Indulging Curiosity: Preliminary Evidence of an Anxiolytic-like Effect of Castor Oil and Ricinoleic Acid.

In the process of validating the elevated zero maze, a common test of anxiety-like behavior, in our laboratory, we demonstrated an anxiolytic-like effect of castor oil and its primary component, ricinoleic acid. We tested the effects of vehicle and chlordiazepoxide in male mice in the elevated zero maze following a 30-min pretreatment time. Chlordiazepoxide is a United States Food and Drug Administration-approved drug that was previously shown to exert anxiolytic-like effects in both the elevated zero maze and elevated plus maze. Chlordiazepoxide was administered at doses of 5 or 10 mg/kg. We used 5% polyoxyl 35 castor oil (Kolliphor® EL) and saline as treatment vehicles and found that the effect of chlordiazepoxide on open zone occupancy and open zone entries was blunted when 5% Kolliphor was used as the vehicle. These tests demonstrated that chlordiazepoxide increased open zone occupancy and entries in the elevated zero maze more effectively when saline was used as the treatment vehicle and that Kolliphor dampened the anxiolytic-like effect of chlordiazepoxide when it was used as the treatment vehicle. Notably, 5% Kolliphor alone slightly increased baseline open zone occupancy and entries. Given that Kolliphor is a derivative of castor oil, we next tested the effect of 5% castor oil and 5% ricinoleic acid, which is a major component of castor oil. We found that both castor oil and ricinoleic acid increased open zone occupancy but not entries compared with saline. Altogether, our findings demonstrate that Kolliphor, castor oil, and ricinoleic acid may exert anxiolytic-like effects in male mice in the elevated zero maze. This potential anxiolytic-like effect of castor oil is consistent with its well-established beneficial effects, including anti-inflammatory, antioxidant, antifungal, and pain-relieving properties.

Discriminative-stimulus effects of cannabidiol oil in Sprague-Dawley rats.

Cannabidiol (CBD) is one of the major centrally active phytocannabinoid components of cannabis, and has been approved by the FDA only for the treatment of seizures associated with three rare disorders. It has also been touted as a potential treatment for anxiety in place of more traditional treatments like benzodiazepines. Although there is some evidence of anxiolytic effects of CBD, its suitability as a substitute for benzodiazepines is unknown. This experiment was designed to assess the extent to which CBD shares interoceptive discriminative-stimulus properties with the anxiolytic drug chlordiazepoxide (CDP), a benzodiazepine. In the present experiment, a range of doses (0-1569 mg/kg) of over-the-counter CBD oil was administered (i.g.) in male Sprague-Dawley rats trained to discriminate 5.6 mg/kg CDP from saline. Due to the long time-course effects of CBD, generalization tests were conducted at 90 and 120 min post-CBD administration. The two highest doses of CBD tested (1064 and 1569 mg/kg) were found to partially substitute for 5.6 mg/kg CDP, with mean percent responding on the CDP-associated lever reaching above 20% at time 2 (120 min post-CBD administration), suggesting that high doses of the over-the-counter CBD oils used in this experiment share interoceptive discriminative-stimulus properties to some degree with CDP. These results are novel in comparison to existing research into stimulus effects of CBD, in which substitution for benzodiazepines has not previously been observed.

Further disentangling the motivational processes underlying benzodiazepine hyperphagia.

