Elevated Plus Maze for Assessment of Anxiety and Memory in Rodents.

The elevated plus maze is the most widely used paradigm to evaluate anxiety-associated behavioral alterations in rodent models of central nervous system (CNS) disorders. Unconditioned aversive behavior for open and elevated areas is a measure of anxiety and can be assessed by the plus maze. Plus maze consists of perpendicularly arranged open arms and closed arms crossed in the middle with a central platform. Rodents are allowed to explore the maze between the open and closed arms. The number of entries and time spent in the open arms and the closed arms are used as indicators for the anxiety nature of the animals. Transfer latency is a memory indicator that measures the amount of time it takes to move an animal from an open arm to a closed arm. This chapter describes the pretest conditions, materials required, and protocol for the conductance and evaluating the results for the anxiety and cognition-related behavior in rodents.

Pharmacological Manipulation of Corticotropin-Releasing Factor Receptors in the Anterior and Posterior Subregions of the Insular Cortex Differently Affects Anxiety-Like Behaviors in the Elevated Plus Maze in Rats.

Neuroimaging data in humans and neurobiological studies in rodents have suggested an involvement of the insular cortex (IC) in anxiety manifestations. However, the local neurochemical mechanisms involved are still poorly understood. Corticotropin-releasing factor (CRF) neurotransmission has been described as a prominent neurochemical mechanism involved in the expression of anxiety-like behaviors, but the brain sites related are poorly understood. Additionally, several findings indicate that control of physiological and behavioral responses by the IC occurs in a site-specific manner along its rostrocaudal axis. Thus, this study is aimed at evaluating the effect of CRF receptor agonism and antagonism within the anterior and posterior subregions of the IC in controlling anxiety-related behaviors in the elevated plus maze (EPM). For this, independent groups (six groups) of animals received bilateral microinjections of vehicle, the selective CRF1 receptor antagonist CP376395, or CRF into either the anterior or posterior subregions of the IC. Ten minutes later, the behavior in the EPM was evaluated for five minutes. Treatment of the anterior IC with CP376395, but not with CRF, increased the time and number of entries into the open arms of the EPM. CRF, but not the CRF1 receptor antagonist, microinjected into the posterior IC also increased exploration of the EPM open arms. Taken together, these data indicate that CRFergic neurotransmission in the anterior IC is involved in the expression of anxiety-related behaviors in the EPM. This neurochemical mechanism does not seem to be activated within the posterior IC during exposure to the EPM, but the effects caused by CRF microinjection indicate that activation of CRF receptors in this IC subregion might evoke anxiolytic-like effects.

Forty-kHz ultrasonic vocalizations of rat pups predict adult behavior in the elevated plus-maze behavior but not the effect of cocaine on 50-kHz ultrasonic vocalizations.

Ultrasonic vocalizations (USV) are emitted by both young pups and adult rats to convey positive or negative emotional states. These USV manifestations are contingent on factors including developmental stage, situational requirements, and individual dispositions. Pups emit 40-kHz USV when separated from their mother and litter, which function to elicit maternal care. Conversely, adult rats can produce 50-kHz USV in response to stimuli that elicit reward-related states, including natural rewards, stimulant drugs, and reward-predictive stimuli. The present study aims to investigate whether pup 40-kHz USV can serve as predictors of behaviors related to positive or negative states in adult rats. Both male and female Wistar pups were initially tested on the 11th postnatal day and subsequently in adulthood. There was no significant difference in the number of 40-kHz ultrasonic vocalizations between male and female pups. However, cocaine elicited more 50-kHz USV and hyperactivity in adult females compared to males. Notably, cocaine increased the proportion of step and trill USV subtypes in both adult males and females. Interestingly, this effect of cocaine was stronger in females that were in the diestrus, compared to the estrus phase. In males, a significant positive correlation was found between pup 40-kHz USV and lower anxiety scores in adult male but not female rats tested on the elevated plus-maze test. Furthermore, no significant correlation was found between pup 40-kHz and adult 50-kHz USV in both males and females, whether in undrugged (saline) or in cocaine-treated rats. It is possible that the 40-kHz USV emitted by pups predicted reduced anxiety-like behavior only for male rats because they could elicit maternal care directed specifically to male pups. These findings suggest that 40-kHz USV can serve as an indicator of the emotional link between the rat mother and male pups. Indeed, this suggests that maternal care exerts a positive influence on the emotional state during adulthood.

