Increase In Exploratory Activity Research Articles

Perinatal environmental enrichment changes anxiety-like behaviours in mice and produces similar intergenerational benefits in offspring

Environmental enrichment implemented in early life is able to induce long-term changes in gene expression, synaptic function and behavioural responses. In this study, we evaluated the adult behavioural effects of perinatal environment enrichment in male and female mice (PEE), as well as the males and females of PEE male offspring (OPEE). For this purpose, animals were submitted to the following battery of behavioural analyses: elevated plus maze, open field test, light-dark box and novelty suppression feeding test. The frontal cortex and ventral hippocampus of PEE mice were collected for the evaluation of the expression of gamma-aminobutyric acid (GABA)-related genes. The PEE animals showed an increase in exploratory activity, associated with a reduction in anxiety-like behaviours on the elevated plus maze; this effect was mainly observed in males. Additionally, the male OPEE showed a reduction in anxiety-like behaviours on the elevated plus maze, mainly observed in a reduction of risk assessment-related behaviours. The PEE male mice also showed reduced expression of Gabra3 in the ventral hippocampus when compared to the control group. These results demonstrate that perinatal environmental enrichment promotes a reduction in anxiety-like behaviour that can be transferred intergenerationally.

Role of Polyinosinic:Polycytidylic Acid-Induced Maternal Immune Activation and Subsequent Immune Challenge in the Behaviour and Microglial Cell Trajectory in Adult Offspring: A Study of the Neurodevelopmental Model of Schizophrenia.

Multiple lines of evidence support the pathogenic role of maternal immune activation (MIA) in the occurrence of the schizophrenia-like disturbances in offspring. While in the brain the homeostatic role of neuron-microglia protein systems is well documented, the participation of the CX3CL1-CX3CR1 and CD200-CD200R dyads in the adverse impact of MIA often goes under-recognized. Therefore, in the present study, we examined the effect of MIA induced by polyinosinic:polycytidylic acid (Poly I:C) on the CX3CL1-CX3CR1 and CD200-CD200R axes, microglial trajectory (MhcII, Cd40, iNos, Il-1β, Tnf-α, Il-6, Arg1, Igf-1, Tgf-β and Il-4), and schizophrenia-like behaviour in adult male offspring of Sprague-Dawley rats. Additionally, according to the “two-hit” hypothesis of schizophrenia, we evaluated the influence of acute challenge with Poly I:C in adult prenatally MIA-exposed animals on the above parameters. In the present study, MIA evoked by Poly I:C injection in the late period of gestation led to the appearance of schizophrenia-like disturbances in adult offspring. Our results revealed the deficits manifested as a diminished number of aggressive interactions, presence of depressive-like episodes, and increase of exploratory activity, as well as a dichotomy in the sensorimotor gating in the prepulse inhibition (PPI) test expressed as two behavioural phenotypes (MIAPPI-low and MIAPPI-high). Furthermore, in the offspring rats subjected to a prenatal challenge (i.e., MIA) we noticed the lack of modulation of behavioural changes after the additional acute immune stimulus (Poly I:C) in adulthood. The important finding reported in this article is that MIA affects the expression and levels of the neuron-microglia proteins in the frontal cortex and hippocampus of adult offspring. We found that the changes in the CX3CL1-CX3CR1 axis could affect microglial trajectory, including decreased hippocampal mRNA level of MhcII and elevated cortical expression of Igf-1 in the MIAPPI-high animals and/or could cause the up-regulation of an inflammatory response (Il-6, Tnf-α, iNos) after the “second hit” in both examined brain regions and, at least in part, might differentiate behavioural disturbances in adult offspring. Consequently, the future effort to identify the biological background of these interactions in the Poly I:C-induced MIA model in Sprague-Dawley rats is desirable to unequivocally clarify this issue.

