Correlation between desynchrony of hippocampal neural activity and hyperlocomotion in the model mice of schizophrenia and therapeutic effects of aripiprazole.

AIMS: The hippocampus has been reported to be morphologically and neurochemically altered in schizophrenia (SZ). Hyperlocomotion is a characteristic SZ-associated behavioral phenotype, which is associated with dysregulated dopamine system function induced by hippocampal hyperactivity. However, the neural mechanism of hippocampus underlying hyperlocomotion remains largely unclear. METHODS: Mouse pups were injected with N-methyl-D-aspartate receptor antagonist (MK-801) or vehicle twice daily on postnatal days (PND) 7-11. In the adulthood phase, one cohort of mice underwent electrode implantation in field CA1 of the hippocampus for the recording local field potentials and spike activity. A separate cohort of mice underwent surgery to allow for calcium imaging of the hippocampus while monitoring the locomotion. Lastly, the effects of atypical antipsychotic (aripiprazole, ARI) were evaluated on hippocampal neural activity. RESULTS: We found that the hippocampal theta oscillations were enhanced in MK-801-treated mice, but the correlation coefficient between the hippocampal spiking activity and theta oscillation was reduced. Consistently, although the rate and amplitude of calcium transients of hippocampal neurons were increased, their synchrony and correlation to locomotion speed were disrupted. ARI ameliorated perturbations produced by the postnatal MK-801 treatment. CONCLUSIONS: These results suggest that the disruption of neural coordination may underly the neuropathological mechanism for hyperlocomotion of SZ.

Acute Hyperkinetic Movement Disorders as a Multifactorial Pharmacodynamic Drug Interaction Between Methylphenidate and Risperidone in Children and Adolescents.

PURPOSE/BACKGROUND: Acute hyperkinetic movement disorders have been reported with the concomitant use of attention-deficit/hyperactivity disorder (ADHD) stimulants and antipsychotics in children and adolescents. We analyzed postmarketing reports of suspected acute hyperkinetic movement disorder associated with concomitant use of ADHD stimulants and antipsychotics. METHODS/PROCEDURES: We searched for postmarketing reports of acute hyperkinetic movement disorders associated with concomitant use of ADHD stimulants-antipsychotics in the US Food and Drug Administration Adverse Event Reporting System through December 6, 2019. PubMed and EMBASE were also searched for acute hyperkinetic movement reports with the concomitant use of ADHD stimulants-antipsychotics through January 13, 2020. FINDINGS/RESULTS: We identified 36 cases resulting in acute hyperkinetic movement disorder associated with the concomitant use of ADHD stimulants-antipsychotics, 19 of which were also identified in the medical literature. From an ADHD stimulant perspective, methylphenidate products accounted for the largest number of cases (n = 23 [64%]), followed by amphetamine products (n = 9 [25%]) and atomoxetine (n = 4 [11%]). From an antipsychotic perspective, all 36 cases were reported with second-generation antipsychotics, particularly risperidone (n = 20 [56%]). Most of the cases were reported in boys (n = 31 [86%]) aged 6 to 12 years (n = 27 [75%]). Approximately 53% of the cases reported a time to onset within 24 hours of the drug change. Acute dystonic reactions (n = 27 [75%]) were the most frequently reported movement disorder. IMPLICATIONS/CONCLUSIONS: As outlined in changes to the US prescribing information for all methylphenidate and risperidone products, health care professionals should be aware that changes to this combination may be associated with a pharmacodynamic drug-drug interaction resulting in acute hyperkinetic movement disorder.

ERK5 inhibitor BIX02189 attenuates methamphetamine-induced hyperactivity by modulating microglial activation in the striatum.

Extracellular signal-regulated protein kinase 5 (ERK5) has various physiological functions. However, the physiological role of ERK5 in the treatment of mice with an illicit drug such as methamphetamine (METH) remains unknown. We revealed that mice treated with METH showed hyperactivity, and increased p-ERK5 and Iba1 (a microglia marker) levels in the striatum. Additionally, these changes were inhibited by pretreatment with the ERK5 inhibitor BIX02189. The results suggest that METH-induced hyperactivity is associated with the activation of microglia via p-ERK5 in the striatum. Thus, the ERK5 pathway components in the central nervous system are potential therapeutic targets for preventing METH addiction.