In addition to their well-known anxiolytic functions, benzodiazepines produce hyperphagia. Previously, we reported that the benzodiazepine, chlordiazepoxide (CDP), increased consumption of both normally-preferred and normally-avoided taste stimuli during long-term (1 h) tests, primarily through changes in licking microstructure patterns associated with hedonic taste evaluation, whereas there was little effect on licking microstructure measures associated with post-ingestive feedback. In this study, we further examined the hedonic and motivational specificity of CDP effects on ingestive behavior. We tested brief access (15 s) licking responses for tastants spanning all taste qualities after treatment with either CDP (5 or 10 mg/kg) or the non-benzodiazepine anxiolytic, buspirone (1.5 or 3 mg/kg). A between-subjects, counterbalanced design compared the CDP or buspirone effects on licking responses for water and a range of weak to strong concentrations of NaCl, Q-HCl, citric acid, MSG, saccharin, and capsaicin under water-restricted (23 h) conditions; and sucrose, saccharin, and MSG under water-replete conditions. In a dose dependent manner, CDP increased licking for taste stimuli that were normally-avoided after saline treatment, with a notable exception observed for the trigeminal stimulus, capsaicin, which was not affected at any concentration or drug dose, suggesting a taste-specific effect of CDP on orosensory processing. Under water-replete conditions, CDP dose-dependently increased licking to normally-accepted concentrations of sucrose, saccharin, and MSG. There was no effect of either drug on licks for water under either water-restricted or water-replete conditions. Buspirone slowed oromotor coordination by increasing brief interlick intervals, but it did not affect licking for any concentrations of the tastants. Overall, these results indicate that benzodiazepines selectively enhance the hedonic acceptance of gustatory orosensory stimuli, independent of general anxiolytic or oromotor coordination effects, or physiological states such as thirst.

Effects of chlordiazepoxide on pausing during rich-to-lean transitions.

Extended pausing during discriminable transitions from rich-to-lean conditions can be viewed as escape (i.e., rich-to-lean transitions function aversively). Thus, an anxiolytic drug would be predicted to mitigate the aversiveness and decrease pausing. In the current experiment, pigeons' key pecking was maintained by a multiple fixed-ratio fixed-ratio schedule of rich (i.e., larger) or lean (i.e., smaller) reinforcers. Intermediate doses (3.0-10.0 mg/kg) of chlordiazepoxide differentially decreased median pauses during rich-to-lean transitions. Relatively small decreases in pauses occurred during lean-to-lean and rich-to-rich transitions. Effects of chlordiazepoxide on pausing occurred without appreciable effects on run rates. These findings suggest that signaled rich-to-lean transitions function aversively.

Effects of linalool on extinction of mouse operant behaviour.

Linalool is an enanitomer monoterpene compound identified as the pharmacologically active constituent in a number of essential oils and has been reported to display anxiolytic properties in humans and in animal models and to exert both GABAergic and glutamatergic effects. In Experiment 1 linalool (100, 200, and 300, i.p.) had no significant effects compared with saline in an activity tracker with C57BL/6j mice. Experiment 2 assessed the effects on operant extinction with mice of chlordiazepoxide at a dose (15 mg/kg, i.p.) previously shown to facilitate extinction, and the same doses of linalool, compared with saline. Linalool had a dose-related facilitatory effect on extinction. While the effects of the highest dose of linalool most closely resembled the effects of chlordiazepoxide, the pattern of results suggested that linalool may affect both the acquisition of extinction learning, which is influenced by glutamatergic processes, and the expression of extinction, known to be affected by GABAergic agents such as chlordiazepoxide.

The elevated gradient of aversion: a new apparatus to study the rat behavior dimensions of anxiety, fear, and impulsivity.

Few behavioral tests allow measuring several characteristics and most require training, complex analyses, and/or are time-consuming. We present an apparatus based on rat exploratory behavior. Composed of three different environments, it allows the assessment of more than one behavioral characteristic in a short 3-min session. Factorial analyses have defined three behavioral dimensions, which we named Exploration, Impulsivity, and Self-protection. Behaviors composing the Exploration factor were increased by chlordiazepoxide and apomorphine and decreased by pentylenetetrazole. Behaviors composing the Impulsivity factor were increased by chlordiazepoxide, apomorphine, and both acute and chronic imipramine treatments. Behaviors composing the Self-protection factor were decreased by apomorphine. We submitted Wistar rats to the open-field test, the elevated-plus maze, and to the apparatus we are proposing. Measures related to exploratory behavior in all three tests were correlated. Measures composing the factors Impulsivity and Self-protection did not correlate with any measures from the two standard tests. Also, compared with existing impulsivity tests, the one we proposed did not require previous learning, training, or sophisticated analysis. Exploration measures from our test are as easy to obtain as the ones from other standard tests. Thus, we have proposed an apparatus that measured three different behavioral characteristics, was simple and fast, did not require subjects to be submitted to previous learning or training, was sensitive to drug treatments, and did not require sophisticated data analyses.