Combined cocaine and clonazepam administration induces REM sleep loss and anxiety-like withdrawal behaviors in rats

Misuse of prescription medications has risen to popularity. Reasons for this practice include the self-medication of sleep and psychiatric disorders and attempts to counteract the dysphoric side effects of stimulant drugs. Clonazepam, a commonly prescribed benzodiazepine, has been increasingly used as a countermeasure to cocaine side-effects, including sleep reduction and anxiety. As both substances may impair sleep and aggravate psychiatric conditions, this study aimed to evaluate the long-term effects of the interaction of clonazepam and cocaine on anxiety-like behavior, and the short-term effects of this drug combination on sleep using male Wistar rats. Animals received saline, cocaine (15 mg/kg), clonazepam (1.25 mg/kg) or both drugs for 16 days. Sleep recording was performed on the first day of treatment to evaluate acute treatment effects. One day after the end of the treatment period, the open field and elevated plus-maze tests were used to assess anxiety-like behavior. Blood samples were collected for analysis of corticosterone levels. Rats receiving both drugs presented an increase in impulsivity when moving between arms in the elevated plus-maze and a reduction in exploratory behavior in the open field test. These findings suggest the presence of a withdrawal behavioral syndrome, which can manifest as a paradoxical increase in exploratory activity after a period without receiving the drug and may indicate the development of dependence. Combined treatment reduced paradoxical sleep time and increased its onset latency. There was no significant difference regarding corticosterone levels across any group. Our results contribute to the understanding of the risks of combining cocaine and clonazepam. Association of these drugs may impair sleep architecture and aggravate the dependence symptoms already seen when these substances are used separately. These findings may be useful in helping to counteract the impairments resulting from the combined use of these 2 substances and to raise awareness of these associated risks.

Effect of Paullinia cupana Mart. Commercial Extract During the Aging of Middle Age Wistar Rats: Differential Effects on the Hippocampus and Striatum.

During aging, there is a marked decline in the antioxidant capacity of brain tissue, leading to a gradual loss of the antioxidant/oxidant balance, which causes oxidative damage. The effects of Paullinia cupana Mart. extract, which is described as being rich in caffeine and many polyphenol compounds, on the central nervous system have not been extensively investigated. The aim of this study was to therefore investigate the effect of a commercial guarana extract (CGE) on cognitive function, oxidative stress, and brain homeostasis proteins related to cognitive injury and senescence in middle age, male Wistar rats. Animals were randomly assigned to a group according to their treatment (saline, CGE, or caffeine). Solutions were administered daily by oral gavage for 6 months. Open field and novel object recognition tasks were performed before and after treatment. Biochemical analyses were carried out on the hippocampus and striatum. Our open field data showed an increase in exploratory activity and a decrease in anxiety-like behavior with caffeine but not with the CGE treatment. In the CGE-treated group, catalase activity decreased in the hippocampus and increased in the striatum. Analyses of the hippocampus and striatum indicate that CGE and/or caffeine altered some of the analyzed parameters in a tissue-specific manner. Our data suggest that CGE intake does not improve cognitive development, but modifies the oxidative stress machinery and neurodegenerative-signaling pathway, inhibiting pro-survival pathway molecules in the hippocampus and striatum. This may contribute to the development of unfavorable microenvironments in the brain and neurodegenerative disorders.

The effect of iron nanoparticles on performance of cognitive tasks in rats.

To assess the influence of 62.5±0.6nm iron nanoparticles on the status of central nervous system, a study was conducted on Wistar rats, which were subjected to abdominal injection of the studied nanoparticles at doses of 2 and 14mg/kg. Based on the analysis of the structural and functional status of the cerebral cortex of rats, behavioral reactions of animals, and the elemental composition of the cerebral cortex, we investigated the nanoparticles' neurotoxic effect, whose degree and nature varied depending on the dosage and the time elapsed after the injection. We identified pathological changes in motor and somatosensory areas of the rats' cerebral cortex and established pronounced changes in the elemental homeostasis of the animals' cerebral cortex in experimental groups. Identified structural changes were accompanied by an increase in exploratory activity, locomotor activity, and emotional status of the animals. At that, these activities were more pronounced in rats, which were administered iron nanoparticles at a dose of 14mg/kg. By the end of the experiment, the excitation processes prevailed over the inhibition processes that have led to the inhibition of central nervous system activity in experimental animals against the adaptation to stress in rats of the control group.