Histamine H3 receptor antagonism modulates autism-like hyperactivity but not repetitive behaviors in BTBR T+Itpr3tf/J inbred mice.

BACKGROUND: Autism spectrum disorders (ASDs) are a group of neurodevelopmental conditions defined by behavioral deficits in social communication and interactions, mental inflexibility and repetitive behaviors. Converging evidence from observational and preclinical studies suggest that excessive repetitive behaviors in people with ASD may be due to elevated histaminergic H3 receptor signaling in the striatum. We hypothesized that systemic administration of pharmacological histamine H3 receptor antagonists would attenuate the expression of repetitive behaviors in the BTBR T+Itpr3tf/J (BTBR) mouse inbred strain, an established mouse model presenting autism-like repetitive behaviors and novelty-induced hyperactivity. We further aimed to investigate whether agonism of the histamine H3 receptor would be sufficient to induce repetitive behaviors in the C57BL/6J control mouse strain. METHODS: Different doses of H3 receptor agonists (i.e., (R)-α-methylhistamine and immethridine) and H3 receptor antagonists/inverse agonists (i.e., ciproxifan and pitolisant) were administered via intraperitoneal (i.p.) injection in male mice to characterize the acute effects of these compounds on ASD-related behavioral readouts. RESULTS: The highly selective H3 receptor agonist immethridine significantly increased the time spent in stereotypic patterns in C57BL/6J mice, but this effect appeared to be driven by general sedative properties of the compound. High doses of pitolisant significantly decreased locomotor hyperactivity in novel environments in BTBR mice, without significant effects on repetitive behaviors. CONCLUSIONS: Based on our findings, we conclude that acute H3 receptor manipulation mainly affected general motor activity levels in novel environments. Small changes in stereotyped behaviors were observed but appeared to be driven by altered general activity levels.

Haloperidol and methylphenidate alter motor behavior and responses to conditioned fear of Carioca Low-conditioned Freezing rats.

Animal models are important tools for studying neuropsychological disorders. Considering their limitations, a more extensive translational research must encompass data that are generated from several models. Therefore, a comprehensive characterization of these models is needed in terms of behavior and neurophysiology. The present study evaluated the behavioral responses of Carioca Low-conditioned Freezing (CLF) rats to haloperidol and methylphenidate. The CLF breeding line is characterized by low freezing defensive responses to contextual cues that are associated with aversive stimuli. CLF rats exhibited a delayed response to haloperidol at lower doses, needing higher doses to reach similar levels of catatonia as control randomly bred animals. Methylphenidate increased freezing responses to conditioned fear and induced motor effects in the open field. Thus, CLF rats differ from controls in their responses to both haloperidol and methylphenidate. Because of the dopamine-related molecular targets of these drugs, we hypothesize that dopaminergic alterations related to those of animal models of hyperactivity and attention disorders might underlie the observed phenotypes of the CLF line of rats.

Recent Advances in the Pharmacological Management of Behavioral Disturbances Associated with Autism Spectrum Disorder in Children and Adolescents.

Autism spectrum disorder (ASD) is a heterogeneous neuropsychiatric condition affecting an estimated one in 36 children. Youth with ASD may have severe behavioral disturbances including irritability, aggression, and hyperactivity. Currently, there are only two medications (risperidone and aripiprazole) approved by the US Food and Drug Administration (FDA) for the treatment of irritability associated with ASD. Pharmacologic treatments are commonly used to target ASD-associated symptoms including irritability, mood lability, anxiety, and hyperactivity. However, evidence for the efficacy of many commonly used treatments is limited by the lack of large placebo-controlled trials of these medications in this population. Research into the pathophysiology of ASD has led to new targets for pharmacologic therapy including the neuroimmune system, the endocannabinoid system, and the glutamatergic neurotransmitter system. The goal of this review is to provide an overview of the current evidence base for commonly used treatments, as well as emerging treatment options for common behavioral disturbances seen in youth with ASD.

Intranasal delivery of tetrabenazine nanoemulsion via olfactory region for better treatment of hyperkinetic movement associated with Huntington's disease: Pharmacokinetic and brain delivery study.