Responses to positive and aversive stimuli in estrous female rats housed in a seminatural environment: Effects of yohimbine and chlordiazepoxide.

The behavioral effects of putative anxiolytic and anxiogenic drugs are usually evaluated in highly standardized tests. Here, we determined the effects of such drugs in rats housed in mixed sex groups in a seminatural environment. Sexually receptive female Wistar rats were treated with either the anxiolytic drug chlordiazepoxide (2 mg/kg), the anxiogenic drug yohimbine (1 mg/kg), or saline (1 ml/kg). Different emotional challenges eliciting purportedly positive affect (lavender odor, Mozart's music, chocolate flavored food) or negative affect (white noise, fox odor) were then introduced into the seminatural environment. A co-occurrence analysis revealed that music was rather aversive to the rats, as were white noise and fox odor. Lavender and chocolate exposure decreased classical indicators of fear. White noise suppressed sexual behaviors and caused avoidance of the open area. Yohimbine increased sexual receptivity during lavender exposure, decreased the latency to flee the white noise, and increased self-grooming regardless of the emotional challenge. Chlordiazepoxide was effective only during exposure to white noise, and increased the frequency of hiding alone. The modest effects of the drugs in the seminatural environment may be the result of social buffering and rats experiencing a high degree of controllability over their environment.

Effects of plus-maze experience and chlordiazepoxide on anxiety-like behavior and serotonin neural activity in the dorsal raphe nucleus in rats.

The extent to which rats express anxiety-like behavior on the elevated plus-maze (EPM) depends on their previous maze experience. Open-arm avoidance develops in maze-experienced rats, and is often accompanied by a diminished anxiolytic response to benzodiazepines. Regions of the dorsal raphe nucleus (DRN) were examined in male Sprague-Dawley rats using c-Fos and serotonin immunohistochemistry following a single exposure, a second exposure or no exposure to the EPM. We then examined the effect of the benzodiazepine anxiolytic chlordiazepoxide (CDP, 5 mg/kg) on EPM behavior and DRN neural activity. Enhanced open-arm avoidance was evident on the second EPM trial in both experiments. The observed pattern of c-Fos expression suggests that the first exposure to the maze activates serotonin cells in the rostral and dorsal regions of the DRN and that only the dorsal subregion is activated by a second exposure. CDP increased open-arm exploration during the first trial, which corresponded to decreased 5-hydroxytryptamine (5-HT) activity in the rostral and ventral subregions of the DRN. However, 5-HT activity in the DRN was reduced in rats on the second maze trial compared with the first trial, when CDP had no effect on open-arm exploration. These results suggest that open-arm avoidance in maze-experienced rats can be characterized as a coping response that is mediated by specific populations of 5-HT neurons in the DRN.

The elevated gradient of aversion: a new apparatus to study the rat behavior dimensions of anxiety, fear, and impulsivity

Few behavioral tests allow measuring several characteristics and most require training, complex analyses, and/or are time-consuming. We present an apparatus based on rat exploratory behavior. Composed of three different environments, it allows the assessment of more than one behavioral characteristic in a short 3-min session. Factorial analyses have defined three behavioral dimensions, which we named Exploration, Impulsivity, and Self-protection. Behaviors composing the Exploration factor were increased by chlordiazepoxide and apomorphine and decreased by pentylenetetrazole. Behaviors composing the Impulsivity factor were increased by chlordiazepoxide, apomorphine, and both acute and chronic imipramine treatments. Behaviors composing the Self-protection factor were decreased by apomorphine. We submitted Wistar rats to the open-field test, the elevated-plus maze, and to the apparatus we are proposing. Measures related to exploratory behavior in all three tests were correlated. Measures composing the factors Impulsivity and Self-protection did not correlate with any measures from the two standard tests. Also, compared with existing impulsivity tests, the one we proposed did not require previous learning, training, or sophisticated analysis. Exploration measures from our test are as easy to obtain as the ones from other standard tests. Thus, we have proposed an apparatus that measured three different behavioral characteristics, was simple and fast, did not require subjects to be submitted to previous learning or training, was sensitive to drug treatments, and did not require sophisticated data analyses.

