Prenatal and perinatal exposure to Per- and polyfluoroalkyl substances (PFAS)-contaminated drinking water impacts offspring neurobehavior and development.

Per- and polyfluoroalkyl substances (PFAS) are persistent organic pollutants ubiquitous in the environment and humans. In-utero PFAS exposure is associated with numerous adverse health impacts. However, little is known about how prenatal PFAS mixture exposure affects offspring's neurobehavioral function. This study aims to determine the causal relationship between in-utero PFAS mixture exposure and neurobehavioral changes in Sprague-Dawley rat offspring. Dams were exposed via drinking water to the vehicle (control), an environmentally relevant PFAS mixture, or a high-dose PFAS mixture. The environmentally relevant mixture was formulated to resemble measured tap water levels in Pittsboro, NC, USA (10 PFAS compounds; sum PFAS =758.6 ng/L). The high-dose PFAS load was 3.8 mg/L (5000×), within the range of exposures in the experimental literature. Exposure occurred seven days before mating until birth. Following exposure to PFAS-laden water or the vehicle during fetal development, neurobehavioral toxicity was assessed in male and female offspring with a battery of motor, cognitive, and affective function tests as juveniles, adolescents, and adults. Just before weaning, the environmentally relevant exposure group had smaller anogenital distances compared to the vehicle and high-dose groups on day 17, and males in the environmentally relevant exposure group demonstrated lower weights than the high-dose group on day 21 (p < 0.05). Reflex development delays were seen in negative geotaxis acquisition for both exposure groups compared to vehicle-exposed controls (p = 0.009). Our post-weaning behavioral measures of anxiety, depression, and memory were not found to be affected by maternal PFAS exposure. In adolescence (week five) and adulthood (week eight), the high PFAS dose significantly attenuated typical sex differences in locomotor activity. Maternal exposure to an environmentally relevant PFAS mixture produced developmental delays in the domains of pup weight, anogenital distance, and reflex acquisition for rat offspring. The high-dose PFAS exposure significantly decreased typical sex differences in locomotor activity.

Transcriptome-based approach to identify mechanisms underlying locomotor abnormality induced by decabromodiphenyl ethane in zebrafish larvae.

The brominated flame retardant decabromodiphenyl ethane (DBDPE) has been extensively used following restrictions on BDE-209 and thus, been frequently detected in aquatic environment. However, information on impact of DBDPE on fish development and the potential mechanisms remains scarce. In present study, developing zebrafish were employed as a study model. Embryos were exposed until 5 d to DBDPE at concentrations of 0, 3, 30, and 300 µg/L, following which the impact on larval development was investigated. DBDPE bioaccumulation and locomotor hyperactivity were observed in developing zebrafish exposed to DBDPE. Transcriptome and bioinformatics analyses indicated that pathways associated with cardiac muscle contraction and retinol metabolism were notably affected. The mechanisms of DBDPE to induce locomotor abnormality were further investigated by analyzing levels of retinol and retinol metabolites, eye and heart histology, heart rates, and ATPase activity. Our results indicate that locomotor hyperactivity observed in larvae exposed to DBDPE results from abnormal heartbeat, which in turn is attributable to inhibition of Na+/K+-ATPase activity. Furthermore, DBDPE did not change larval eye histology and contents of retinoid (retinol, retinal, and retinoic acid). This study provides insight into the mechanisms underlying DBDPE-induced developmental toxicity and highlights the need for addressing the environmental risks for aquatic organisms.

The ATP6V1B2 DDOD/DOORS-Associated p.Arg506* Variant Causes Hyperactivity and Seizures in Mice.