Tetrabenazine reduces chorea symptoms associated with Huntington's disease by depleting monoamines in pre-synaptic vesicles. It exhibits low aqueous solubility and undergoes first pass metabolism due to which it has low oral bioavailability. The aim of present work was to formulate intranasal tetrabenazine loaded nanoemulsion for better management and treatment of hyperkinesia related with Huntington's disease. A quality by design (QbD) technique was employed as statistical multivariate approach for formulation and optimization of nanoemulsion. Optimized formulation showed droplet size of 106.80 ±â€¯1.96 nm with polydispersity index (PDI) value of 0.198 ±â€¯0.005 and -9.63 ±â€¯0.63 mV zeta potential. Ex-vivo drug permeation studies were carried out and found that the formulation has an augmented permeation by 1.68 times as compared to tetrabenazine suspension. MTT assay on neuro-2a cell lines showed that tetrabenazine loaded nanoemulsion displayed better cell viability than placebo and aqueous drug solution at ½ × Cmax, Cmax and 2 × Cmax. Pharmacokinetic parameters in brain after intranasal administration of tetrabenazine nanoemulsion were found to be Cmax = 3.497 ±â€¯0.275 µg/mL, AUC0-12 = 29.196 ±â€¯0.870 µg h/mL and elimination rate constant (ke) = 0.097 ±â€¯0.012 h-1 where as in plasma the pharmacokinetic parameters were Cmax = 1.400 ±â€¯0.084 µg/mL, AUC0-12 = 12.925 ±â€¯0.340 µg h/mL and ke = 0.061 ±â€¯0.010 h-1. Histopathological studies of porcine nasal mucosa showed that nasal mucosa remains intact when treated with tetrabenazine loaded nanoemulsion. Thus it can be concluded from study that optimized nanoemulsion formulation of a tetrabenazine was robust and its delivery through nasal route is a viable alternative to other routes of administration for treatment of hyperkinesia associated with Huntington's disease.

In vivo evaluation of effects of histamine H3 receptor antagonists on methamphetamine-induced hyperlocomotion in mice.

A single administration with METH (3 mg/kg) induced a hyperlocomotion in male ICR mice. Pretreatment of mice with pitolisant, a histamine H3 receptor antagonist (5 and 10 mg/kg), for 30 min showed a significant reduction of the hyperlocomotion induced by METH, as compared with vehicle (saline)-pretreated subjects. Pretreatment of mice with the histamine H3 receptor antagonists JNJ-10181457 (5 and 10 mg/kg) or conessine (20 mg/kg), also showed similar inhibitory effects on METH-induced hyperlocomotion, similar to pitolisant. No significant change in locomotion was observed in mice pretreated with pitolisant, JNJ-10181457, or conessine alone. The pitolisant (10 mg/kg) action on METH-induced hyperlocomotion was completely abolished by the histamine H1 receptor antagonist pyrilamine (10 mg/kg), but not by the peripherally acting histamine H1 receptor antagonist fexofenadine (20 mg/kg), the brain-penetrating histamine H2 receptor antagonist zolantidine (10 mg/kg), or the brain-penetrating histamine H4 receptor antagonist JNJ-7777120 (40 mg/kg). Pretreatment with a histamine H3 receptor agonist immepip (10 mg/kg) augmented METH--induced behavior, including hyperlocomotion and stereotyped biting, and combined pretreatment with pitolisant (10 mg/kg) significantly attenuated stereotyped biting. These observations suggest that pretreatment with histamine H3 receptor antagonists attenuate METH-induced hyperlocomotion via releasing histamine after blocking H3 receptors, which then bind to the post-synaptic histamine receptor H1 (but not H2 or H4). It is likely that activation of brain histamine systems may be a good strategy for the development of agents, which treat METH abuse and dependence.

VMAT2 inhibitors for the treatment of hyperkinetic movement disorders.

Hyperkinetic movement disorders comprise a variety of conditions characterized by involuntary movements, which include but are not limited to tardive dyskinesia, chorea associated with Huntington's Disease, and tic disorders. The class of medications that have been used to treat these conditions includes Vesicular Monoamine Transporter-2 (VMAT2) inhibitors. In 2008, the FDA approved tetrabenazine as a treatment for chorea associated with Huntington's Disease. Optimization of the pharmacology of tetrabenazine has since led to the approval of two new VMAT2 inhibitors, deutetrabenazine and valbenazine. The objective of this review is to provide background on the role of VMAT in monoamine neurotransmission, the mechanism of VMAT2 inhibition on the treatment of hyperkinetic disorders (specifically tardive dyskinesia and chorea associated with Huntington's Disease), the pharmacology and pharmacokinetics of the commercially available VMAT2 inhibitors, and a summary of the clinical data to support application of these medications.

