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Probiotics, defined as live bacteria or bacterial products, confer a significant health benefit to the host, including amelioration of anxiety-like behavior and psychiatric illnesses. Here we administered Lactobacillus plantarum PS128 (PS128) to a germ-free (GF) mouse model to investigate the impact of the gut–brain axis on emotional behaviors. First, we demonstrated that chronic administration of live PS128 showed no adverse effects on physical health. Then, we found that administration of live PS128 significantly increased the total distance traveled in the open field test and decreased the time spent in the closed arm in the elevated plus maze test, whereas the administration of PS128 had no significant effects in the depression-like behaviors of GF mice. Also, chronic live PS128 ingestion significantly increased the levels of both serotonin and dopamine in the striatum, but not in the prefrontal cortex or hippocampus. These results suggest that the chronic administration of PS128 is safe and could induce changes in emotional behaviors. The behavioral changes are correlated with the increase in the monoamine neurotransmitters in the striatum. These findings suggest that daily intake of the L. plantarum strain PS128 could improve anxiety-like behaviors and may be helpful in ameliorating neuropsychiatric disorders. [ABSTRACT FROM AUTHOR]

CD44 is a transmembrane receptor for the glycosaminoglycan hyaluronan, a component of the extracellular matrix. CD44 is expressed by neural stem/progenitor cells, astrocytes, and some neurons but its function in the central nervous system is unknown. To determine the role of CD44 in brain function, we behaviorally analyzed CD44-null (KO) and wild-type (WT) mice. KO mice showed increased activity levels in the light-dark test and a trend toward increased activity in the open field. In addition, KO mice showed impaired hippocampus-dependent spatial memory retention in the probe trial following the first hidden-platform training day in the Morris water maze: WT mice showed spatial memory retention and spent more time in the target quadrant than any other quadrant, while KO mice did not. Although there were no genotype differences in swim speeds during the water maze training sessions with the visible or hidden platform, sensorimotor impairments were seen in other behavioral tests. In the inclined screen and balance beam tests, KO mice moved less than WT mice. In the wire hang test, KO mice also fell off of the wire faster than WT mice. In contrast, there was no genotype difference when emotional learning and memory were assessed in the passive avoidance test. These data support an important role for CD44 in locomotor and sensorimotor functions, and in spatial memory retention. [ABSTRACT FROM AUTHOR]

There is evidence that early deprivation of vision prompts the use of body-based, egocentric spatial representations in congenitally blind individuals, whereas previous visual experience favors the use of object-based, allocentric representations (e.g. Pasqualotto A, Spiller MJ, Jansari AS, Proulx MJ. Visual experience facilitates allocentric spatial representation. Behav Brain Res 2013;236:175–79). Here we investigated whether the influence of the visual status on the capacity to represent egocentric and allocentric spatial relations is mediated by the scale of space explored: large-scale (where a haptic + locomotor exploration is required) and small-scale space (where haptic exploration is needed). Our results showed that congenitally blind people had more difficulty in representing spatial information allocentrically with respect to late blind and sighted individuals, but this difficulty was stronger with large-scale than small-scale space. Instead, egocentric performance was better than the allocentric one for all groups, particularly in the small scale condition. These results suggest that visual experience is necessary to develop accurate allocentric representations especially of large-scale spaces. This is probably due to its capacity to convey a large amount of spatial information simultaneously and to its role on the setting up of multisensory brain areas underlying spatial cognition. In the absence of any kind of visual experience, egocentric spatial representations are favored, especially in small-scale space, when the body offers a stable anchor point. [ABSTRACT FROM AUTHOR]