The vacuolar H+-ATPase is a multisubunit enzyme which plays an essential role in the acidification and functions of lysosomes, endosomes, and synaptic vesicles. Many genes encoding subunits of V-ATPases, namely ATP6V0C, ATP6V1A, ATP6V0A1, and ATP6V1B2, have been associated with neurodevelopmental disorders and epilepsy. The autosomal dominant ATP6V1B2 p.Arg506* variant can cause both congenital deafness with onychodystrophy, autosomal dominant (DDOD) and deafness, onychodystrophy, osteodystrophy, mental retardation, and seizures syndromes (DOORS). Some but not all individuals with this truncating variant have intellectual disability and/or epilepsy, suggesting incomplete penetrance and/or variable expressivity. To further explore the impact of the p.Arg506* variant in neurodevelopment and epilepsy, we generated Atp6v1b2emR506* mutant mice and performed standardized phenotyping using the International Mouse Phenotyping Consortium (IMPC) pipeline. In addition, we assessed the EEG profile and seizure susceptibility of Atp6v1b2emR506* mice. Behavioral tests revealed that the mice present locomotor hyperactivity and show less anxiety-associated behaviors. Moreover, EEG analyses indicate that Atp6v1b2emR506* mutant mice have interictal epileptic activity and that both heterozygous (like patients) and homozygous mice have reduced seizure thresholds to pentylenetetrazol. Our results confirm that variants in ATP6V1B2 can cause seizures and that the Atp6v1b2emR506* heterozygous mouse model is a valuable tool to further explore the pathophysiology and potential treatments for vacuolar ATPases-associated epilepsy and disorders.

Dopamine Transporter Deficient Rodents: Perspectives and Limitations for Neuroscience.

The key element of dopamine (DA) neurotransmission is undoubtedly DA transporter (DAT), a transmembrane protein responsible for the synaptic reuptake of the mediator. Changes in DAT's function can be a key mechanism of pathological conditions associated with hyperdopaminergia. The first strain of gene-modified rodents with a lack of DAT were created more than 25 years ago. Such animals are characterized by increased levels of striatal DA, resulting in locomotor hyperactivity, increased levels of motor stereotypes, cognitive deficits, and other behavioral abnormalities. The administration of dopaminergic and pharmacological agents affecting other neurotransmitter systems can mitigate those abnormalities. The main purpose of this review is to systematize and analyze (1) known data on the consequences of changes in DAT expression in experimental animals, (2) results of pharmacological studies in these animals, and (3) to estimate the validity of animals lacking DAT as models for discovering new treatments of DA-related disorders.

Sex Differences in Psychosis: Focus on Animal Models.

Most psychiatric illnesses, such as schizophrenia, show profound sex differences in incidence, clinical presentation, course, and outcome. Fortunately, more recently the literature on sex differences and (to a lesser extent) effects of sex steroid hormones is expanding, and in this review we have focused on such studies in psychosis, both from a clinical/epidemiological and preclinical/animal model perspective. We begin by briefly describing the clinical evidence for sex differences in schizophrenia epidemiology, symptomatology, and pathophysiology. We then detail sex differences and sex hormone effects in behavioral animal models of psychosis, specifically psychotropic drug-induced locomotor hyperactivity and disruption of prepulse inhibition. We expand on the preclinical data to include developmental and genetic models of psychosis, such as the maternal immune activation model and neuregulin transgenic animals, respectively. Finally, we suggest several recommendations for future studies, in order to facilitate a better understanding of sex differences in the development of psychosis.

Discovery of Trace Amine Associated Receptor 1 (TAAR1) Agonist 2-(5-(4'-Chloro-[1,1'-biphenyl]-4-yl)-4H-1,2,4-triazol-3-yl)ethan-1-amine (LK00764) for the Treatment of Psychotic Disorders.

A focused in-house library of about 1000 compounds comprising various heterocyclic motifs in combination with structural fragments similar to ß-phenethylamine (PEA) or tyramine was screened for the agonistic activity towards trace amine-associated receptor 1 (TAAR1). The screening yielded two closely related hits displaying EC50 values in the upper submicromolar range. Extensive analog synthesis and testing for TAAR1 agonism in a BRET-based cellular assay identified compound 62 (LK00764) with EC50 = 4.0 nM. The compound demonstrated notable efficacy in such schizophrenia-related in vivo tests as MK-801-induced hyperactivity and spontaneous activity in rats, locomotor hyperactivity of dopamine transporter knockout (DAT-KO) rats, and stress-induced hyperthermia (i.p. administration). Further preclinical studies are necessary to evaluate efficacy, safety and tolerability of this potent TAAR1 agonist for the potential development of this compound as a new pharmacotherapy option for schizophrenia and other psychiatric disorders.