Pharmacodynamics and metabonomics study of Tianma Gouteng Decoction for treatment of spontaneously hypertensive rats with liver-yang hyperactivity syndrome.

ETHNOPHARMACOLOGICAL RELEVANCE: Essential hypertension is a prevalence chronic cardiovascular disease, which is treated by traditional Chinese medicine (TCM) in China. Metabolomics approach has achieved more attention in pharmacology studies of natural products. Tianma Gouteng Decoction (TGD) is effective for the therapeutic of hypertension in China. We aimed to investigate antihypertension effect of TGD on spontaneous hypertension rat (SHR) with live-Yang hyperactivity hypertension (Gan Yang Shang Kang, GYSK) and explore the mechanism by metabolomics method. MATERIALS AND METHODS: After establishing the GYSK-SHR model by giving aconite decoction, rats were randomly divided into four groups including model group, TGD qd group (66.88 mg/kg, once a day), TGD bid group (33.44 mg/kg, twice a day), TGD tid group (22.29 mg/kg, three times a day). Blood pressure (BP) and indexes of renin-angiotensin-aldosterone system (RAAS system) were measured. Metabolic profiling of rat plasma samples was performed by UPLC-Q-TOF/MS, which was analyzed with principal component analysis (PCA) and partial least-squares-discriminate analysis (PLS-DA) to explore the relationship between metabolic pathways and hypertension. RESULTS: To better explain the role of TGD on hypertension, we detected three different frequencies of TGD treatment with equal dosage. TGD reduced the BP in GYSH-SHR model and regulated the serum levels of NE, Ang II, ET, 5-HT, CRP, RENIN and ALD especially at TGD bid group. By UPLC-Q-TOF/MS analysis, we found 47 potential biomarkers in GYSK-SHR rats from the plasma metabolites, among which 15 biomarkers were regulated by TGD. Consisted with the antihypertension activity, TGD bid group showed the significantly moderating effect on the regulating biomarkers. CONCLUSIONS: TGD exhibited the antihypertensive activity at the frequency of administration twice a day, which had the association with RAAS system and mediated 15 biomarkers by regulating metabolisms of glycerol phospholipid, sphingomyelin, energy and amino acid.

ASP2905, a specific inhibitor of the potassium channel Kv12.2 encoded by the Kcnh3 gene, is psychoactive in mice.

Schizophrenia is a major psychiatric disorder associated with positive and negative symptoms and cognitive impairments. In this study, we used animal models of behavior to evaluate the antipsychotic activity of ASP2905, a potent and selective inhibitor of the potassium channel Kv12.2 encoded by the Kcnh3/BEC1 gene. ASP2905 inhibited hyperlocomotion induced by methamphetamine and by phencyclidine. In contrast, ASP2905 did not affect spontaneous locomotion, suggesting that ASP2905 selectively inhibits abnormal behaviors induced by stimulants. Chronic infusion of ASP2905 significantly ameliorated phencyclidine-induced prolongation of immobility time in mice subjected to the forced swimming test. These findings suggest that ASP2905 potentially mitigates symptoms of schizophrenia, such as apathy. The antipsychotic clozapine also reversed phencyclidine-induced prolonged immobility, while risperidone and haloperidol had no effect. Assessment of the effects of ASP2905 on latent learning deficits in mice treated with phencyclidine as neonates subjected to the water-finding task showed that ASP2905 significantly ameliorated phencyclidine-induced prolongation of finding latency, which reflects latent learning performance. These findings suggest that ASP2905 potentially mitigates cognitive impairments caused by schizophrenia, such as attention deficits. In contrast, administration of clozapine did not ameliorate phencyclidine-induced prolongation of finding latency. Therefore, ASP2905 may alleviate the broad spectrum of symptoms of schizophrenia, including positive and negative symptoms and cognitive impairments, which is in contrast to currently available antipsychotics, which are generally only partially effective for ameliorating these symptoms.

G protein-coupled receptor binding and pharmacological evaluation of indole-derived thiourea compounds.