Abstract: Serotonin (5-HT) plays a role in several psychiatric disorders including drug addiction. The 5-HT system modulates the activity of midbrain dopamine (DA) systems, and the behavioural effects of psychostimulants mediated by these systems. The direction of this modulation depends upon the 5-HT receptor subtypes involved, with 5-HT2A and 5-HT2C receptors having opposing effects. For example the 5-HT2A receptor antagonist M100907 and the 5-HT2C receptor agonist Ro60-0175 both attenuate several cocaine-induced behavioural and neurochemical effects. To investigate the possible brain regions involved in the interactions between 5-HT2A or 5-HT2C receptor ligands and cocaine-induced behaviour, we examined the effects of M100907 or Ro60-0175 on cocaine-induced locomotion and mRNA expression of the immediate early gene zif268. Sprague-Dawley rats were pre-treated with M100907 (0.5mg/kg), Ro60-0175 (1.0mg/kg) or vehicle, and then injected with cocaine (15mg/kg) or vehicle. Locomotor activity was monitored for 60min before rats were sacrificed for zif268 mRNA in situ hybridization mapping. Cocaine increased locomotor activity and zif268 mRNA expression consistently in the nucleus accumbens core, the orbitofrontal cortex and the caudate. M100907 attenuated cocaine-induced locomotion and zif268 mRNA expression in these brain regions in a defined subset of rats but failed to alter any effects of cocaine in another defined subset of rats. Ro60-0175 blocked cocaine-induced locomotion and zif268 mRNA expression in similar brain regions. Our results suggest that despite the opposing actions of 5-HT at 5-HT2A and 5-HT2C receptors, ligands acting on these receptors likely modulate cocaine-induced locomotion via a common mechanism to influence DA-dependent circuitry. [Copyright &y& Elsevier]

Abstract: Methylphenidate hydrochloride (MPD) is a psychostimulant used in the treatment of attention deficit hyperactive disorder (ADHD) in adolescents and adults alike. Adolescence involves a period of neural development that is highly susceptible to environmental and pharmacological influence. Exposure to a psychostimulant like MPD during this crucial time period may cause permanent changes in neuronal function and formation. Another factor that may influence changes in neuronal function and formation is genetic variability. It has been reported that genetic variability affects both the initial behavioral response to drugs in general and psychostimulants in particular, and subsequently whether tolerance or sensitization is induced. The objective of the present study is to investigate the dose-response effects of repeated MPD administration (0.6, 2.5, or 10.0mg/kg, i.p.) using an open field assay to investigate if there are differences between adolescent and adult Wistar-Kyoto (WKY), Spontaneously Hyperactive rat (SHR), and Sprague-Dawley (SD) rats, respectively, and if the genetic variability between the strains influences the degree of change in locomotion. The acute and chronic administration of MPD resulted in unique differences in the level of increasing intensity in locomotor activity in each rat strain, with adult rats for the most part having a more intense increase in locomotor activity when compared to their adolescent counterparts. In conclusion, significant response differences among rat strains and age to acute and chronic MPD administration were observed only following the 2.5 and 10.0mg/kg i.p. doses and not following the lower MPD dose (0.6mg//kg i.p.). In addition the variability in activity among the rat strain and age suggests that MPD may affect the same neuronal circuit differently in each strain and age. The unique differences among the individual locomotor indices suggest also that each locomotor index is regulated by different neuronal circuits, and each affected differently by MPD. [Copyright &y& Elsevier]

Abstract: Dopamine receptor partial agonists have been proposed as potential candidate agents to treat psycho-stimulant abuse. Aripiprazole is a dopamine D2/D3 receptor partial agonist that is currently used as an antipsychotic drug in clinical settings. This study aimed to examine whether aripiprazole can suppress the methamphetamine-induced locomotor response in mice that is used as an indicator for potential clinical use. In ICR mice pre-exposed to methamphetamine (1mg/kg subcutaneous injection once daily for 7 days), we found that mice receiving repetitive treatments with aripiprazole (1, 5, and 10mg/kg, respectively; intraperitoneal injection once daily for 1 week) showed a significantly enhanced locomotor response upon re-exposure to methamphetamine (0.5mg/kg), compared with animals that received a vehicle treatment. Furthermore, we found that methamphetamine-naïve mice receiving repetitive treatment with aripiprazole (5mg/kg intraperitoneal injection once daily for 1 week) also showed a significantly enhanced locomotor response to acute challenge with methamphetamine (0.5mg/kg), compared with animals receiving the vehicle treatment. The enhanced locomotor response to methamphetamine in both methamphetamine-pre-exposed and methamphetamine-naïve mice lasted at least four weeks in this study. Our data suggest that aripiprazole may enhance the effects of methamphetamine, so caution should be exercised when prescribing to individuals with histories of stimulant use. [Copyright &y& Elsevier]