HDAC2 Inhibits Hippocampal Neurogenesis and Impairs the Cognitive Function in Prenatally Stressed Adult Offspring / HDAC2 Inhibe la Neurogénesis del Hipocampo y Afecta la Función Cognitiva en la Descendencia Adulta Estresada Prenatalmente

SUMMARY: The objective of this study was to investigate the mechanism of prenatal stress on the cognitive function of offspring, and clarify the change of histone deacetylase 2 (HDAC2) expression in hippocampal neurons of offspring. 16 pregnant SD rats were randomly divided into control group and stress group, with eight rats in each group. The stress group received restrained stress from 15 to 21 days of pregnancy, while the control group did not receive any treatment. Anxiety-like behavior and spatial memory, learning and memory ability were detected in open field, elevated plus maze, novel object recognition test, and Barnes maze. Nissl staining was used to detect the function of hippocampal neurons. Western blot was used to detect the expression of HDAC2 protein in hippocampal neurons of adult offspring. Immunofluorescence staining was used to detect the expression of HDAC2 protein and hippocampal neurogenesis. The learning and memory ability of adult offspring was decreased. The prenatal stress damaged the function of hippocampal neurons , the expression of HDAC2 was down-regulated, and the number of neurons was reduced. Maternal prenatal stress can down- regulate the expression of HDAC2 in the hippocampus of offspring, inhibits hippocampal neurogenesis and impairs the cognitive function.

El objetivo de este estudio fue investigar el mecanismo del estrés prenatal en la función cognitiva de la descendencia y aclarar el cambio de la expresión de la histona desacetilasa 2 (HDAC2) en las neuronas del hipocampo de la descendencia. 16 ratas SD preñadas se dividieron aleatoriamente en un grupo de control y un grupo de estrés, con ocho ratas en cada grupo. El grupo de estrés recibió estrés durante 15 a 21 días de pre, preñez, mientras que el grupo de control no recibió ningún tratamiento. El comportamiento similar a la ansiedad y la memoria espacial, el aprendizaje y la capacidad de memoria se detectaron en campo abierto, laberinto en cruz elevado, prueba de reconocimiento de objetos novedosos y laberinto de Barnes. La tinción de Nissl se utilizó para detectar la función de las neuronas del hipocampo. Se utilizó Western blot para detectar la expresión de la proteína HDAC2 en las neuronas del hipocampo de la descendencia adulta. La tinción de inmunofluorescencia se utilizó para detectar la expresión de la proteína HDAC2 y la neurogénesis del hipocampo. La capacidad de aprendizaje y memoria de la descendencia adulta se redujo. El estrés prenatal dañó la función de las neuronas del hipocampo, se reguló negativamente la expresión de HDAC2 y se redujo el número de neuronas. El estrés prenatal materno puede regular a la baja la expresión de HDAC2 en el hipocampo de la descendencia, inhibe la neurogénesis del hipocampo y deteriora la función cognitiva.

Сhanges of trace elements in the cerebellum and their influence on the rats behavior in elevated plus maze in the acute period of mild blast-induced brain injury.

