantly, escitalopram normalizes OFC neural activity and restores behavioural flexibility of Npy1rY5R-/- male mice. These findings suggest that the inactivation of Y1R in Y5R containing neurons increases pyramidal neuron activity and dysregulates serotoninergic tone in OFC, whereby contributing to reversal learning impairment.

Adenosine (A)(2A)receptor modulation of nicotine-induced locomotor sensitization. A pharmacological and transgenic approach.

Preclinical evidence indicates an important role of adenosine (A)(2A) receptors in drug addiction while their therapeutic relevance is still a matter of debate. We examined the influence of the A(2A) receptor agonist CGS 21680 and the antagonist KW 6002 on nicotine sensitization and conditioned locomotor activity in adult (8-week old) male Sprague-Dawley rats (WT). Moreover, behavioral responses to nicotine were studied in rats overexpressing A(2A) receptors under the control of the neuronal specific enolase (NSE) promotor. Changes in the levels of dopamine, glutamate and γ-aminobutyric acid in wild type (WT) and NSEA(2A) rats were determined with using LC-MS. KW 6002 significantly enhanced expression of nicotine sensitization and conditioned locomotion, while CGS 21680 reduced all these effects in WT rats. A reduction of the expression of nicotine-evoked conditioned locomotor activity was also observed in the NSEA(2A) animals. The transgenic rats displayed a reduced basal tissue level of glutamate in the prefrontal cortex and hippocampus while dopamine basal levels in the nucleus accumbens were raised. Chronic nicotine treatment caused a significant reduction in the glutamate tissue level in the dorsal and ventral striatum, prefrontal cortex and cerebellum in wild type rats. In NSEA(2A) animals the same drug treatment instead produced a rise of glutamate levels in the hippocampus and dorsal striatum. Taken together, A(2A) receptor signaling in the rat brain can counteract locomotor sensitization and conditioned locomotion to nicotine which are related to nicotine reward-learning. It is suggested that treatment with A(2A) receptor agonists can help counteract the abuse actions of nicotine.

Prenatal cigarette smoke exposure causes hyperactivity and aggressive behavior: role of altered catecholamines and BDNF.

Smoking during pregnancy is associated with a variety of untoward effects on the offspring. However, recent epidemiological studies have brought into question whether the association between neurobehavioral deficits and maternal smoking is causal. We utilized an animal model of maternal smoking to determine the effects of prenatal cigarette smoke (CS) exposure on neurobehavioral development. Pregnant mice were exposed to either filtered air or mainstream CS from gestation day (GD) 4 to parturition for 4h/d and 5d/wk, with each exposure producing maternal plasma concentration of cotinine equivalent to smoking <1 pack of cigarettes per day (25ng/ml plasma cotinine level). Pups were weaned at postnatal day (PND) 21 and behavior was assessed at 4weeks of age and again at 4-6months of age. Male, but not female, offspring of CS-exposed dams demonstrated a significant increase in locomotor activity during adolescence and adulthood that was ameliorated by methylphenidate treatment. Additionally, male offspring exhibited increased aggression, as evidenced by decreased latency to attack and number of attacks in a resident-intruder task. These behavioral abnormalities were accompanied by a significant decrease in striatal and cortical dopamine and serotonin and a significant reduction in brain-derived neurotrophic factor (BDNF) mRNA and protein. Taken in concert, these data demonstrate that prenatal exposure to CS produces behavioral alterations in mice that are similar to those observed in epidemiological studies linking maternal smoking to neurodevelopmental disorders. Further, these data also suggest a role for monaminergic and BDNF alterations in these effects.

Heteromeric nicotinic receptors are involved in the sensitization and addictive properties of MDMA in mice.