Analysis of striatum and brain levels reveals sex differences in conversion of methamphetamine to amphetamine in mice.

The aim of this study was to compare methamphetamine (Meth) and amphetamine (Amph) levels in the brain of male and female mice. Meth and Amph levels were significantly higher at 30 min after systemic administration of 2 mg/kg of Meth than at 120 min. Meth levels were similar in striatum as in the rest of the brain and there was no sex difference. However, females showed significantly higher levels of Amph compared to males in both regions. The ratio of Amph to Meth levels was significantly higher in female mice than in males at 120 min after Meth administration. In a separate cohort of mice, treatment with 3 mg/kg of Meth induced significant locomotor hyperactivity which was maximum in the first 60 min after injection and not different between male and female mice. Treatment with 1 mg/kg Meth induced mild hyperactivation in female, but not male mice at 60-120 min post-injection. These data show sex differences in conversion of Meth to Amph in mice, which could play a role in sex differences in the behavioural, addictive and neurotoxic properties of Meth in rodents as well as in humans.

Upregulation of Glutamatergic Receptors in Hippocampus and Locomotor Hyperactivity in Aged Spontaneous Hypertensive Rat.

Epidemiologic studies have indicated that chronic hypertension may facilitate the progression of abnormal behavior, such as emotional irritability, hyperactivity, and attention impairment. However, the mechanism of how chronic hypertension affects the brain and neuronal function remains unclear. In this study, 58-week-old male spontaneously hypertensive rats (SHR) and age-matched Wistar-Kyoto (WKY) control rats were used. Their locomotor activity and neuronal function were assessed by the open field test, novel object, and Y maze recognition test. Moreover brain tissues were analyzed. We found that the aged SHR exhibited significant locomotor hyperactivity when compared to the WKY rats. However, there was no significant difference in novel object and novel arm recognition between aged SHR and the WKY rats. In the analysis of synaptic membrane protein, the expression of glutamatergic receptors, such as the N-methyl-D-aspartate (NMDA) receptor receptors subunits 2B (GluN2B) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor 1 (GluA1) in the hippocampus of SHR were significantly higher than those of WKY rats. In addition, in the synaptic membrane of SHR's hippocampus and medial prefrontal cortex (mPFC), a down-regulation of astrocytes was found, though the excitatory amino acid transporter 2 (EAAT2) remained constant. Moreover, a down-regulation of microglia in the hippocampus and mPFC was seen in the SHR brain. Long-term exposure to high blood pressure causes upregulation of glutamate receptors. The upregulation of glutamatergic receptors in hippocampus may contribute to the hyper-locomotor activity of aged rodents and may as a therapeutic target in hypertension-induced irritability and hyperactivity.

Suppressing effect of the novel positive allosteric modulator of the GABAB receptor, COR659, on locomotor hyperactivity induced by different drugs of abuse.

COR659 is a recently synthesized positive allosteric modulator (PAM) of the GABAB receptor. Similarly to all GABAB PAMs tested to date, COR659 has been reported to suppress different alcohol-related behaviors in rodents. The present study was designed to assess whether the anti-addictive properties of COR659 extend to drugs of abuse other than alcohol. Specifically, it investigated the effect of COR659 on cocaine-, amphetamine-, nicotine-, and morphine-induced locomotor hyperactivity in mice. To this aim, independent groups of CD1 mice were acutely pretreated with COR659 (0, 10, and 20 mg/kg; i.p.), then acutely treated with cocaine (0 and 10 mg/kg, s.c.), amphetamine (0 and 5 mg/kg; s.c.), nicotine (0 and 0.05 mg/kg; s.c.), or morphine (0 and 20 mg/kg; s.c.), and finally exposed for 60 min to a photocell-equipped motility cage. When given alone, both doses of COR659 were ineffective on spontaneous locomotor activity. Pretreatment with COR659 reduced, or even suppressed, the increase in motility counts induced by cocaine, amphetamine, nicotine, and morphine. Since locomotor hyperactivity is an attribute common to drugs of abuse, the results of the present study constitute the first line of evidence on the extension of the preclinical, anti-addictive profile of COR659 to cocaine, amphetamine, nicotine, and morphine.