BACKGROUND: In connection with the widespread use of explosive devices in military conflicts, in particular in Ukraine, is relevant to detect the biometals changes in the cerebellum and determine the presence of their influence on the behavior changes of rats in the elevated plus maze in the acute period of a mild blast-traumatic brain injury (bTBI). METHODS: The selected rats were randomly divided into 3 groups: Group I - Experimental with bTBI (with an excess pressure of 26-36 kPa), Group II - Sham and Group III - Intact. Behavior studies was in the elevated plus maze. Brain spectral analysis was with using of energy dispersive X-ray fluorescence analysis, after obtaining the quantitative mass fractions of biometals, the ratios of Cu/Fe, Cu/Zn, Zn/Fe were calculated and the data between the three groups were compared. RESULTS: The results showed an increase in mobility in the experimental rats, which indicates functional disorders of the cerebellum in the form of maladaptation in space. Changes in cognitive activity also is an evidence of cerebellum suppression, which is indicated by changes in vertical locomotor activity. Grooming time was shortened. We established a significant increase in Cu/Fe and Zn/Fe ratios in the cerebellum, a decrease in Cu/Zn. CONCLUSIONS: Changes in the Cu/Fe, Cu/Zn, and Zn/Fe ratios in the cerebellum correlate with impaired locomotor and cognitive activity in rats in the acute posttraumatic period. Accumulation of Fe on the 1st and 3rd day leads to disturbance of the Cu and Zn balance on the 7th day and starts a "vicious cycle" of neuronal damage. Cu/Fe, Cu/Zn, and Zn/Fe imbalances are secondary factors in the pathogenesis of brain damage as a result of primary bTBI.

Behavior of In Utero Stressed Rats in the Elevated Plus Maze Test during Different Periods of Postnatal Ontogeny.

We studied the effect of prenatal stress (dams were forced to swim in cold water (10°C; 5 min) from day 10 to 16 of gestation) on the behavioral parameters of the offspring in an elevated plus maze on days 21, 30, and 60 of life (suckling, infantile, and juvenile ages, respectively). Females at the suckling age demonstrated suppressed orientation and exploratory activity and increased anxiety, which returned to normal by the infantile and juvenile periods. Prenatally stressed males in juvenile age were characterized by reduced anxiety (assessed by the time spent in the closed and open arms of the plus maze). Thus, the effect of prenatal stress on the behavioral parameters manifested differently depending on the sex and stage of postnatal ontogeny. The modulatory effects of prenatal stress on the analyzed behavioral parameters were more pronounced in females at early stages of postnatal ontogeny (suckling and infantile ages).

Effects of Δ9-THC and Type-1 Cannabinoid Receptor Agonists in the Elevated Plus Maze Test of Anxiety: A Systematic Review and Meta-Analysis.

Δ9-THC (the main active compound from Cannabis sativa) and related cannabinoids have been used as drugs of abuse and as medications. They induce a complex set of emotional responses in humans and experimental animals, consisting of either anxiolysis or heightened anxiety. These discrepant effects pose a major challenge for data reproducibility and for developing new cannabinoid-based medicines. In this study, we review and analyze previous data on cannabinoids and anxiety-like behavior in experimental animals. Systematic review and meta-analysis on the effects of type-1 cannabinoid receptor agonists (full or partial, selective or not) in rodents exposed to the elevated plus maze, a widely used test of anxiety-like behavior. Cannabinoids tend to reduce anxiety-like behavior if administered at low doses. THC effects are moderated by the dose factor, with anxiolytic- and anxiogenic-like effects occurring at low-dose (0.075-1 mg/kg) and high-dose (1-10 mg/kg) ranges, respectively. However, some studies report no effect at all regardless of the dose tested. Finally, motor impairment represents a potential confounding factor when high doses are administered. The present analysis may contribute to elucidate the experimental factors underlying cannabinoid effects on anxiety-like behavior and facilitate data reproducibility in future studies.

Static magnetic field blocked alprazolam-induced behavior of Wistar rats in the elevated plus-maze test.

Studies have shown that psychotropic drugs change rat behavior in the elevated plus-maze test (EPM). This study investigated whether static magnetic fields could alter alprazolam-induced rat behavior in the EPM. 66 male Wistar rats (270-300 g weight) were assigned to one of the following groups: Sham Magnetic + Saline (SMS), North Pole + Saline (NPS), South Pole + Saline (SPS), Sham magnetic + alprazolam (SMA), NP + alprazolam (NPA), and SP + alprazolam (SPA). After five days of static magnetic stimulation (3200 Gauss), they received alprazolam or saline (1 mg/kg), and their behavior was evaluated. Two-way ANOVA and Holm-Sidak post-hock were used, with a significant P value of <0.05. The SMA and NPA groups showed an increased number of entries and time in the open arms compared with the SMS group. SPA showed a decrease in these measures when compared to SMA [F(2,61) = 6.43 and F(2,61) = 3.72, respectively]. The SMA and NPA groups showed increased head dipping and end-arm activity compared with the SMS group. SPA showed a decrease in these measures when compared to SMA [F(2,61) = 3.37 and [F(2,61) = 4.72, respectively]. These results show that the south magnetic pole of a static magnetic field blocked the alprazolam effect in the space-time variables of the open arms and ethological anxiolytic-like behavior in the EPM.