We have investigated the effect of nicotinic receptor ligands in the behavioral sensitization (hyperlocomotion) and rewarding properties (conditioned place preference paradigm, CPP) of 3,4-methylenedioxy-methamphetamine (MDMA) in mice. Each animal received intraperitoneal pretreatment with either saline, dihydro-ß-erythroidine (DHßE, 1 mg/kg) or varenicline (VAR, 0.3 mg/kg), 15 min prior to subcutaneous saline or MDMA (5 mg/kg), for 10 consecutive days. On day 1, both DHßE and VAR inhibited the MDMA-induced hyperlocomotion. After 10 days of treatment, MDMA induced a hyperlocomotion that was not reduced (rather enhanced) in antagonist-pretreated animals. This early hyperlocomotion was accompanied by a significant increase in heteromeric nicotinic receptors in cortex that was not blocked by DHßE or VAR. Behavioral sensitization to MDMA was highest 2 weeks after the discontinuation of MDMA treatment. This additional increase in sensitivity was prevented in animals pretreated with DHßE or VAR. At this time, MDMA-treated mice showed a significant increase in heteromeric receptors in cortex that was prevented by DHßE and VAR. An involvement of α7 nicotinic receptors in this effect is ruled out. MDMA (10 mg/kg) induced positive CPP that was abolished by DHßE (2 mg/kg) and VAR (2 mg/kg). Moreover, chronic nicotine pretreatment (2 mg/kg, ip, b.i.d., for 14 days) caused MDMA, administered at a low dose (3 mg/kg), to induce CPP, which would otherwise not occur. Finally, present results point out that heteromeric nicotinic receptors are involved in locomotor sensitization and addictive potential induced by MDMA. Thus, varenicline might be a useful drug to treat both tobacco and MDMA abuse at once.

The synaptic adhesion molecule SynCAM 1 contributes to cocaine effects on synapse structure and psychostimulant behavior.

Drugs of abuse have acute and persistent effects on synapse structure and addiction-related behaviors. Trans-synaptic interactions can control synapse development, and synaptic cell adhesion molecule (SynCAM) proteins (also named nectin-like molecules) are immunoglobulin adhesion proteins that span the synaptic cleft and induce excitatory synapses. Our studies now reveal that the loss of SynCAM 1 in knockout (KO) mice reduces excitatory synapse number in nucleus accumbens (NAc). SynCAM 1 additionally contributes to the structural remodeling of NAc synapses in response to the psychostimulant cocaine. Specifically, we find that cocaine administration increases the density of stubby spines on medium spiny neurons in NAc, and that maintaining this increase requires SynCAM 1. Furthermore, mushroom-type spines on these neurons are structurally more plastic when SynCAM 1 is absent, and challenging drug-withdrawn mice with cocaine shortens these spines in SynCAM 1 KO mice. These effects are correlated with changes on the behavioral level, where SynCAM 1 contributes to the psychostimulant effects of cocaine as measured after acute and repeated administration, and in drug-withdrawn mice. Together, our results provide evidence that the loss of a synapse-organizing adhesion molecule can modulate cocaine effects on spine structures in NAc and increases vulnerability to the behavioral actions of cocaine. SynCAM-dependent pathways may therefore represent novel points of therapeutic intervention after exposure to drugs of abuse.

Hyperactivity in anorexia nervosa: warming up not just burning-off calories.

Excessive physical activity is a common feature in Anorexia Nervosa (AN) that interferes with the recovery process. Animal models have demonstrated that ambient temperature modulates physical activity in semi-starved animals. The aim of the present study was to assess the effect of ambient temperature on physical activity in AN patients in the acute phase of the illness. Thirty-seven patients with AN wore an accelerometer to measure physical activity within the first week of contacting a specialized eating disorder center. Standardized measures of anxiety, depression and eating disorder psychopathology were assessed. Corresponding daily values for ambient temperature were obtained from local meteorological stations. Ambient temperature was negatively correlated with physical activity (p = -.405) and was the only variable that accounted for a significant portion of the variance in physical activity (p = .034). Consistent with recent research with an analogous animal model of the disorder, our findings suggest that ambient temperature is a critical factor contributing to the expression of excessive physical activity levels in AN. Keeping patients warm may prove to be a beneficial treatment option for this symptom.

Neural basis of the potentiated inhibition of repeated haloperidol and clozapine treatment on the phencyclidine-induced hyperlocomotion.

Clinical observations suggest that antipsychotic effect starts early and increases progressively over time. This time course of antipsychotic effect can be captured in a rat phencyclidine (PCP)-induced hyperlocomotion model, as repeated antipsychotic treatment progressively increases its inhibition of the repeated PCP-induced hyperlocomotion. Although the neural basis of acute antipsychotic action has been studied extensively, the system that mediates the potentiated effect of repeated antipsychotic treatment has not been elucidated. In the present study, we investigated the neuroanatomical basis of the potentiated action of haloperidol (HAL) and clozapine (CLZ) treatment in the repeated PCP-induced hyperlocomotion. Once daily for five consecutive days, adult Sprague-Dawley male rats were first injected with HAL (0.05 mg/kg, sc), CLZ (10.0 mg/kg, sc) or saline, followed by an injection of PCP (3.2 mg/kg, sc) or saline 30 min later, and motor activity was measured for 90 min after the PCP injection. C-Fos immunoreactivity was assessed either after the acute (day 1) or repeated (day 5) drug tests. Behaviorally, repeated HAL or CLZ treatment progressively increased the inhibition of PCP-induced hyperlocomotion throughout the five days of drug testing. Neuroanatomically, both acute and repeated treatment of HAL significantly increased PCP-induced c-Fos expression in the nucleus accumbens shell (NAs) and the ventral tegmental area (VTA), but reduced it in the central amygdaloid nucleus (CeA). Acute and repeated CLZ treatment significantly increased PCP-induced c-Fos expression in the ventral part of lateral septal nucleus (LSv) and VTA, but reduced it in the medial prefrontal cortex (mPFC). More importantly, the effects of HAL and CLZ in these brain areas underwent a time-dependent reduction from day 1 to day 5. These findings suggest that repeated HAL achieves its potentiated inhibition of the PCP-induced hyperlocomotion by acting on the NAs, CeA and VTA, while CLZ does so by acting on the mPFC, LSv and VTA.