Effects of environmental enrichment on anxiety-like behavior, sociability, sensory gating, and spatial learning in male and female C57BL/6J mice

The influence of housing on cognition and emotional regulation in mice presents a problem for the study of genetic and environmental risk factors for neuropsychiatric disorders: standard laboratory housing may result in low levels of cognitive function or altered levels of anxiety that leave little room for assessment of deleterious effects of experimental manipulations. The use of enriched environment (EE) may allow for the measurement of a wider range of performance in cognitive domains. Cognitive and behavioral effects of EE in male mice have not been widely reproduced, perhaps due to variability in the application of enrichment protocols, and the effects of EE in female mice have not been widely studied. We have developed an EE protocol using common laboratory equipment that, without a running wheel for exercise, results in significant cognitive and behavioral effects relative to standard laboratory housing conditions. We compared male and female wild-type C57BL/6J mice reared from weaning age in an EE to those reared in a standard environment (SE), using common measures of anxiety-like behavior, sensory gating, sociability, and spatial learning and memory. Sex was a significant factor in relevant elevated plus maze (EPM) measures, and bordered on significance in a social interaction (SI) assay. Effects of EE on anxiety-like behavior and sociability were indicative of a general increase in exploratory activity. In male and female mice, EE resulted in reduced prepulse inhibition (PPI) of the acoustic startle response, and enhanced spatial learning and use of spatially precise strategies in a Morris water maze task.

Noradrenaline microinjected into the dorsal periaqueductal gray matter causes anxiolytic-like effects in rats tested in the elevated T-maze

AimsThe dorsal periaqueductal gray matter (dPAG) is involved in the integration of behavioral and cardiovascular responses caused by fear and anxiety situations. Some studies suggest an involvement of noradrenergic neurotransmission in the dPAG in anxiety modulation, however, there is no evidence about its role in panic attacks. The goal of this work was to study the effect of NA microinjection in dPAG in rats submitted to the elevated T-maze (ETM). Materials and methodsMale Wistar had a cannula implanted in the PAG where it was injected NA in the doses of 1, 3, 15, 45nmol/50nl or artificial cerebrospinal fluid previous the ETM test. Key findings.NA intra-dPAG decreased inhibitory avoidance behavior in the ETM without changing escape, indicating only an anxiolytic-like effect. Furthermore, the microinjection of NA did not change the general exploratory activity of the animals submitted to the open field test, suggesting that the anxiolytic-like effect is not due to an increase in exploratory activity. SignificanceThe results indicate an involvement of noradrenergic neurotransmission in the dPAG in defensive reactions associated with generalized anxiety, but not as main mechanisms for the panic, in rats submitted to the elevated T-maze providing support for other research aimed at improving the treatment of generalized anxiety.

Protein tyrosine phosphatase receptor type R deficient mice exhibit increased exploration in a new environment and impaired novel object recognition memory

Mouse gene Ptprr encodes multiple protein tyrosine phosphatase receptor type R (PTPRR) isoforms that negatively regulate mitogen-activated protein kinase (MAPK) signaling pathways. In the mouse brain, PTPRR proteins are expressed in cerebellum, olfactory bulb, hippocampus, amygdala and perirhinal cortex but their precise role in these regions remains to be determined. Here, we evaluated phenotypic consequences of loss of PTPRR activity and found that basal smell was normal for Ptprr(-/-) mice. Also, spatial learning and fear-associated contextual learning were unaffected. PTPRR deficiency, however, resulted in impaired novel object recognition and a striking increase in exploratory activity in a new environment. The data corroborate the importance of proper control of MAPK signaling in cerebral functions and put forward PTPRR as a novel target to modulate synaptic processes.

Effects of maternal exposure to thiamazole on behavioral development in infant cynomolgus monkeys

Thiamazole, an anti-hyperthyroidism agent, was administered orally to pregnant cynomolgus monkeys at doses of 2.0 and 3.5 mg/kg per day from GD 120 to GD 150 to investigate effects on behavioral development of their infants. Swelling of the throat region due to enlargement of the thyroid glands was observed at birth in thiamazole-treated infants, and it returned to normal around postnatal day (PND) 30. At necropsy of infants at 12 months of age, thyroidal weight in the thiamazole groups was increased. This finding suggested the likelihood that administration of thiamazole to maternal animals during the late gestational period induced thyroid goiter in fetal/infant monkeys through placental transfer of thiamazole. No clear changes were noted in thyroid histopathology or serum thyroid hormone levels in maternal animals or infants, but goiter formation might have been indicative of exposure to high thyroid stimulating hormone (TSH) and low T3 or T4 in utero from maternal treatment with thiamazole. Age-related changes were observed in the control in behavioral development tests, while infants at 3.5 mg/kg showed no age-related decrease in contact behavior and no increase in exploratory activity on PND 90 or PND 170. In addition, the number of eye contacts between PND 210 and PND 240 was less frequent. This indicated that maternal exposure to thiamazole induced mental retardation-like behaviors in infants. Thiamazole may directly inhibit thyroid hormone synthesis in the fetus by placental transfer. From these results, it was speculated that oral administration of thiamazole to maternal animals during the late gestational period induced retardation of behavioral development in their infants.