Abstract: Rats classified as high responders (HR) based on their response to an inescapable novel environment self-administer more amphetamine and have greater amphetamine-induced sensitization than rats classified as low responders (LR). Recent research suggests that the central nucleus of the amygdala (ACe) contributes to the elevated self-administration in HR rats. Therefore, the current study examined the role of the ACe in the expression of both amphetamine-induced sensitization and conditioned hyperactivity in HR and LR rats. Male Sprague–Dawley rats were screened for their response to inescapable novelty and classified as HR or LR rats. Rats were implanted with bilateral cannulae into the ACe and received amphetamine (1.0mg/kg, s.c.) or saline injections immediately prior to 1-h locomotor sessions. Following five training sessions, all rats received an infusion of muscimol (0.5μg/0.5μl) or phosphate buffered saline (PBS) followed by a saline injection to measure conditioned hyperactivity. HR rats displayed conditioned hyperactivity, while LR rats did not, suggesting that HR and LR rats differ in the expression of conditioned hyperactivity. While ACe inactivation attenuated the expression of conditioned hyperactivity, it did not differentially affect HR and LR rats. Following additional training and a 10-day rest period, all rats were then tested for amphetamine-induced sensitization (1.0mg/kg) following an infusion of muscimol or PBS. Inactivation of the ACe attenuated the expression of sensitization only in HR rats. These results suggest the ACe contributes to the greater amphetamine sensitization in HR rats. [Copyright &y& Elsevier]

Methamphetamine-induced behavioral effects are mediated by several neurotransmitters that act via the G-protein coupled receptors (GPCRs). The functioning of GPCRs are negatively regulated by regulators of G-protein signaling (RGS) proteins. The goal of this study was to assess the role of two specific RGS proteins namely the RGS2 and the RGS4 proteins in methamphetamine-induced behaviors. The effects of methamphetamine (1 mg/kg; i.p.) on conditioned place preference (CPP) and locomotor activity were assessed in genetically modified male and female mice lacking either RGS2 or RGS4 and their wildtype littermates to achieve the above goal. Locomotor activity after methamphetamine administration was assessed in both methamphetamine-naïve and -experienced mice. Methamphetamine-induced CPP at the tested dose was blocked in male, but not female, mice lacking RGS4 compared to respective controls. Interestingly, methamphetamine-induced increase in locomotor activity at the tested dose was observed in methamphetamine-experienced, but not in the methamphetamine-naïve, male mice lacking RGS4. However, methamphetamine-induced increase in locomotor activity at the tested dose was blocked in both methamphetamine-naïve and -experienced female mice lacking RGS4. Interestingly, methamphetamine-induced rewarding effects and methamphetamine-induced increase in locomotor activity at the tested dose were observed in mice lacking RGS2, irrespective of sex and/or history of methamphetamine exposure. Together, the data suggest that RGS4 plays a role in methamphetamine-induced behaviors and could serve as a potential target for medications intended to treat the acute effects of methamphetamine. • Deletion of RGS4 attenuated methamphetamine(meth)-induced CPP in male mice. • Deletion of RGS4 influenced meth-induced locomotor activity in female mice. • Deletion of RGS2 did not influence meth-induced CPP irrespective of sex. • Deletion of RGS2 did not influence meth-induced increase in locomotor activity. [ABSTRACT FROM AUTHOR]

Abstract: Insulin is a polypeptide hormone that is present in mammals and its main function is the maintenance of adequate blood sugar level. Insulin receptors are widely but unevenly distributed in the brain. Insulin has been reported to be involved in the regulation of neurotransmitters release. It has also been linked to the pathogenesis of neurodegenerative disorders such as Alzheimer''s and Parkinson''s diseases. Although there is abundant literature on the study of biochemical and molecular properties of insulin, there has been no literature on its central behavioural effects on anxiety and pain relief among other behavioural effects. This study therefore investigates whether insulin has any anxiolytic and other CNS effects. This experiment was carried out in mice using animal behavioural models including a hot plate analgesic test, holeboard and elevated plus maze for anxiolytic test. A Y-maze was used for the locomotor activity and spontaneous alternation investigations. Mice were administered intraperitoneally with insulin at different doses of 0.5, 1.0 and 2.0IU/kg. The results obtained showed that insulin has no analgesic activity, however, it caused significant central inhibitory effects by decreasing both locomotor activity in both holeboard and Y-maze models and also decreased the exploratory behaviour in holeboard at doses administered dose-dependently indicating its sedative effects. In elevated plus maze, insulin had no effects on percentage of open arm entries at all doses but had a significant effect on percentage of open arm duration at the dose of 1.0IU/kg only. Insulin administration at lower doses (0.5 and 1.0IU/kg, i.p.) had no effect on spatial working memory, however, it had significant spatial working memory impairment at the dose of 2.0IU/kg, i.p. in mice. The study showed that insulin has several neuropharmacological effects at doses used. [Copyright &y& Elsevier]