Four 2-(1H-indol-3-yl)ethylthiourea derivatives were prepared by condensation of 2-(1H-indol-3-yl)ethanamine with the corresponding aryl/alkylisothiocyanates in a medium-polarity solvent. Their structures were confirmed by spectral techniques, and the molecular structure of 3 was determined by X-ray crystal analysis. For all derivatives, the binding affinities at the 5-HT2A and 5-HT2C receptors, as well as their functional activities at the 5-HT1A and D2 receptors, were determined. The arylthioureas 1 and 4 were the most active at the 5-HT1A receptor, showing, at the same time, significant selectivity over the studied 5-HT2 and D2 receptor subtypes. The compounds were tested for their pharmacological activities within the central nervous system in relevant mouse models. The involvement of the serotonergic system in the activity of 1 and 4 was indicated. The antinociceptive action of 4 was linked to its anti-inflammatory activity.

α7 nicotinic receptor full agonist reverse basolateral amygdala hyperactivity and attenuation of dopaminergic neuron activity in rats exposed to chronic mild stress.

Neuroimaging and preclinical studies showing that nicotinic receptors (nAChR) may play a role in mood control has increased interest in targeting the cholinergic system for treatment of major depressive disorder. Indeed, modulation of nAChRs in the basolateral amygdala (BLA) are sufficient to produce an anti-immobility effect in the mouse tail suspension test. However, how α7 nAChR modulation impacts BLA neuronal activity in vivo as well as the downstream mechanisms involved in its mood-related effects are not understood. In this work, we used the unpredictable chronic mild stress (CMS) model to investigate the mechanisms underlying the antidepressant-like effect of an α7 nAChR full agonist on BLA-induced changes in dopaminergic neurotransmission. Male adult Sprague-Dawley rats were exposed to four weeks of CMS. Behavioral and electrophysiological experiments were performed within one week following stress. CMS exposure increased rats' immobility time in the forced swimming test, decreased the number of spontaneously active dopamine neurons in the ventral tegmental area and increased the firing rate of putative projection neurons in the BLA. Stress-induced behavioral and electrophysiological changes were reversed by a single systemic administration of PNU282987. In summary, our findings corroborate previous descriptions of a potential rapid antidepressant effect for the α7 nAChR full agonist. This effect appears to involve a mechanism distinct from those of classic antidepressants: normalization of BLA hyperactivity and, consequently, of DA hypofunction. These observations corroborate the role of α7 nAChR as a potential target for novel antidepressant drug development.

Effects of the Hyptis martiusii Benth. leaf essential oil and 1,8-cineole (eucalyptol) on the central nervous system of mice.

The aim of this study was to characterize the central effects of the Hyptis martiusii leaf essential oil (OEHM) and 1,8-cineole (eucalyptol) using behavioral animal models. Gas chromatography coupled to mass spectrometry (GC/MS) was used to characterize the chemical compounds present in the OEHM. For the behavioral tests, female Swiss mice treated with the OEHM (25, 50, 100 and 200 mg/kg, i.p.) and 1,8-cineole (50 mg/kg, i.p.) were used and subjected to the following tests: open field, elevated cross maze, rotarod, sodium pentobarbital- or ethyl ether-induced sleep time, pentylenetetrazol-induced convulsions, haloperidol-induced catalepsy, and ketamine-induced hyperkinesia. GC/MS analysis identified 20 constituents with the majority of them being monoterpenes and sesquiterpenes, with eucalyptol (1,8-cineol), the major sample compound (25.93%), standing out. The results showed the OEHM (25, 50 100 and 200 mg/kg, i.p.) and its major compound (50 mg/kg, i.p.) reduced animal motility in the open field test, increased pentobarbital- and ethyl ether-induced sleep time, as well as death latency in the pentylenetetrazole-induced convulsion model. However, the tested compounds were devoid of anxiolytic-like and myorelaxant activity. In addition, the OEHM (100 and 200 mg/kg, i.p.) and 1,8-cineole (50 mg/kg, i.p.) potentiated haloperidol-induced catalepsy and reduced ketamine-induced hyperkinesia. Taken together, the results suggest the OEHM has important hypnotic-sedative and antipsychotic-like effects, which appear to be due to the monoterpene 1,8-cineole, the major compound identified in the essential oil.