Memory, learning, and participation of the cholinergic system in young rats exposed to environmental enrichment

The present study demonstrates the consequences of animal exposure to an enriched environment compared to animals living in a standard environment regarding learning and space memory. Male albino Wistar rats were exposed to an enriched environment for 4 weeks after the lactation period and tested in the Morris water maze in the distal and proximal clue version and in the arena. In the former test, the animals were tested at 50 days of age with 12 daily trials on two consecutive days. At the end of each session, scopolamine at the dose of 0.6mg/kg/ml or saline solution was injected intraperitoneally. Twenty-eight days after the first phase, a new test consisting of a single trial was held (retest). An independent group of animals receiving no drug was subjected to the arena test and to the proximal clue version of the Morris maze. In the distal clue version the results did not show differences between groups in the first phase of the experiment. After 28 days (retest), the animals reared in a standard environment and treated with scopolamine exhibited a significant increase in latency compared to the group receiving the same drug and stimulated and to the group receiving saline. The arena data demonstrated a significant increase in exploratory activity in the group of animals reared in an enriched environment. The proximal clue version of the Morris maze did not show differences between groups. The results of the present study indicate that animals exposed to environmental enrichment react less to the amnesic effects of scopolamine and show an increase in exploratory activity.

Reducing Behavioral Inhibition to Novelty via Systematic Neonatal Novelty Exposure: The Influence of Maternal Hypothalamic-Pituitary-Adrenal Regulation

Behavioral inhibition (BI) to novelty is thought to be a stable temperament type that appears early in life and is a major risk factor for anxiety disorders. In the rat, habituation of such inhibition can be facilitated via neonatal novelty exposure (NNE), thus reducing BI to novelty. Here, we tested the hypothesis that this early intervention effect is modulated by the context of maternal self-stress regulation. The NNE was carried out during postnatal days 1-21, in which one half of each litter was exposed to a relatively novel nonhome environment for 3-min daily while the remaining one half stayed in the home cage. After weaning, BI to novelty was assessed in an open field with a measure of disinhibition defined as a greater increase in exploration across two brief trials. Maternal context was characterized by trait measures of hypothalamic-pituitary-adrenal (HPA) axis reactivity, including basal and stress-evoked corticosterone (CORT) responses. Family-to-family variations in the NNE effect were associated with variations in maternal HPA function-a low-basal CORT and high-evoked CORT response profile constituting the context for a novelty-induced facilitation of disinhibition (i.e., a greater increase in exploratory activity over repeated trials) and an opposite HPA profile constituting the context for a novelty-induced reduction of disinhibition. This result is consistent with the hypothesis that maternal self-stress regulation modulates the effect of early life intervention on BI to novelty and suggests that effective interventions should include strategies to help mothers improve their self-stress regulation.

Facilitated neurogenesis in the developing hippocampus after intake of theanine, an amino acid in tea leaves, and object recognition memory.

Theanine, γ-glutamylethylamide, is one of the major amino acid components in green tea. In this study, cognitive function and the related mechanism were examined in theanine-administered young rats. Newborn rats were fed theanine through dams, which were fed water containing 0.3% theanine, and then fed water containing 0.3% theanine after weaning. Theanine level in the brain was under the detectable limit 6 weeks after the start of theanine administration. Theanine administration did not influence locomotor activity in the open-field test. However, rearing behavior was significantly increased in theanine-administered rats, suggesting that exploratory activity is increased by theanine intake. Furthermore, object recognition memory was enhanced in theanine-administered rats. The increase in exploratory activity in the open-field test seems to be associated with the enhanced object recognition memory after theanine administration. On the other hand, long-term potentiation (LTP) induction at the perforant path-granule cell synapse was not changed by theanine administration. To check hippocampal neurogenesis, BrdU was injected into rats 3 weeks after the start of theanine administration, and brain-derived neurotropic factor (BDNF) level was significantly increased at this time. Theanine intake significantly increased the number of BrdU-, Ki67-, and DCX-labeled cells in the granule cell layer 6 weeks after the start of theanine administration. This study indicates that 0.3% theanine administration facilitates neurogenesis in the developing hippocampus followed by enhanced recognition memory. Theanine intake may be of benefit to the postnatal development of hippocampal function.