The contribution of contextual fear in the anxiolytic effect of chlordiazepoxide in the fear-potentiated startle test.

This study evaluated the extent to which a reduction in contextual fear contributes to the anxiolytic effect of benzodiazepines in the fear-potentiated startle response. To this end, chlordiazepoxide, an anxiolytic often used as positive control in preclinical drug studies, and zolpidem, known to have sedative properties and to be devoid of anxiolytic effects, were tested in two contexts: the same context as training had taken place and an alternative context. In addition, the level of muscle relaxation was assessed in a grip strength test. Chlordiazepoxide (2.5-10 mg/kg) decreased the fear-potentiated startle response, confirming its anxiolytic activity. In addition, it dose-dependently decreased the overall startle response in the same, but not the alternative context, and did not affect grip strength, indicating that chlordiazepoxide inhibits contextual fear in the absence of non-specific drug effects. Zolpidem (1.0-10 mg/kg) reduced the overall startle response in both contexts equally and decreased grip strength, indicating that its effects on fear-potentiated startle are due to non-specific drug effects, and not anxiolytic effects. The present findings show that chlordiazepoxide reduces contextual conditioned fear in the absence of non-specific drug effects. In addition, they show that training and testing rats in different contexts makes it possible to distinguish between cued, contextual and non-specific drug effects. As exaggerated contextual fear conditioning contributes to the fear generalization processes implicated in pathological anxiety, focus in screening of anxiolytic effects could be directed more towards the suppression of contextual fear and, therefore, this approach would be a valuable addition to standard preclinical screening.

No effect of sex and estrous cycle on the fear potentiated startle response in rats.

The prevalence of anxiety disorders is higher in women than in men. Yet preclinical studies on anxiety are mostly performed in male subjects. This may have limited our understanding of mechanisms contributing to anxiety disorders. Since fear conditioning is considered an important factor in the etiology of anxiety disorders, the present study aimed to investigate the effect of sex and estrous cycle on conditioned fear and the anxiolytic effect of benzodiazepines in rats. We measured the fear-potentiated startle response in male and female rats during different estrous cycle stages and performed a replication study in a separate cohort. In addition, we assessed the response to diazepam (0-3.0 mg/kg IP) and chlordiazepoxide (0-10 mg/kg IP) in male and female rats in proestrous/estrous and diestrous stage. Our results showed that there were no sex differences in the expression of fear-potentiated startle. The estrous cycle also did not affect the fear-potentiated startle response. In addition, male and female rats did not differ in their fear-potentiated startle response following treatment with either diazepam or chlordiazepoxide. In conclusion, the current study shows that male and female rats do not differ in their conditioned fear response and the responsiveness to benzodiazepines. The results further indicate that conditioned fear-related processes are not affected by gonadal hormone fluctuations in this paradigm. These findings may suggest that the higher prevalence of anxiety disorders in women more likely results from differences in responding to previous experiences or differences in other predisposing factors, rather than differences in conditioned fear per se.

Proximity as a predictor of social behavior in rats.