Mu-Opioid Receptors Expressed in Glutamatergic Neurons are Essential for Morphine Withdrawal.

Although opioids still remain the most powerful pain-killers, the chronic use of opioid analgesics is largely limited by their numerous side-effects, including opioid dependence. However, the mechanism underlying this dependence is largely unknown. In this study, we used the withdrawal symptoms precipitated by naloxone to characterize opioid dependence in mice. We determined the functional role of mu-opioid receptors (MORs) expressed in different subpopulations of neurons in the development of morphine withdrawal. We found that conditional deletion of MORs from glutamatergic neurons expressing vesicular glutamate transporter 2 (Vglut2+) largely eliminated the naloxone-precipitated withdrawal symptoms. In contrast, conditional deletion of MORs expressed in GABAergic neurons had a limited effect on morphine withdrawal. Consistently, mice with MORs deleted from Vglut2+ glutamatergic neurons also showed no morphine-induced locomotor hyperactivity. Furthermore, morphine withdrawal and morphine-induced hyperactivity were not significantly affected by conditional knockout of MORs from dorsal spinal neurons. Taken together, our data indicate that the development of morphine withdrawal is largely mediated by MORs expressed in Vglut2+ glutamatergic neurons.

Developmental exposure to mepanipyrim induces locomotor hyperactivity in zebrafish (Danio rerio) larvae.

Mepanipyrim is a widely used fungicide, and residues of mepanipyrim are frequently detected in commodities. However, the neurotoxicity and underlying mechanisms of mepanipyrim are still insufficiently understood. In this study, zebrafish embryos at 0.5-1.0 post-fertilization hours (hpf) were exposed to 0.1, 1, 10 and 100 µg/L mepanipyrim for 7 days. Our results showed that mepanipyrim could cause the locomotor hyperactivity and increase the concentration of γ-amino butyric acid (GABA) and the Na+/K+- and Ca2+-ATPase activities in zebrafish larvae. We have conducted the RNA-sequence and RT-qPCR to analyze the gene expressions. The mRNA expression levels of calcium/sodium ion conduction associated genes were observably up-regulated, demonstrating that mepanipyrim could enhance the cell energy metabolism, the synaptic transmission and skeletal muscle contraction, which were consistent with the locomotor hyperactivity. Meanwhile, exposure to mepanipyrim could significantly change the gene expression levels of gad1, bdnf, nlgn1, and type A and B GABA receptors in zebrafish larvae. This is the first study focusing on the underlying mechanisms of the neurotoxic effects that are induced by mepanipyrim.

Mu-Opioid Receptors Expressed in Glutamatergic Neurons are Essential for Morphine Withdrawal / 神经科学通报·英文版

Although opioids still remain the most powerful pain-killers, the chronic use of opioid analgesics is largely limited by their numerous side-effects, including opioid dependence. However, the mechanism underlying this dependence is largely unknown. In this study, we used the withdrawal symptoms precipitated by naloxone to characterize opioid dependence in mice. We determined the functional role of mu-opioid receptors (MORs) expressed in different subpopulations of neurons in the development of morphine withdrawal. We found that conditional deletion of MORs from glutamatergic neurons expressing vesicular glutamate transporter 2 (Vglut2) largely eliminated the naloxone-precipitated withdrawal symptoms. In contrast, conditional deletion of MORs expressed in GABAergic neurons had a limited effect on morphine withdrawal. Consistently, mice with MORs deleted from Vglut2 glutamatergic neurons also showed no morphine-induced locomotor hyperactivity. Furthermore, morphine withdrawal and morphine-induced hyperactivity were not significantly affected by conditional knockout of MORs from dorsal spinal neurons. Taken together, our data indicate that the development of morphine withdrawal is largely mediated by MORs expressed in Vglut2 glutamatergic neurons.