Chronic Adolescent Exposure to Δ-9-Tetrahydrocannabinol in COMT Mutant Mice: Impact on Psychosis-Related and Other Phenotypes

Cannabis use confers a two-fold increase in the risk for psychosis, with adolescent use conferring even greater risk. A high-low activity catechol-O-methyltransferase (COMT) polymorphism may modulate the effects of adolescent Δ-9-tetrahydrocannabinol (THC) exposure on the risk for adult psychosis. Mice with knockout of the COMT gene were treated chronically with THC (4.0 and 8.0 mg/kg over 20 days) during either adolescence (postnatal days (PDs) 32-52) or adulthood (PDs 70-90). The effects of THC exposure were then assessed in adulthood across behavioral phenotypes relevant for psychosis: exploratory activity, spatial working memory (spontaneous and delayed alternation), object recognition memory, social interaction (sociability and social novelty preference), and anxiety (elevated plus maze). Adolescent THC administration induced a larger increase in exploratory activity, greater impairment in spatial working memory, and a stronger anti-anxiety effect in COMT knockouts than in wild types, primarily among males. No such effects of selective adolescent THC administration were evident for other behaviors. Both object recognition memory and social novelty preference were disrupted by either adolescent or adult THC administration, independent of genotype. The COMT genotype exerts specific modulation of responsivity to chronic THC administration during adolescence in terms of exploratory activity, spatial working memory, and anxiety. These findings illuminate the interaction between genes and adverse environmental exposures over a particular stage of development in the expression of the psychosis phenotype.

Behavioral Impact of the Regulation of the Brain 2-Oxoglutarate Dehydrogenase Complex by Synthetic Phosphonate Analog of 2-Oxoglutarate: Implications into the Role of the Complex in Neurodegenerative Diseases

Decreased activity of the mitochondrial 2-oxoglutarate dehydrogenase complex (OGDHC) in brain accompanies neurodegenerative diseases. To reveal molecular mechanisms of this association, we treated rats with a specific inhibitor of OGDHC, succinyl phosphonate, or exposed them to hypoxic stress. In males treated with succinyl phosphonate and in pregnancy-sensitized females experiencing acute hypobaric hypoxia, we revealed upregulation of brain OGDHC (within 24 hours), with the activity increase presumably representing the compensatory response of brain to the OGDHC inhibition. This up-regulation of brain OGDHC was accompanied by an increase in exploratory activity and a decrease in anxiety of the experimental animals. Remarkably, the hypoxia-induced elevation of brain OGDHC and most of the associated behavioral changes were abrogated by succinyl phosphonate. The antagonistic action of hypoxia and succinyl phosphonate demonstrates potential therapeutic significance of the OGDHC regulation by the phosphonate analogs of 2-oxoglutarate.

Anxiolytic-like effect of noradrenaline microinjection into the dorsal periaqueductal gray of rats

The brain noradrenergic system has been implicated in the expression of defensive behaviors elicited by acute stress. The dorsal periaqueductal gray area (dPAG) is a key structure involved in the behavioral and cardiovascular responses elicited by fear and anxiety situations. Although there are noradrenergic terminals in the dPAG, few studies have investigated the role of noradrenaline (NA) in the dPAG on anxiety modulation. The aim of this study was to evaluate the effect of NA microinjection into the dPAG of rats subjected to two animal models of anxiety, the elevated plus-maze and the Vogel conflict test. Male Wistar rats implanted with a guide cannula aimed at the dPAG received microinjections of NA (3, 15, or 45 nmol/0.05 microl) or artificial cerebral spinal fluid into the dPAG immediately before being exposed to the elevated plus-maze or the Vogel conflict test. NA increased the exploration of the open arms and the number of enclosed arm entries in the elevated plus-maze. The increase in open arm exploration remained significant after being subjected to an analysis of covariance using the latter variable as covariate. Moreover, the NA microinjection into the dPAG did not increase general exploratory activity of animals subjected to the open-field test, indicating that the increase in open arm exploration cannot be attributed to a nonspecific increase in exploratory activity. In the Vogel test, the NA microinjection into the dPAG increased the number of punished licks without changing the number of nonpunished licks or interfering with the tail-flick test. The results, therefore, indicate that the NA microinjection into the dPAG produces anxiolytic-like effects, suggesting its possible involvement in the anxiety modulation.