Y5 neuropeptide Y receptor overexpression in mice neither affects anxiety- and depression-like behaviours nor seizures but confers moderate hyperactivity.

Neuropeptide Y (NPY) has been implicated in anxiolytic- and antidepressant-like behaviour as well as seizure-suppressant effects in rodents. Although these effects appear to be predominantly mediated via other NPY receptors (Y1 and/or Y2), several studies have also indicated a role for Y5 receptors. Gene therapy using recombinant viral vectors to induce overexpression of NPY, Y1 or Y2 receptors in the hippocampus or amygdala has previously been shown to modulate emotional behaviour and seizures in rodents. The present study explored the potential effects of gene therapy with the Y5 receptor, by testing effects of recombinant adeno-associated viral vector (rAAV) encoding Y5 (rAAV-Y5) in anxiety- and depression-like behaviour as well as in kainate-induced seizures in adult mice. The rAAV-Y5 vector injected into the hippocampus and amygdala induced a pronounced and sustained increase in Y5 receptor mRNA expression and functional Y5 receptor binding, but no significant effects were found with regard to anxiety- and depression-like behaviours or seizure susceptibility. Instead, rAAV-mediated Y5 receptor transgene overexpression resulted in moderate hyperactivity in the open field test. These results do not support a potential role for single transgene overexpression of Y5 receptors for modulating anxiety-/depression-like behaviours or seizures in adult mice. Whether the induction of hyperactivity by rAAV-Y5 could be relevant for other conditions remains to be studied.

Down-regulation of Decapping Protein 2 mediates chronic nicotine exposure-induced locomotor hyperactivity in Drosophila.

Long-term tobacco use causes nicotine dependence via the regulation of a wide range of genes and is accompanied by various health problems. Studies in mammalian systems have revealed some key factors involved in the effects of nicotine, including nicotinic acetylcholine receptors (nAChRs), dopamine and other neurotransmitters. Nevertheless, the signaling pathways that link nicotine-induced molecular and behavioral modifications remain elusive. Utilizing a chronic nicotine administration paradigm, we found that adult male fruit flies exhibited locomotor hyperactivity after three consecutive days of nicotine exposure, while nicotine-naive flies did not. Strikingly, this chronic nicotine-induced locomotor hyperactivity (cNILH) was abolished in Decapping Protein 2 or 1 (Dcp2 or Dcp1) -deficient flies, while only Dcp2-deficient flies exhibited higher basal levels of locomotor activity than controls. These results indicate that Dcp2 plays a critical role in the response to chronic nicotine exposure. Moreover, the messenger RNA (mRNA) level of Dcp2 in the fly head was suppressed by chronic nicotine treatment, and up-regulation of Dcp2 expression in the nervous system blocked cNILH. These results indicate that down-regulation of Dcp2 mediates chronic nicotine-exposure-induced locomotor hyperactivity in Drosophila. The decapping proteins play a major role in mRNA degradation; however, their function in the nervous system has rarely been investigated. Our findings reveal a significant role for the mRNA decapping pathway in developing locomotor hyperactivity in response to chronic nicotine exposure and identify Dcp2 as a potential candidate for future research on nicotine dependence.

Effects of the histamine H3 receptor antagonist ABT-239 on acute and repeated nicotine locomotor responses in rats.