Abstract: The heat shock factor 1 (HSF1) is a major transcriptional factor that controls the rapid induction of heat shock proteins in response to various environmental stressors. In this study, we globally investigated the effect of HSF1 deficiency on animal behaviors during postnatal growth, and abnormalities in hippocampal neurons and behavior in response to chronic unpredictable stressors (CUS). Mouse behaviors were measured in several behavioral paradigms, including elevated plus maze, open field, closed field, T-maze continuous alternation task (T-CAT), bridge-walking, and wire suspension tests. The hsf1-null mice exhibited reduction in basal anxiety levels and exploratory behavior, and working memory deficits, but normal motor coordination abilities. Chronic unpredictable stressors significantly increased apoptosis in hippocampal CA3 cells in both the hsf1-null and wild-type (WT) mice in the in situ TUNEL staining and induced more anxiety-like behavior in the hsf1-null mice than WT mice in the plus T-maze paradigm. We conclude that hsf1 gene deficiency results in significant abnormalities in mouse basal behaviors and sensitization to chronic unpredictable stressors. [Copyright &y& Elsevier]

Abstract: Oleamide, a fatty acid amide accumulates selectively in the cerebrospinal fluid of sleep deprived cats and rats. Oleamide has been reported to have effects on a wide range of receptors and neurotransmitter systems especially the centrally acting ones for example, dopamine acetylcholine, serotonin, gamma aminobutyric acid (GABA), cannabinoid and vanilloid among others. This suggests a wide range of central nervous system effects of the compound. The effects of intraperitoneal administered oleamide on Novelty-induced behaviours, learning and memory and forced swimming-induced depression were studied. The relative effects of the compound on the male and female mice were also noted. Oleamide dose-dependently reduced (p <0.05) novelty induced rearing, grooming and locomotion. The effects on the all NIBs started within the first 10min of the test and the peak of the effects was observed during the third 10min period of the test. Effect of oleamide on short-term working memory was significantly (p <0.05) affected only with the dose of 5mg/kg while the other dose of 10mg/kg had no effect. In the forced swimming test, acute triple intraperitoneal administration of oleamide at 10mg/kg induced a significant reduction in the immobility duration in mice signifying an antidepressant effect. Sex differences in the effects of oleamide (10mg/kg, i.p.) were clearly evident in active behaviours in FST. These results confirm the multiplicity of central nervous system receptors and neurotransmitters that Oleamide interacts with hence its numerous and diverse neuropharmacological effects. Most importantly, the present study suggests that oleamide has antidepressant-like property. [Copyright &y& Elsevier]

• Acute methamphetamine exposure increases anxiety-like behavior. • There are age differences in the locomotor response to acute methamphetamine. • Adult mice show greater locomotor activity to low doses of methamphetamine. • Adolescent mice show greater locomotor activity to high doses of methamphetamine. • Acute methamphetamine exposure does not alter corticosterone levels in either age. Methamphetamine (MA) is a highly addictive psychomotor stimulant drug. Research has shown that the acute effects of MA can be modulated by age, although previous findings from our lab do not find age differences in the effects of MA. Relatively little research has examined the effects of adolescent MA exposure; thus, it is important to understand how MA affects adolescent behavior and brain function compared to adults. In order to better understand the age differences in the effects of acute MA exposure, this research examined the effects of MA exposure on locomotor and anxiety-like behavior and plasma corticosterone levels in adolescent and adult C57BL/6 J mice. Mice were exposed to saline, 2 mg/kg MA, or 4 mg/kg MA and behavior was measured in the open field test. Immediately following behavioral testing, serum was collected, and plasma corticosterone levels were measured. MA-exposed mice showed increased locomotor activity and anxiety-like behavior compared to saline controls, regardless of age and dose of MA. However, adolescent mice showed the greatest locomotor response to the high dose of MA (4 mg/kg), whereas the adult mice showed the greatest locomotor response to the low dose of MA (2 mg/kg). There were no differences in stereotyped behavior between the adolescent and adult mice exposed to the low dose of MA (2 mg/kg) and the high dose of MA (4 mg/kg). There was no effect of MA exposure on plasma corticosterone levels. These data suggest age modulates the locomotor response to MA and further research is warranted to determine the developmental neurobiological mechanism underlying the dose-response age differences in the response to acute MA exposure. [ABSTRACT FROM AUTHOR]