Psychopharmacological Profile of the Water Extract of Gardenia jasminoides and Its Constituents, Genipin and Geniposide, in Mice

Gardenia jasminoides (G. jasminoides) is traditionally used to treat insomnia, jaundice, emotional disorders, hepatic disease, and inflammatory disease. Previously, we found that geniposide and the water extract of G. jasminoides increased <TEX>$Cl^-$</TEX> influx in neuroblastoma. Here we examined the sychopharmacological activities of G. jasminoides and its constituents. G. jasminoides extract was orally administered at 100 and 200 mg/kg, and genipin and geniposide were intraperitoneally injected at 2, 10, and 20 mg/kg. G. jasminoides extract (200 mg/kg) significantly decreased total open field activity but increased rearing activity in the center of the open field, suggesting an increase in exploratory activity. Genipin and geniposide did not change open field activity, but geniposide (20 mg/kg) increased rearing activity in the central area. The extract (200 mg/kg) significantly decreased rotarod and wire-balancing activity, but genipin and geniposide did not. No compounds influenced thiopental-induced sleeping or electroshock-induced seizures. The extract (200 mg/kg) significantly increased staying time in the open arms of the elevated plus maze and the entry ratio into the open arms, and geniposide (20 mg/kg) also increased open arm entry. Electroshock stress decreased open arm activity, but the extract and geniposide (20 mg/kg) significantly reversed that effect. This results indicate that G. jasminoides extract and geniposide alleviated anxiety with greater efficacy in stressed animals than normal animals.

Intermittent hypoxia and sleep restriction: Motor, cognitive and neurochemical alterations in rats

The present study evaluated the effects of intermittent hypoxia (IH) and sleep restriction (SR) upon motor and cognitive function in rats. Also evaluated were catecholamine concentrations and tyrosine hydroxylase (TH) protein expression in different regions of the forebrain. Wistar Hannover rats were submitted to IH for 4 days or 21 days (2min room air to 2min 10% O2 for 10:00–16:00h), followed by SR for 18h (16:00–10:00h). Rats were randomly assigned into four experimental groups: (1) control (2) IH (3) SR and (4) IH–SR. In the inhibitory avoidance task, an additional group of rats was submitted to paradoxical sleep deprivation (PSD) for 96 consecutive hours. Results showed that SR induced an increase in motor activity without modifying catecholaminergic turnover in the frontal cortex and striatum. The increase in exploratory activity in SR rats could be the result of impaired habituation. Neither SR periods induced cognitive deficits in the inhibitory avoidance task after 5 or 21 days. However, 96h of PSD impaired acquisition/retention in rats. Exposure to IH did not affect motor and cognitive function but IH was associated with SR in increased motor activity. After 21 days, IH and IH–SR reduced striatal norepinephrine concentration although neither SR nor IH affected TH protein expression. The results presented here suggest that hypoxia and sleep loss exert distinct deleterious effects upon the central nervous system.

Effects of Byrsocarpus coccineus (Connaraceae) extract on the central nervous system (CNS)

In establishing the pharmacological profile of Byrsocarpus coccineus, we investigated the CNS effects of the aqueous leaf extract using the Y-maze, hexobarbitone sleeping time and hole board models in mice. In the Y-maze test, Byrsocarpus coccineus, BC (50–100mg/kg, p.o.) produced significant (P<0.05) increases in the time spent in the open arm at post-treatment times of 30–90min. Peak effect was elicited at 100mg/kg 30min post-treatment, with mice spending 2.63±0.21min in the open arm vs. 0.62±0.21min for control. This effect was significantly higher than that of diazepam, 1mg/kg p.o. (2.00±0.20min). At doses of 200 and 400mg/kg, the effect of BC in increasing the time spent in the open arm diminished with the effect at the higher dose (1.24±0.29min) being not significantly different from the control. In the hexobarbitone sleeping time test, BC (50–100mg/kg) increased the onset and decreased the duration of sleep, with effects only being significant at 100mg/kg (onset=7.00±1.18min and duration=10.00±1.84min vs. onset=3.43±0.81min and duration=20.71±2.34min for control). At doses of 200 and 400mg/kg, BC decreased onset and significantly increased sleeping time with the effect at the higher dose (onset=3.29±0.61min and duration=39.86±3.78min) being significantly lower than that of diazepam, 3mg/kg p.o., in respect of duration of sleep only (onset=3.14±0.26min and duration=87.29±9.87min). In the modified hole board experiment, BC (50–100mg/kg) caused an increase in both exploratory activity and locomotion, while at 200 and 400mg/kg the reverse was the case. These effects were not significant. Diazepam, 1mg/kg p.o., caused a non-significant increase in exploratory activity and a significant increase in locomotion (25.71±4.44 sectional crossings in 5min vs. 10.86±2.30 sectional crossings in 5min for control). Results obtained suggest that the aqueous leaf extract of Byrsocarpus coccineus possess a dose determined anxiolytic – sedative activity with no effect on exploratory activity and locomotion.