Mu-Opioid Receptors Expressed in Glutamatergic Neurons are Essential for Morphine Withdrawal / 神经科学通报·英文版

Although opioids still remain the most powerful pain-killers, the chronic use of opioid analgesics is largely limited by their numerous side-effects, including opioid dependence. However, the mechanism underlying this dependence is largely unknown. In this study, we used the withdrawal symptoms precipitated by naloxone to characterize opioid dependence in mice. We determined the functional role of mu-opioid receptors (MORs) expressed in different subpopulations of neurons in the development of morphine withdrawal. We found that conditional deletion of MORs from glutamatergic neurons expressing vesicular glutamate transporter 2 (Vglut2) largely eliminated the naloxone-precipitated withdrawal symptoms. In contrast, conditional deletion of MORs expressed in GABAergic neurons had a limited effect on morphine withdrawal. Consistently, mice with MORs deleted from Vglut2 glutamatergic neurons also showed no morphine-induced locomotor hyperactivity. Furthermore, morphine withdrawal and morphine-induced hyperactivity were not significantly affected by conditional knockout of MORs from dorsal spinal neurons. Taken together, our data indicate that the development of morphine withdrawal is largely mediated by MORs expressed in Vglut2 glutamatergic neurons.

FAM19A1, a brain-enriched and metabolically responsive neurokine, regulates food intake patterns and mouse behaviors.

Cytokines and chemokines play diverse roles in different organ systems. Family with sequence similarity 19, member A1-5 (FAM19A1-A5; also known as TAFA1-5) is a group of conserved chemokine-like proteins enriched in the CNS of mice and humans. Their functions are only beginning to emerge. Here, we show that the expression of Fam19a1-a5 in different mouse brain regions are induced or suppressed by unfed and refed states. The striking nutritional regulation of Fam19a family members in the brain suggests a potential central role in regulating metabolism. Using a knockout (KO) mouse model, we show that loss of FAM19A1 results in sexually dimorphic phenotypes. In male mice, FAM19A1 deficiency alters food intake patterns during the light and dark cycle. Fam19a1 KO mice are hyperactive, and locomotor hyperactivity is more pronounced in female KO mice. Behavior tests indicate that Fam19a1 KO female mice have reduced anxiety and sensitivity to pain. Spatial learning and exploration, however, is preserved in Fam19a1 KO mice. Altered behaviors are associated with elevated norepinephrine and dopamine turnover in the striatum. Our results establish an in vivo function of FAM19A1 and highlight central roles for this family of neurokines in modulating animal physiology and behavior.-Lei, X., Liu, L., Terrillion, C. E., Karuppagounder, S. S., Cisternas, P., Lay, M., Martinelli, D. C., Aja, S., Dong, X., Pletnikov, M. V., Wong, G. W. FAM19A1, a brain-enriched and metabolically responsive neurokine, regulates food intake patterns and mouse behaviors.

Sex differences in psychotomimetic-induced behaviours in rats.

Animal model studies using equal numbers of males and females are sparse in psychiatry research. Given the marked sex differences observed in psychiatric disorders, such as schizophrenia, using both males and females in research studies is an important requirement. Thus the aim of this study was to examine sex differences in psychotomimetic-induced behavioural deficits relevant to psychosis. We therefore compared the acute effect of amphetamine or phencyclidine on locomotor activity and prepulse inhibition in adult male and female Sprague-Dawley rats. The results of this study were that: (1) amphetamine-induced distance travelled was greater in female rats than in male rats, (2) phencyclidine-induced locomotor hyperactivity was similar in male and female rats; (3) there were no sex differences in amphetamine- or phencyclidine-induced disruption of prepulse inhibition; (4) male rats had an increased startle response after amphetamine. These findings suggest that sensitivity to amphetamine, but not phencyclidine, differs between male and female rats, and that this sex difference is selective to locomotor hyperactivity and startle, but not prepulse inhibition. This study used two widely-used, validated preclinical assays relevant to psychosis; the results of this study have implications for psychiatry research, particularly for disorders where marked sex differences in onset and symptomology are observed.