The addictive potential of nicotine is linked to psychomotor and cognition-enhancing effects. Histamine (H)(3) receptor antagonism has similarly received attention for a role in cognition, however, the role of H(3) receptors are far less studied for affects on nicotine-induced locomotor responses. In the present study we tested whether the H(3) receptor antagonist 4-(2-{2-[(2R)-2 methylpyrrolidinyl] ethyl}-benzofuran-5-yl) benzonitrile (ABT-239) influenced the psychomotor responses to acute and repeated nicotine, including sensitization and conditioned locomotion. ABT-239 (0.3-3 mg/kg) did not alter basal, nicotine-evoked (0.4 mg/kg) locomotor responses, the expression of sensitization, or cue-conditioned locomotion. However, in combination studies rats pretreated with a separate dose of ABT-239 (1 mg/kg) prior to nicotine (0.4 mg/kg) for 5 days and then challenged with nicotine (0.4 mg/kg) after a 5-day withdrawal period, showed significantly higher locomotor hyperactivity in comparison with the effect observed in nicotine-pretreated and challenged rats. Our findings implicate a limited role for H(3) receptors in locomotor responses to nicotine.

Hyperactivity and enhanced curiosity of mice expressing PKB/SGK-resistant glycogen synthase kinase-3 (GSK-3).

BACKGROUND: Mounting evidence suggests that bipolar disorder symptoms could be favorably influenced by modification of glycogen synthase kinase-3 (GSK-3) activity. Specifically, the well known antimanic and mood stabilizing medications lithium, valproate, olanzapine and clozapine have been shown to inhibit GSK-3 activity. GSK-3 is phosphorylated and thus inhibited by protein kinase B (PKB/Akt) and serum and glucocorticoid inducible kinase (SGK) isoforms. The present study explored, whether PKB/SGK-dependent GSK-3 regulation influences the behavior of mice. METHODS: Gene-targeted knockin mice with mutated and thus PKB/SGK-resistant GSK-3alpha, beta (gsk-3(KI)) were compared to corresponding wild type mice (gsk-3(WT)). The mice were analyzed by open-field, light-dark (LD-) box, O-maze, emergence test, object exploration test and forced swimming test (FST). RESULTS: In open-field, LD-box and O-maze, gsk-3(KI) mice displayed a hyperactive and more curious phenotype when compared to wild type mice. Speed and total distance moved as well as rearings were significantly increased in gsk-3(KI) compared to gsk-3(WT) mice. In the O-maze, gsk-3(KI) mice tended to travel a larger distance in the open, unprotected area thangsk-3(WT) mice, and performed significantly more unprotected head dips suggesting decreased anxiety behavior. In the forced swimming test, the immobility time was significantly decreased in gsk-3(KI) mice indicating a phenotype less prone to depression. Moreover, gsk-3(KI)mice were less sensitive to the application of chronic mild stress and showed a decreased HPA axis activity. CONCLUSIONS: The present observations disclose a significant role of PKB/SGK-dependent regulation of GSK-3 in the control of activity, anxiety and proneness to depression. Accordingly, mice expressing SGK/PKB resistant GSK-3 may be a valuable model of hyperactivity and mania.

Involvement of high plasma corticosterone status and activation of brain regional serotonin metabolism in long-term erythrosine-induced rearing motor hyper activity in young adult male rats.

Long-term consumption of artificial food color(s) can induce behavioral hyperactivity in human and experimental animals, but no neurobiochemical mechanism is defined. This study investigates the role of brain regional serotonin metabolism including its turnover, MAO-A activity, and plasma corticosterone status in relation to behavioral disturbances due to an artificial food color, erythrosine. Long-term (15 or 30 consecutive days) erythrosine administration with higher dosage (10 or 100 mg/kg/day, p.o.) produced optimal hyperactive state in exploratory behavior (rearing motor activity) after 2 h of last erythrosine administration, in young adult male albino rats. Erythrosine-induced stimulation in brain regional (medulla-pons, hypothalamus, hippocampus, and corpus striatum) serotonin metabolism (measuring steady state levels of 5-HT and 5-HIAA, MAO-A activity), including its turnover (pargyline-induced 5-HT accumulation and 5-HIAA declination rate), as well as plasma corticosterone were also observed depending on dosage(s) and duration(s) of erythrosine administration under similar experimental conditions. The lower dosage of erythrosine (1 mg/kg/day, p.o.) under similar conditions did not affect either of the above. These findings suggests (a) the induction as well as optimal effect of long-term erythrosine (artificial food color) on behavioral hyperactivity in parallel with increase in 5-HT level in brain regions, (b) the activation of brain regional serotonin biosynthesis in accordance with plasma corticosterone status under such behavioral hyperactivity, and (c) a possible inhibitory influence of the enhanced glucocorticoids-serotonin interaction on erythrosine-induced rearing motor hyperactivity in young adult mammals.