Localized injections of midazolam into the amygdala and hippocampus induce differential changes in anxiolytic-like motor activity in mice

Various strains of mice display a reliable increase in motor activity in response to benzodiazepines given at low to moderate doses. This hyperactivity has been described as both an anxiolytic-associated increase in exploratory activity and a nonspecific stimulant effect controlled by central neural mechanisms separate from those involved in the anxiolytic-like effects. The purpose of the current study was to investigate the neural circuitry underlying the hyperactivity effects of benzodiazepines in mice. Specifically, we examined the relationship between anxiety and motor activity after bilateral intra-amygdala or intra-hippocampal microinjections of the nonselective full benzodiazepine receptor agonist midazolam in C57BL/6 mice. Behavioral measures of anxiety and motor activity in open field were examined in mice given localized injections of 0, 2, 8 or 32 nmol of midazolam directed into the amygdala or hippocampus. Midazolam injected into the amygdala at the low dose produced an anxiolytic-like effect, as reflected by an increase in central open field activity. Higher doses injected into the amygdala produced a motor-depressant action, indicative of a drug-induced sedative effect. Infusions into the hippocampus produced a biphasic effect on motor activity with the two lower doses of midazolam producing a motor-stimulant action and the high dose producing a motor-depressant effect. Hippocampus injections produced no anxiolytic-like effects. The current findings demonstrate that injections of midazolam produced a regional dissociation of the anxiety-related and motor-related parameters and provide evidence that the stimulant and anxiolytic effects of benzodiazepines are independent phenomena regulated by different central mechanisms.

Effects of low dose N-(2-chloroethyl)- N-ethyl-2-bromobenzylamine administration on exploratory and amphetamine-induced behavior and dopamine D 2 receptor function in rats with high or low exploratory activity

Individual differences in behavioral traits are associated with sensitivity to various neurochemical and psychopharmacological manipulations. In this study exploratory and amphetamine-induced behavior in rats with persistently high or low exploratory activity (HE and LE, respectively) was examined before and after a partial denervation of the locus coeruleus (LC) projections with the selective neurotoxin DSP-4 ( N-(2-chloroethyl)- N-ethyl-2-bromobenzylamine; 10 mg/kg). Partial LC denervation prevented the increase in exploratory activity over repeated test sessions in the LE animals, but had no effect in HE-rats. Amphetamine- (0.5 mg/kg) induced locomotor activity was attenuated by DSP-4 pretreatment only in HE-rats. These results suggest differential involvement of LC noradrenergic transmission in novelty- and amphetamine-induced behavior in animals with persistent differences in novelty-related behavior. In addition to partial noradrenaline depletion in the frontal cortex and hippocampus, which occurred in both HE- and LE-rats, DSP-4 treatment also decreased the content of dopamine and its metabolites in the nucleus accumbens, and the metabolite levels in striatum, but only in the LE-animals. 5-HIAA levels were also reduced in the nucleus accumbens and striatum in LE-rats by the neurotoxin. D 2 receptor function, as determined by dopamine-stimulated [ 35S]GTPγS binding, was increased by DSP-4 treatment in the striatum of LE-rats, but reduced in HE-rats. No effect of partial LC denervation was found on dopamine-stimulated [ 35S]GTPγS binding in the nucleus accumbens. Together these findings suggest that LC noradrenergic neurotransmission is differently involved in dopaminergic mechanisms which mediate novelty-related vs amphetamine-induced behavior.