Nicotine-induced acute hyperactivity is mediated by dopaminergic system in a sexually dimorphic manner.

Short-term exposure to nicotine induces positive effects in mice, monkeys and humans, including mild euphoria, hyperactivity, and enhanced cognition. However, the underlying neural basis and molecular mechanisms for these effects remain poorly understood. Here, using a video recording system, we find that acute nicotine administration induces locomotor hyperactivity in Drosophila, similar to observations made in higher model organisms. Suppressing dopaminergic neurons or down-regulating dopamine 1-like receptor (DopR) abolishes this acute nicotine response, but surprisingly, does so only in male flies. Using a GFP reconstitution across synaptic partners (GRASP) approach, we show that dopaminergic neurons possess potential synaptic connections with acetylcholinergic neurons in wide regions of the brain. Furthermore, dopaminergic neurons are widely activated upon nicotine perfusion in both sexes, while the response curve differs significantly between the sexes. Moreover, knockdown of the ß1 nicotine acetylcholine receptor (nAChR) in dopaminergic neurons abolishes the acute nicotine response only in male flies, while panneural knock-down occurs in both sexes. Taken together, our results reveal that in fruit flies, dopaminergic neurons mediate nicotine-induced acute locomotor hyperactivity in a sexually dimorphic manner, and Drosophila ß1 nAChR subunit plays a crucial role in this nicotine response. These findings provide important insights into the molecular and neural basis of acute nicotine effects, and the underlying mechanisms may play conserved roles across species.

Alpha-asarone improves striatal cholinergic function and locomotor hyperactivity in Fmr1 knockout mice.

Hyperactivity is a symptom found in several neurological and psychiatric disorders, including Fragile X syndrome (FXS). The animal model of FXS, fragile X mental retardation gene (Fmr1) knockout (KO) mouse, exhibits robust locomotor hyperactivity. Alpha (α)-asarone, a major bioactive component isolated from Acorus gramineus, has been shown in previous studies to improve various disease conditions including central nervous system disorders. In this study, we show that treatment with α-asarone alleviates locomotor hyperactivity in Fmr1 KO mice. To elucidate the mechanism underlying this improvement, we evaluated the expressions of various cholinergic markers, as well as acetylcholinesterase (AChE) activity and acetylcholine (ACh) levels, in the striatum of Fmr1 KO mice. We also analyzed the AChE-inhibitory activity of α-asarone. Striatal samples from Fmr1 KO mice showed decreased m1 muscarinic acetylcholine receptor (m1 mAChR) expression, increased AChE activity, and reduced ACh levels. Treatment with α-asarone improved m1 mAChR expression and ACh levels, and attenuated the increased AChE activity. In addition, α-asarone dose-dependently inhibited AChE activity in vitro. These results indicate that direct inhibition of AChE activity and up-regulation of m1 mAChR expression in the striatum might contribute to the beneficial effects of α-asarone on locomotor hyperactivity in Fmr1 KO mice. These findings might improve understanding of the neurobiological mechanisms responsible for locomotor hyperactivity.

Enkephalin and dynorphin neuropeptides are differently correlated with locomotor hypersensitivity and levodopa-induced dyskinesia in parkinsonian rats.