Guanabenz Reverses a Key Behavioral Change Caused by Latent Toxoplasmosis in Mice by Reducing Neuroinflammation.

Toxoplasma gondii is an intracellular parasite that has infected one-third of humans. The infection is permanent because the replicative form (tachyzoite) converts into a latent tissue cyst form (bradyzoite) that evades host immunity and is impervious to current drugs. The continued presence of these parasitic cysts hinders treatment and leads to chronic infection that has been linked to behavioral changes in rodents and neurological disease in humans. How these behavioral changes occur, and whether they are due to parasite manipulation or the host response to infection, remains an outstanding question. We previously showed that guanabenz possesses antiparasitic activity; here, we show that guanabenz reproducibly lowers brain cyst burden up to 80% in chronically infected male and female BALB/cJ mice when given intraperitoneally but not when administered by gavage or in food. Regardless of the administration route, guanabenz reverses Toxoplasma-induced hyperactivity in latently infected mice. In contrast, guanabenz increases cyst burden when given to chronically infected C57BL/6J mice yet still reverses Toxoplasma-induced hyperactivity. Examination of the brains from chronically infected BALB/cJ and C57BL/6J mice shows that guanabenz decreases inflammation and perivascular cuffing in each strain. Our study establishes a robust model for cyst reduction in BALB/cJ mice and shows for the first time that it is possible to reverse a key behavioral change associated with latent toxoplasmosis. The rescue from parasite-induced hyperactivity correlates with a decrease in neuroinflammation rather than reduced cyst counts, suggesting that some behavioral changes arise from host responses to infection.IMPORTANCEToxoplasma gondii is a common parasite of animals, including up to one-third of humans. The single-celled parasite persists within hosts for the duration of their life as tissue cysts, giving rise to chronic infection. Latent toxoplasmosis is correlated with neurological dysfunction in humans and results in dramatic behavioral changes in rodents. When infected, mice and rats adapt behaviors that make them more likely to be devoured by cats, the only host that supports the sexual stage of the parasite. In this study, we establish a new mouse model of tissue cyst depletion using a drug called guanabenz and show that it is possible to reverse a key behavior change back to normal in infected animals. We also show that the mechanism appears to have nothing to do with parasite cyst burden but rather the degree of neuroinflammation produced by chronic infection.

Reversal of morphine conditioned behavior by an anti-dopaminergic post-trial drug treatment during re-consolidation.

Morphine has potent pro-dopamine effects that can be manifested as hyper-locomotion and these behavioral effects can undergo conditioning and sensitization. The aim of the present study was to assess whether an inhibitory dopaminergic post-trial treatment (0.05 mg/kg apomorphine) given during re-consolidation could reduce morphine conditioning. To induce conditioned morphine hyperactivity and control for morphine exposure, a paired/unpaired Pavlovian conditioning protocol was used. The morphine paired groups received morphine in the open-field test arena and the unpaired groups received the same morphine (10 mg/kg) treatments but in a different environment. The morphine treatments were administered once per day for 5 days. With repeated treatments, the paired morphine groups developed a sensitized hyper-locomotion response whereas the unpaired morphine groups did not differ from vehicle groups. Subsequently, the paired, unpaired and vehicle groups were given four daily non-drug 5 min conditioning tests. In these conditioning tests, the paired but not the unpaired and vehicle groups exhibited a conditioned locomotor stimulant response. These groups were subdivided into matched groups and received either vehicle or 0.05 mg/kg apomorphine either during re-consolidation immediately post-test or after re-consolidation 15 min post-test. In the immediate post-trial treatment groups, the morphine conditioned response in the paired group was eliminated after only one post-trial apomorphine treatment. The same immediate 0.05 mg/kg apomorphine post-trial treatments had no effect on the unpaired morphine or vehicle groups. In the paired group that received vehicle immediately post-trial, the conditioned response remained robust and unchanged over the four conditioning tests. In the post-trial 15 min delay treatment groups, the post-trial apomorphine treatments had no effect on the morphine conditioned response. These results showed that the inhibition of dopamine activity by apomorphine during the re-consolidation of a cue activated morphine conditioned response eliminated morphine conditioned effects. In that morphine conditioned effects are important for the initiation of addiction and in triggering drug craving and relapse, this finding has potential relevance to opioid addiction treatment.