Anxiolytic-like effects of citral in the mouse elevated plus maze: involvement of GABAergic and serotonergic transmissions.

Citral, a monoterpene which is a part of the essential oil of several medicinal plants, is generally regarded as safe for human and animal consumption. Studies have introduced citral as a functional component of some essential oils in anxiolytic and antidepressant therapies; however, the neuropharmacological characteristics of citral have not yet been reported. In the present study, we evaluated the anxiolytic activities of citral in comparison to two standard anxiolytics, diazepam and buspirone, in Swiss albino mice by intraperitoneal administration of 1, 2, 5, 10, and 20 mg/kg using elevated plus maze (EPM) and open-field test (OFT). Moreover, we also examined whether the GABAA-benzodiazepine and 5-HT1A receptor are involved in the anxiolytic-like effects of citral by pretreatment with flumazenil and WAY-100635, respectively. Citral dose-dependently decreased the number of border crossings and time spent in borders, and also the number of grooming and rearing in OFT without altering the exploratory behavior of mice. In the EPM, this monoterpene led to a significant increase in number of entries in open arms and time spent in open arms, as well as a decrease in time spent in closed arms. Pretreatment with flumazenil and WAY-100635 both could reverse the anxiolytic effects of the citral in the EPM. These results suggest that anxiolytic activity of citral occurs via the GABAA and 5-HT1A receptor modulation.

Reactivity to conditioned threat cues is distinct from exploratory drive in the elevated plus maze.

Fear and anxiety are adaptive states that allow humans and animals alike to respond appropriately to threatening cues in their environment. Commonly used tasks for studying behaviour akin to fear and anxiety in rodent models are Pavlovian threat conditioning and the elevated plus maze (EPM), respectively. In threat conditioning the rodents learn to associate an aversive event with a specific stimulus or context. The learnt association between the two stimuli (the 'memory') can then be recalled by re-exposing the subject to the conditioned stimulus. The elevated plus maze is argued to measure the agoraphobic avoidance of the brightly lit open maze arms in crepuscular rodents. These two tasks have been used extensively, yet research into whether they interact is scarce. We investigated whether recall of an aversive memory, across contextual, odour or auditory modalities, would potentiate anxiety-like behaviour in the elevated plus maze. The data did not support that memory recall, even over a series of time points, could influence EPM behaviour. Furthermore, there was no correlation between EPM behaviour and conditioned freezing in independent cohorts tested in the EPM before or after auditory threat conditioning. Further analysis found the production of 22 kHz ultrasonic vocalisations revealed the strongest responders to a conditioned threat cue. These results are of particular importance for consideration when using the EPM and threat conditioning to identify individual differences and the possibility to use the tasks in batteries of tests without cross-task interference.

Handling method affects measures of anxiety, but not chronic stress in mice.

Studies in mice have shown that less aversive handling methods (e.g. tunnel or cup handling) can reduce behavioural measures of anxiety in comparison to picking mice up by their tail. Despite such evidence, tail handling continues to be used routinely. Besides resistance to change accustomed procedures, this may also be due to the fact that current evidence in support of less aversive handling is mostly restricted to effects of extensive daily handling, which may not apply to routine husbandry practices. The aim of our study was to assess whether, and to what extent, different handling methods during routine husbandry induce differences in behavioural and physiological measures of stress in laboratory mice. To put the effects of handling method in perspective with chronic stress, we compared handling methods to a validated paradigm of unpredictable chronic mild stress (UCMS). We housed mice of two strains (Balb/c and C57BL/6) and both sexes either under standard laboratory conditions (CTRL) or under UCMS. Half of the animals from each housing condition were tail handled and half were tunnel handled twice per week, once during a cage change and once for a routine health check. We found strain dependent effects of handling method on behavioural measures of anxiety: tunnel handled Balb/c mice interacted with the handler more than tail handled conspecifics, and tunnel handled CTRL mice showed increased open arm exploration in the elevated plus-maze. Mice undergoing UCMS showed increased plasma corticosterone levels and reduced sucrose preference. However, we found no effect of handling method on these stress-associated measures. Our results therefore indicate that routine tail handling can affect behavioural measures of anxiety, but may not be a significant source of chronic husbandry stress. Our results also highlight strain dependent responses to handling methods.