BACKGROUND: In studies that measure social behavior of a freely interacting pair rats social behavior of one rat is strongly influenced by the behavior of the other. This prevents evaluating social behavior of one single rat. NEW METHOD: We assessed the motivation to interact socially in a modified open-field, by measuring the time a rat attempted to interact with a co-specific separated by a grid in a birdcage outside of the apparatus. We propose time in front of the birdcage is an indicator of social behavior. RESULTS: We showed that the focal rat allocates more time in front of the birdcage, interacting with another rat through the grid. Also, that the presence of the other rat that attracts the focal rat. Habituation to the apparatus, repeated testing and illumination condition did not alter the proximity measures of rats. Finally, treatment with chlordiazepoxide (3.0mg/kg) either increased the time spent in front of the cage by males and females or (5.6mg/kg) increased the proximity measure of females. COMPARING WITH EXISTING METHOD: Our method prevents partners from influencing the target rat's social behavior; existing methods do not. Also, it is more sensitive to the effect of chlordiazepoxide than the broadly used method proposed by File and Hyde (1978). CONCLUSIONS: Proximity is an advantageous measure: it allows the assessment of only one focal animal without the interference of a partner; it is simple to take; it requires little interpretation skills or training from the experimenter, no special equipment or conditions.

Vicarious Social Defeat Stress Induces Depression-Related Outcomes in Female Mice.

BACKGROUND: Stress is a prevailing risk factor for mood-related illnesses, wherein women represent the majority of those affected by major depression. Despite the growing literature suggesting that affective disorders can arise after a traumatic event is vicariously experienced, this relationship remains understudied in female subjects at the preclinical level. Thus, the objective of the current investigation was to examine whether exposure to emotional and/or psychological stress (ES) mediates depression-related outcomes in female mice. METHODS: Female C57BL/6 mice (8 weeks old, null parity) vicariously experienced the defeat bout of a male conspecific, by a male CD1 aggressor, for 10 consecutive days. Twenty-four hours after the last stress exposure, female mice were tested in the social interaction, sucrose preference, tail suspension, or elevated plus maze tests. Furthermore, we examined whether ketamine and chlordiazepoxide, pharmacological agents used to treat mood-related disorders in the clinical population, would reverse the ES-induced social dysfunction. RESULTS: When compared with control mice, female mice exposed to ES displayed decreased social behavior and preference for sucrose, along with increased immobility in the tail suspension test. Also, they displayed higher levels of blood serum corticosterone, as well as decreased body weight. Lastly, the ES-induced avoidance-like phenotype was ameliorated by both ketamine and chlordiazepoxide. CONCLUSIONS: Our data indicate that female mice exposed to ES display a behavioral and physiologic profile that mimics symptoms of depression in the clinical population. As such, this experimental model may be adopted to examine vicarious stress-induced mood-related disorders, as well as pharmacological antidepressant response, in a sex-specific manner.

Social harassment induces anxiety-like behaviour in crayfish.

Social interactions leading to dominance hierarchies often elicit psychological disorders in mammals including harassment and anxiety. Here, we demonstrate that this sequence also occurs in an invertebrate, the crayfish Procambarus clarkii. When placed in the restricted space of an aquarium, crayfish dyads generally fight until one of the opponents suddenly escapes, thereafter clearly expressing a submissive behaviour. Nevertheless, the winner frequently keeps on displaying excessive aggressive acts, having deleterious consequences in losers and interpreted as harassment behaviour. We indeed observed that, contrary to winners, losers expressed anxiety-like behaviour (ALB) in correlation with the stress intensity they suffered during the harassment period mainly. Injections of an anxiolytic abolished ALB, confirming its homology with anxiety. A serotonin (5-HT) antagonist had the same effect, suggesting a role for 5-HT, whose brain concentrations increased much more in losers than in winners. Our findings suggest that the bases of harassment and of its anxiogenic consequences have emerged very early during evolution, and emphasize crayfish as an unexpected but potentially fruitful model for the study of these social disorders.

Investigation of rat exploratory behavior via evolving artificial neural networks.