• Ketamine produces locomotor stimulation at low subanesthetic doses. • Repeated administration of ketamine produces robust and reliable sensitization. • Dose, environment, and social isolation affect sensitization. • Ketamine sensitization is influenced by factors that influence addiction. Ketamine is a dissociative anesthetic first developed in the 1960s but is increasingly used at subanesthetic doses for both clinical and non-clinical purposes. There is evidence from human recreational users of compulsive use and addiction. Sensitization is an increase in an effect of a drug with repeated use that is thought to be important in the development of addiction. Research on psychomotor stimulants has shown the development of sensitization in laboratory animals to be modified by factors that influence addiction. In the current paper we describe four experiments on the development of sensitization in laboratory rats aimed at determining if ketamine sensitization is also influenced by factors thought to be important in addiction. Adult, male Sprague-Dawley rats received ketamine (5, 10, 20 or 50 mg/kg i.p.) for five or more days and the development of locomotor sensitization was followed. Experiment 1 examined the ability of low doses of ketamine to produce sensitization and found sensitization at 5, 10 and 20 mg/kg. Experiment 2 examined the influence of environmental context and found that ketamine sensitization (20 mg/kg) was greater when administration occurred in a novel environment (the experimental apparatus) than in home cages. Experiment 3 found that ketamine sensitization (20 mg/kg) did not occur when animals were housed in social isolation but occurred readily in pair-housed animals. Finally, Experiment 4 found that ketamine sensitization (20 or 50 mg/kg) was similar whether drug was administered daily or at 3-day intervals. Together, the results demonstrate that ketamine sensitization is robust and reliable, occurring under a variety of circumstances. Moreover, ketamine sensitization is influenced by factors that influence the development of addiction in humans. The current results may lead to a better understanding of ketamine abuse and addiction and may help inform clinical use of the drug. [ABSTRACT FROM AUTHOR]

• Ketamine-induced locomotor stimulation is greater is adolescents than adults. • Ketamine sensitization persists after a 20-day abstinence period in adults. • Repeated use of ketamine produces long-lasting neuroadaptations. Initiation of ketamine use often occurs in adolescence, yet little is known about long-term consequences when use begins in this developmental period. The current experiments were designed to examine the effects of repeated exposure to ketamine in adolescence on behavior in adulthood. We examined locomotor activity, as well as cognitive function, in animals that received repeated administration of ketamine. Groups of adolescent and adult male rats were treated with ketamine (25 mg/kg) once daily for 10 days. Locomotor activity was assessed following the first injection, following 10 days of injection, and following 20 days of abstinence. Acute locomotor effects and locomotor sensitization were compared in adolescents and adults; cross-sensitization to dextromethorphan, another dissociative with abusive potential, was also examined. In a separate group of animals cognitive deficits were assessed following the 20 day abstinence period in spatial learning and novel object recognition tasks. The locomotor stimulant effect of ketamine was much greater in adolescents than adults. Animals that were repeatedly administered ketamine demonstrated locomotor sensitization immediately after the final injection. However, sensitization only persisted after the abstinence period in animals treated as adults. No cross-sensitization to dextromethorphan was evident. Ketamine failed to produce statistically significant cognitive deficits in either age group, although drug-treated adults showed a trend towards deficits in spatial learning. Repeated use of ketamine produces long-lasting neuroadaptations that may contribute to addiction. Mild lasting memory deficits may occur in adults, although further work is necessary to confirm these findings. The results extend the understanding of potential long-term consequences of ketamine use in adolescents and adults. [ABSTRACT FROM AUTHOR]