Design, Synthesis and Pharmacological Evaluation of Novel C2,C3-Quinoxaline Derivatives as Promising Anxiolytic Agents.

A new series of quinoxaline derivatives, 2a-4b, were synthesized and their anxiolytic potential was evaluated in vivo using elevated plus maze (EPM), open field (OF) and light-dark box (LDB) techniques. According to the results of the EPM, four active compounds were found in 2a, 2b, 2c, 4b. Their anxiolytic properties were confirmed in terms of LDB and the most active was compound 2b. In the OF, only 2c had an influence on the locomotor activity of the rodents. Thus, the most promising substance was determined; this was 2b, which has the structure of 2-(2-{[3-(4-tert-butylphenyl)quinoxaline-2-yl]methyl}-4,5-dimethoxyphenyl)-N-methylethan-1-amine hydrochloride. The obtained data were analyzed with the pharmacophore feature prediction approach, which made it possible to compare the structures of the studied compounds with the reference drug diazepam, and to determine the contribution of pharmacophores to the manifestation of the activity under study. ADMET analysis was carried out for compound 2b and the acute oral toxicity of this substance was also tested in vivo. As a result of the study, a promising compound with a high anxiolytic effect and low level of toxicity 2b was found, which is of interest for further preclinical study of its properties.

Sex-dependent differences in the anxiolytic-like effect of cannabidiol in the elevated plus-maze.

RATIONALE: Cannabidiol (CBD), the major non-psychoactive constituent of cannabis, has therapeutic potential for the treatment of anxiety. Most preclinical studies investigate only acute effects of CBD and only in males, yet the drug is most likely to be used over a sustained period in clinical practice. OBJECTIVES: The objectives of this study were to investigate the anxiolytic-like effect of CBD in female rats compared to males and to determine whether the responsiveness of females was influenced by the stage of the estrous cycle. METHODS: We carried out experiments to compare the effect of CBD in male and female rats in the elevated plus maze (EPM) in response to acute and short-term (4 days) administration through a complete cycle in females. RESULTS: Male and female rats behaved in a similar manner in the EPM, but females in the late diestrus (LD) phase exhibited more anxiety-like behavior than at other stages, the difference reaching statistical significance compared to proestrus stages. CBD produced anxiolytic-like effects in both sexes, but female rats were responsive only in LD and 10-fold lower dose than males. After sub-chronic (4 days) treatment, responsiveness to CBD was maintained in females in LD, but females in proestrus remained unresponsive to CBD treatment. CONCLUSIONS: We suggest that there are sex differences in the anxiolytic-like effects of CBD in rats that reflect different underlying mechanisms: based on literature data, gonadal hormone status linked to GABAA receptor expression in females, and 5-HT1A receptor activation in males.

Oxycodone decreases anxiety-like behavior in the elevated plus-maze test in male and female rats.

The prescription opioid oxycodone is widely used for the treatment of pain in humans. Oxycodone misuse is more common among people with an anxiety disorder than those without one. Therefore, oxycodone might be misused for its anxiolytic properties. We investigated if oxycodone affects anxiety-like behavior in adult male and female rats. The rats were treated with oxycodone (0.178, 0.32, 0.56, or 1 mg/kg), and anxiety-like behavior was investigated in the elevated plus-maze test. Immediately after the elevated plus-maze test, a small open field test was conducted to determine the effects of oxycodone on locomotor activity. In the elevated plus-maze test, oxycodone increased the percentage of time spent on the open arms, the percentage of open arm entries, time on the open arms, open arm entries, and the distance traveled. The males treated with vehicle had a lower percentage of open arm entries than the females treated with vehicle, and oxycodone treatment led to a greater increase in the percentage of open arm entries in the males than females. Furthermore, the females spent more time on the open arms, made more open arm entries, spent less time in the closed arms, and traveled a greater distance than the males. In the small open field test, treatment with oxycodone did not affect locomotor activity or rearing. Sex differences were observed; the females traveled a greater distance and displayed more rearing than the males. In conclusion, oxycodone decreases anxiety-like behavior in rats, and oxycodone has a greater anxiolytic-like effect in males than females.