BACKGROUND: Neuroevolution comprises the use of evolutionary computation to define the architecture and/or to train artificial neural networks (ANNs). This strategy has been employed to investigate the behavior of rats in the elevated plus-maze, which is a widely used tool for studying anxiety in mice and rats. NEW METHOD: Here we propose a neuroevolutionary model, in which both the weights and the architecture of artificial neural networks (our virtual rats) are evolved by a genetic algorithm. COMPARISON WITH EXISTING METHOD(S): This model is an improvement of a previous model that involves the evolution of just the weights of the ANN by the genetic algorithm. In order to compare both models, we analyzed traditional measures of anxiety behavior, like the time spent and the number of entries in both open and closed arms of the maze. RESULTS: When compared to real rat data, our findings suggest that the results from the model introduced here are statistically better than those from other models in the literature. CONCLUSIONS: In this way, the neuroevolution of architecture is clearly important for the development of the virtual rats. Moreover, this technique allowed the comprehension of the importance of different sensory units and different number of hidden neurons (performing as memory) in the ANNs (virtual rats).

Anxiolytic-like effects of leptin on fixed interval responding.

Leptin has been shown to affect energy homeostasis, learning and memory, and some models of anxiolytic action. However, leptin has produced inconsistent results in previous non-operant behavioural tests of anxiety. Here, we test the anxiolytic potential of leptin in an operant paradigm that has produced positive results across all classes of anxiolytic so far tested. Rats were tested in the Fixed Interval 60 Seconds (FI60) task following administration of 0/0.5/1.0mg/kg (i.p.) leptin or an active anxiolytic control of 5mg/kg (i.p.) chlordiazepoxide (CDP). By the end of the 14days of testing in the FI60 task, 0.5mg/kg leptin released suppressed responding in a manner similar to CDP, and 1.0mg/kg leptin produced a relative depression in responding, a similar outcome pattern to previously tested 5HT-agonist anxiolytics. This suggests that leptin behaves similarly to established serotonergic anxiolytics such as buspirone and fluoxetine; with the delay in development of effect during testing, and the inverted-U dose-response curve explaining the inconsistent behaviour of leptin in behavioural tests of anxiety, as this type of pattern is common to serotonergic anxiolytics.

A Selective Nociceptin Receptor Antagonist to Treat Depression: Evidence from Preclinical and Clinical Studies.

Nociceptin/Orphanin FQ (N/OFQ) is an endogenous ligand of the N/OFQ peptide (NOP) receptor, which is a G protein-coupled receptor in brain regions associated with mood disorders. We used a novel, potent, and selective orally bioavailable antagonist, LY2940094, to test the hypothesis that blockade of NOP receptors would induce antidepressant effects. In this study we demonstrate that targeting NOP receptors with LY2940094 translates to antidepressant-like effects in rodent models and, importantly, to antidepressant efficacy in patients with major depressive disorder (MDD). The proof-of-concept study (POC) was an 8-week, double-blind, placebo-controlled trial that evaluated LY2940094 as a novel oral medication for the treatment of patients with MDD. Once daily oral dosing of LY2940094 at 40 mg for 8 weeks vs placebo provided some evidence for an antidepressant effect based on the change from baseline to week 8 in the GRID-Hamilton Depression Rating Scale-17 item total score, although the predefined POC efficacy criterion (probability of LY2940094 being better than placebo⩾88%) was not met (82.9%). LY2940094 also had an early effect on the processing of emotional stimuli at Week 1 as shown by an increased recognition of positive relative to negative facial expressions in an emotional test battery. LY2940094 was safe and well tolerated. Overall, these are the first human data providing evidence that the blockade of NOP receptor signaling represents a promising strategy for the treatment of MDD.

Serotonin, but not dopamine, controls the stress response and anxiety-like behavior in the crayfish Procambarus clarkii.