Pharmacological profile of lurasidone, a novel antipsychotic agent with potent 5-hydroxytryptamine 7 (5-HT7) and 5-HT1A receptor activity.

Lurasidone [(3aR,4S,7R,7aS)-2-[(1R,2R)-2-[4-(1,2-benzisothiazol-3-yl)piperazin-1-ylmethyl]cyclohexylmethyl]hexahydro-4,7-methano-2H-isoindole-1,3-dione hydrochloride; SM-13496] is an azapirone derivative and a novel antipsychotic candidate. The objective of the current studies was to investigate the in vitro and in vivo pharmacological properties of lurasidone. Receptor binding affinities of lurasidone and several antipsychotic drugs were tested under comparable assay conditions using cloned human receptors or membrane fractions prepared from animal tissue. Lurasidone was found to have potent binding affinity for dopamine D(2), 5-hydroxytryptamine 2A (5-HT(2A)), 5-HT(7), 5-HT(1A), and noradrenaline alpha(2C) receptors. Affinity for noradrenaline alpha(1), alpha(2A), and 5-HT(2C) receptors was weak, whereas affinity for histamine H(1) and muscarinic acetylcholine receptors was negligible. In vitro functional assays demonstrated that lurasidone acts as an antagonist at D(2) and 5-HT(7) receptors and as a partial agonist at the 5-HT(1A) receptor subtype. Lurasidone showed potent effects predictive of antipsychotic activity, such as inhibition of methamphetamine-induced hyperactivity and apomorphine-induced stereotyped behavior in rats, similar to other antipsychotics. Furthermore, lurasidone had only weak extrapyramidal effects in rodent models. In animal models of anxiety disorders and depression, treatment with lurasidone was associated with significant improvement. Lurasidone showed a preferential effect on the frontal cortex (versus striatum) in increasing dopamine turnover. Anti-alpha(1)-noradrenergic, anticholinergic, and central nervous system (CNS) depressant actions of lurasidone were also very weak. These results demonstrate that lurasidone possesses antipsychotic activity and antidepressant- or anxiolytic-like effects with potentially reduced liability for extrapyramidal and CNS depressant side effects.

Ampullosporin A, a peptaibol from Sepedonium ampullosporum HKI-0053 with neuroleptic-like activity.

The potential neuroleptic-like effect of ampullosporin A, a new peptaibol, isolated from the fungus Sepedonium ampullosporum HKI-0053, was characterized using specific behavioural models and methods. Ampullosporin A (amp) disrupted the retrieval of a well-trained conditioned reaction and normalized the behavioural effects of subchronic ketamine treatment in the social interaction test in a dose which showed only inconsiderable side effects. The experiments demonstrated that the substance did not antagonize the apomorphine (apo) induced hyperactivity. On the other hand, the locomotor stimulation induced by the NMDA receptor antagonist MK-801 was nearly completely suppressed by ampullosporin A, supposing interactions with the glutamatergic system. Binding studies demonstrated no interaction with dopaminergic D(1) and D(2) receptors. However, amp can alter the activity of glutamate receptors. The results resemble characteristics of an atypical neuroleptic drug. But further experiments are necessary to validate the suggested neuroleptic-like activity.

Unusual circadian locomotor activity and pathophysiology in mutant CRY1 transgenic mice.

In the widely accepted molecular model underlying mammalian circadian rhythm, cryptochrome proteins (CRYs) play indispensable roles as inhibitive components of the CLOCK-BMAL1-mediated transcriptional-translational negative feedback loop. In order to clarify yet uncovered aspects of mammalian CRYs in vivo, we generated transgenic (Tg) mice ubiquitously overexpressing CRY1 as well as CRY1 having a mutation in the dipeptide motif of cysteine and proline that is conserved beyond evolutional divergence among animal CRYs: cysteine414 of the motif was replaced with alanine (CRY1-AP). The mice overexpressing CRY1 (CRY1 Tg) exhibited robust circadian rhythms of locomotor activity. In sharp contrast, the mice overexpressing CRY1-AP (CRY1-AP Tg) displayed a unique circadian phenotype. Their locomotor free-running periods were very long (around 28h) with rhythm splitting: the bout of activity of CRY1-AP Tg mice was split into two equal components in constant darkness. Moreover, CRY1-AP Tg mice displayed abnormal entrainment behavior: their bout of activity shifted immediately in response to a shift of the light-dark cycles. In addition, we found that CRY1-AP Tg mice showed symptoms characteristic of diabetes mellitus. The results indicate that the motif of CRY1 is crucial to the mammalian clock system and physiology.