The effect of cannabinoid receptor agonist WIN 55,212-2 on anxiety-like behavior and locomotion in a genetic model of absence seizures in the elevated plus-maze.

GAERS and NEC rats were treated with cannabinoid 1/2 receptor agonist WIN 55,212-2 2 mg/kg and tested on the Elevated Plus-Maze.

GABA-ergic agents modulated the effects of histamine on the behaviour of male mice in the elevated plus maze test.

NEW FINDINGS: What is the central question of this study? Is there an interaction between histamine and the GABAergic system in modulation of anxiety in mice? What is the main finding and its importance? There is a synergistic anxiogenic effect between histamine and bicuculline in mice. This effect may be due to a direct or an indirect effect of the histaminergic system on the GABAergic system. ABSTRACT: It has been documented that both histaminergic and GABAergic systems participate in the neurobiology of anxiety behaviour. In the current research, we investigated the effects of the histaminergic system and GABAA receptor agents on anxiety-related behaviours and their interaction using the elevated plus maze test in mice. Intraperitoneal (i.p.) administration of muscimol (0.12 and 0.25 mg/kg) increased the open arm time (OAT) (P < 0.001) without affecting the open arm entries (OAE) and locomotor activity, showing an anxiolytic effect. i.p. injection of bicuculline (0.5 and 1 mg/kg) decreased OAT (P < 0.001) but not OAE and locomotor activity, suggesting an anxiogenic behaviour. Intracerebroventricular (i.c.v.) microinjection of histamine (2.5 and 5 µg/mouse) resulted in a decline in OAT (P < 0.001) but not OAE and locomotor activity, indicating an anxiogenic response. Co-administration of histamine with GABAergic agents, muscimol (0.06 mg/kg; i.p.) and bicuculline (0.25 mg/kg; i.p.), decreased (P < 0.001) and increased (P < 0.05), respectively, the anxiogenic-like response to the effective dose (5 µg/mouse; i.c.v.) of histamine. In addition, co-treatment of effective doses of histamine (2.5 and 5 µg/mouse;i.c.v.) with an effective dose of muscimol (0.12 mg/kg; i.p.) and a non-effective dose of bicuculline (0.25 mg/kg; i.p.) significantly decreased OAT (P < 0.001), suggesting a likely interaction between the histaminergic and GABAergic systems in the regulation of anxiety. The results demonstrated a synergistic anxiogenic-like effect between histamine and bicuculline in mice. In conclusion, our results present an interaction between the histaminergic and GABAergic systems in anxiolytic/anxiogenic-like behaviours in the elevated plus maze test.

Exogenous polyserine and polyleucine are toxic to recipient cells.

Repeat-associated non-AUG (RAN) translation of mRNAs/transcripts responsible for polyglutamine (polyQ) diseases may generate peptides containing different mono amino acid tracts such as polyserine (polyS) and polyleucine (polyL). The propagation of aggregated polyQ from one cell to another is also an intriguing feature of polyQ proteins. However, whether the RAN translation-related polyS and polyL have the ability to propagate remains unclear, and if they do, whether the exogenous polyS and polyL exert toxicity on the recipient cells is also not known yet. In the present study, we found that aggregated polyS and polyL peptides spontaneously enter neuron-like cells and astrocytes in vitro. Aggregated polyS led to the degeneration of the differentiated neuron-like cultured cells. Likewise, the two types of aggregates taken up by astrocytes induced aberrant differentiation and cell death in vitro. Furthermore, injection of each of the two types of aggregates into the ventricles of adult mice resulted in their behavioral changes. The polyS-injected mice showed extensive vacuolar degeneration in the brain. Thus, the RAN translation-related proteins containing polyS and polyL have the potential to propagate and the proteins generated by all polyQ diseases might exert universal toxicity in the recipient cells.