In the animal kingdom, biogenic amines are widespread modulators of the nervous system that frequently interact to control mood. Our previous investigations in crayfish (Procambarus clarkii) have established that stress induces changes in brain serotonin (5-HT) concentrations that are responsible for the appearance of anxiety-like behavior (ALB). Here, we further analyze the roles of 5-HT and another biogenic amine, dopamine (DA), on the crayfish response to stress. We show that the intensity of crayfish ALB depends on the intensity of stressful stimulation and is associated with increased concentrations of 5-HT in the brain. These 5-HT levels were significantly correlated, before, as well as after stress, with those of DA, which were approximately 3- to 5-times less abundant. However, whereas the degree of ALB was clearly correlated with brain 5-HT concentrations, it was not significantly correlated with DA. Moreover, in contrast to injections of 5-HT, DA injections were not able to elicit a stress response or ALB. In addition, 5-HT and DA levels were not modified by treatment with the anxiolytic chlordiazepoxide, confirming that suppression of ALB by this GABA-A receptor ligand acts downstream and is independent of changes in crayfish bioamine levels. Our study also provides evidence that the anxiogenic effect of 5-HT injections can be prevented by a preliminary injection of 5-HT antagonists. Altogether, our results emphasize that the rises in brain concentrations of 5-HT, but not DA, play a role in controlling the induction and the intensity of crayfish ALB.

Anxiogenic role of vasopressin during the early postnatal period: maternal separation-induced ultrasound vocalization in vasopressin-deficient Brattleboro rats.

Both animal and human studies suggest that in adulthood, plasma vasopressin level correlates well with anxiety. Little is known about the mood regulation during the perinatal period. Here, we aim to investigate the influence of vasopressin on anxiety during the early postnatal age. As a sign of distress, rat pups emit ultrasonic vocalizations (USVs) when they are separated from their mother. This USV was detected in 7- to 8-day-old vasopressin-deficient Brattleboro pups, and they were compared to their heterozygote littermates and wild-type pups. The results were confirmed by V1b antagonist treatment (SSR149415 10 mg/kg ip 30 min before test) in wild-types. Chlordiazepoxide (3 mg/kg ip 30 min before test)-an anxiolytic-was used to test the interaction with the GABAergic system. At the end of the test, stress-hormone levels were measured by radioimmunoassay. Vasopressin-deficient pups vocalized substantially less than non-deficient counterparts. Treatment with V1b antagonist resulted in similar effect. Chlordiazepoxide reduced the frequency and duration of the vocalization only in wild-types. Reduced vocalization was accompanied by smaller adrenocorticotropin levels but the level of corticosterone was variable. Our results indicate that the anxiolytic effect of vasopressin deficiency (both genetic and pharmacological) exists already during the early postnatal age. Vasopressin interacts with the GABAergic system. As mood regulation does not go parallel with glucocorticoid levels, we suggest that vasopressin might have a direct effect on special brain areas.

DSR-98776, a novel selective mGlu5 receptor negative allosteric modulator with potent antidepressant and antimanic activity.

Modulation of monoaminergic systems has been the main stream of treatment for patients with mood disorders. However, recent evidence suggests that the glutamatergic system plays an important role in the pathophysiology of these disorders. This study pharmacologically characterized a structurally novel metabotropic glutamate 5 (mGlu5) receptor negative allosteric modulator, DSR-98776, and evaluated its effect on rodent models of depression and mania. First, DSR-98776 in vitro profile was assessed using intracellular calcium and radioligand binding assays. This compound showed dose-dependent inhibitory activity for mGlu5 receptors by binding to the same allosteric site as 2-methyl-6-(phenylethynyl)-pyridine (MPEP), a known mGlu5 inhibitor. The in vivo therapeutic benefits of DSR-98776 were evaluated in common rodent models of depression and mania. In the rat forced swimming test, DSR-98776 (1-3mg/kg) significantly reduced rats immobility time after treatment for 7 consecutive days, while paroxetine (3 and 10mg/kg) required administration for 2 consecutive weeks to reduce rats immobility time. In the mouse forced swimming test, acute administration of DSR-98776 (10-30 mg/kg) significantly reduced immobility time. This effect was not influenced by 4-chloro-DL-phenylalanine methyl ester hydrochloride-induced 5-HT depletion. Finally, DSR-98776 (30 mg/kg) significantly decreased methamphetamine/chlordiazepoxide-induced hyperactivity in mice, which reflects this compound antimanic-like effect. These results indicate that DSR-98776 acts as an orally potent antidepressant and antimanic in rodent models and can be a promising therapeutic option for the treatment of a broad range of mood disorders with depressive and manic states.