The opioidergic neuropeptides dynorphin (DYN) and enkephalin (ENK) and the D1 and D2 dopaminergic receptors (D1R, D2R) are involved in the striatal control of motor and behavioral function. In Parkinson's disease, motor disturbances such as "on-off" motor fluctuations and involuntary movements (dyskinesia) are severe complications that often arise after chronic l-dihydroxyphenylalanine (l-DOPA) treatment. Changes in the striatal expression of preproENK (PPENK), proDYN (PDYN), D1R, and D2R mRNA have been observed in parkinsonian animals treated with l-DOPA. Enhanced opioidergic transmission has been found in association with l-DOPA-induced dyskinesia, but the connection of PPENK, PDYN, D1R, and D2R mRNA expression with locomotor activity remains unclear. In this study, we measured PPENK, PDYN, D1R and D2R mRNA levels by in situ hybridization in the striatum of 6-OHDA hemi-parkinsonian rats treated with l-DOPA (PD+l-DOPA group), along with two control groups (PD+saline and naive+l-DOPA). We found different levels of expression of PPENK, PDYN, D1R and D2R mRNA across the experimental groups and correlated the changes in mRNA expression with dyskinesia and locomotor variables assessed by open field test during several phases of l-DOPA treatment. Both PDYN and PPENK mRNA levels were correlated with the severity of dyskinesia, while PPENK mRNA levels were also correlated with the frequency of contralateral rotational movements and with locomotor variables. Moreover, a strong correlation was found between D1R mRNA expression and D2R mRNA expression in the PD+l-DOPA group. These findings suggest that, in parkinsonian animals treated with l-DOPA, high levels of PPENK are a prerequisite for a locomotor sensitization to l-DOPA treatment, while PDYN overexpression is responsible only for the development of dyskinesia.

Hyperactivity and depression-like traits in Bax KO mice.

The Bax gene is a member of the Bcl-2 gene family and its pro-apoptotic Bcl-associated X (Bax) protein is believed to be crucial in regulating apoptosis during neuronal development as well as following injury. With the advent of mouse genomics, mice lacking the pro-apoptotic Bax gene (Bax KO) have been extensively used to study how cell death helps to determine synaptic circuitry formation during neurodevelopment and disease. Surprisingly, in spite of its wide use and the association of programmed neuronal death with motor dysfunctions and depression, the effects of Bax deletion on mice spontaneous locomotor activity and depression-like traits are unknown. Here we examine the behavioral characteristics of Bax KO male mice using classical paradigms to evaluate spontaneous locomotor activity and depressive-like responses. In the open field, Bax KO animals exhibited greater locomotor activity than their control littermates. In the forced swimming test, Bax KO mice displayed greater immobility times, a behavior despair state, when compared to controls. Collectively, our findings corroborate the notion that a fine balance between cell survival and death early during development is critical for normal brain function later in life. Furthermore, it points out the importance of considering depressive-like and hyperactivity behavioral phenotypes when conducting neurodevelopmental and other studies using the Bax KO strain.

The Effect of Subchronic Dosing of Ciproxifan and Clobenpropit on Dopamine and Histamine Levels in Rats.

The present study was designed to investigate the effect of once daily for 7-day (subchronic treatment) dosing of histamine H3 receptor antagonists, ciproxifan (CPX) (3 mg/kg, i.p.), and clobenpropit (CBP) (15 mg/kg, i.p), including clozapine (CLZ) (3.0 mg/kg, i.p.) and chlorpromazine (CPZ) (3.0 mg/kg, i.p.), the atypical and typical antipsychotic, respectively, on MK-801(0.2 mg/kg, i.p.)-induced locomotor activity, and dopamine and histamine levels in rats. Dopamine and histamine levels were measured in striatum and hypothalamus, respectively, of rat brain. Atypical and typical antipsychotics were used to serve as clinically relevant reference agents to compare the effects of the H3 receptor antagonists. MK-801-induced increase of horizontal activity was reduced with CPX and CBP. The attenuation of MK-801-induced locomotor hyperactivity produced by CPX and CBP was comparable to CLZ and CPZ. MK-801 raised dopamine levels in the striatum, which was reduced in rats pretreated with CPX and CBP. CPZ also lowered striatal dopamine levels, though the decrease was less robust compared to CLZ, CPX and CBP. MK-801 increased histamine content although to a lesser degree. Subchronic treatment with CPX and CBP exhibited further increase in histamine levels in the hypothalamus compared to the MK-801 treatment alone. Histamine H3 receptor agonist, R-α methylhistamine (10 mg/kg, i.p.) counteracted the effects of CPX and CBP. In conclusion, the subchronic dosing of CPX/CBP suggests some antipsychotic-like activities as CPX/CBP counteracts the modulatory effects of MK-801 on dopamine and histamine levels and prevents MK-801-induced hyperlocomotor behaviors.