Two opposing hippocampus to prefrontal cortex pathways for the control of approach and avoidance behaviour.

The decision to either approach or avoid a potentially threatening environment is thought to rely upon the coordinated activity of heterogeneous neural populations in the hippocampus and prefrontal cortex (PFC). However, how this circuitry is organized to flexibly promote both approach or avoidance at different times has remained elusive. Here, we show that the hippocampal projection to PFC is composed of two parallel circuits located in the superficial or deep pyramidal layers of the CA1/subiculum border. These circuits have unique upstream and downstream connectivity, and are differentially active during approach and avoidance behaviour. The superficial population is preferentially connected to widespread PFC inhibitory interneurons, and its activation promotes exploration; while the deep circuit is connected to PFC pyramidal neurons and fast spiking interneurons, and its activation promotes avoidance. Together this provides a mechanism for regulation of behaviour during approach avoidance conflict: through two specialized, parallel circuits that allow bidirectional hippocampal control of PFC.

Attenuation of nicotine-induced rewarding and antidepressant-like effects in male and female mice lacking regulator of G-protein signaling 2.

Nicotine-induced rewarding and mood altering effects contribute to the continued use of nicotine and the subsequent development of nicotine dependence. The goal of this study was to assess the role of two specific regulators of G-protein signaling (RGS) proteins namely RGS2 and RGS4 in the above described effects of nicotine. Male and female mice lacking either RGS2 (RGS2 KO) or RGS4 (RGS4 KO), and their respective wildtype (WT) littermates were used in this study. The rewarding effects of nicotine (0.5 mg/kg, base; s.c.) were assessed using the conditioned place preference model. Nicotine-induced anxiolytic-like (0.1 mg/kg, base; i.p.) and antidepressant-like (1 mg/kg, base; i.p.) effects were assessed using the elevated plus maze and tail suspension test, respectively. We also assessed effects of nicotine (0, 0.05, 0.1 & 0.5 mg/kg, base; s.c.) on spontaneous locomotor activity. Nicotine-induced rewarding and antidepressant-like effects were observed in both male and female RGS2 WT mice, but not in mice lacking RGS2 compared to respective controls. In contrast, nicotine-induced rewarding and antidepressant-like effects were observed in both male and female mice lacking RGS4 and their WT littermates. Interestingly, deletion of RGS4 facilitated antidepressant-like effect of nicotine in male, but not female mice compared to respective WT littermates. Nicotine-induced anxiolytic-like effect was not influenced by deletion of either RGS2 or RGS4, irrespective of sex. Nicotine (0.5 mg/kg) decreased locomotor activity in both WT and KO mice compared to respective saline, irrespective of genotype and sex. Taken together, these data provide evidence that RGS2, but not RGS4, plays a role in mediating the rewarding and antidepressant-like effects of nicotine. Further research is required to explore the role of RGS2 after chronic exposure to nicotine.

Effects of cannabidiol and Δ9-tetrahydrocannabinol in the elevated plus maze in mice.

The present study tested the effects of cannabidiol (CBD) alone, Δ-9-tetrahydrocannabinol (THC) alone, and CBD and THC in combination (15:1 ratio) in the elevated plus maze (EPM), a test useful for the study of anxiety. In dose-response studies, adult, male CD1 mice were injected intraperitoneally with (1) CBD alone (0-96 mg/kg), (2) THC alone (0-6.4 mg/kg) or (3) CBD+THC in a 15:1 combination (0.0 + 0.0 mg/kg to 96.0 + 6.4 mg/kg). Diazepam (2.5 mg/kg) was also tested as a positive control. It was found that diazepam significantly increased open arm time in the EPM. CBD alone had no significant effect at any dose or injection-test interval. THC alone, however, caused a significant increase in open arm time at 3.2 and 6.4 mg/kg - doses which did not affect locomotion as measured by closed-arm entries. The effect of the combination of CBD and THC was not significantly different than the effect of THC alone. CBD alone did not have anxiolytic-like effects. THC had anxiolytic-like effects at nontoxic doses. No interaction between THC and CBD was seen when the two were combined.