Aversive learning as a mechanism for lack of repeated anxiolytic-like effect in the elevated plus-maze

Rodents re-exposed to the elevated plus-maze no longer respond to anxiolytic-like drugs, such as benzodiazepines. This phenomenon is thought to be due to retrieval of aversive learning associated with the initial exploration of this potentially dangerous environment. Based on this assumption, one might expect the maintenance of the drug's anxiolytic-like effect in rodents already experienced in the elevated plus-maze if the acquisition and/or consolidation of this learning were impaired. Using male Wistar rats, we investigated whether the systemic administration of propranolol, at putative learning-impairing doses, prior to or immediately after the first (Trial 1) elevated plus-maze exposure would retain the midazolam anxiolytic-like effect on the second (Trial 2) exposure to this apparatus. There was an anxiolytic-like effect, characterized by an increase in the open-arms exploration, in response to 0.25 mg/kg of midazolam on Trial 2 only in rats administered with 20 mg/kg of propranolol before Trial 1. Although propranolol had a dose-dependent and behaviorally-selective anti-anxiety effect (significant at 20 mg/kg) on Trial 1, further minute-by-minute analysis confirmed the propranolol-induced learning acquisition deficit in this group on Trial 2. The knowledge of the environment actually contributes to the unresponsiveness to anxiolytic-like drugs observed in rats re-exposed to the elevated plus-maze.     

Factors triggering abolishment of benzodiazepines effects in the Four-Plate Test--retest in mice.

Abolishment of anxiolytic-like effects of diazepam occurs during re-exposure to some animal tests of anxiety. We investigated the loss of anxiolytic-like effects of diazepam during Trial 2 on previously undrugged mice, namely one-trial tolerance (OTT). Swiss mice were subjected to 1) Four-Plate Test (FPT) without punishments in Trial 1 or 2) FPT without punishments in both Trials or 3) FPT with spatial modifications in Trial 1 or 4) Elevated Plus Maze (EPM), then 24 h later to FPT, with saline, diazepam (1 mg/kg) or DOI (1 mg/kg). Removing punishments in Trial 1 does not counteract the effect reduction of diazepam in Trial 2, but spatial modifications of the aversive environment. Previous exposure to EPM does not trigger a loss of efficacy of diazepam in FPT. Electric punishments do not trigger OTT to benzodiazepines; whilst knowledge of the environment seems to be responsible for this phenomenon. FPT may be useful to study OTT because punishments potentate OTT in this model of anxiety.     

Lack of midazolam-induced anxiolysis in the plus-maze Trial 2 is dependent on the length of Trial 1

The influence of the first exposure length upon the effect of midazolam (MDZ) administration prior to the second exposure in the elevated plus-maze (EPM) was investigated. Drug-free rats were assigned to freely explore the EPM for 1, 2 or 5 min (Trial 1). Twenty-four hours later, each group was subdivided in two further groups, which were retested in the EPM for 5 min, 30 min after either saline or MDZ (1.5 mg kg(-1)) administration (Trial 2). The data showed that during Trial 2, the percentage of entries (%Open arm entries) and time spent in the open arms (%Open arm time) were decreased if rats were pre-exposed to the EPM for 2- or 5-min Trial 1, while the group submitted to 1-min Trial 1 length displayed decreased %Open arm time only. The anxiolytic effect of MDZ prior to Trial 2 was present in the group submitted to 1-min, impaired in the group submitted to 2-min and absent in the group submitted to 5-min Trial 1 length. Data are analyzed taking into account the emotional learning which underlies the exploratory behavior during the EPM Trial 2.     

Prior maze experience required to alter midazolam effects in rats submitted to the elevated plus-maze

In rodents, prior maze experience increases open arm avoidance (OAA) and compromises the anxiolytic effects of benzodiazepines in a subsequent exposure to the elevated plus-maze (EPM), a phenomenon referred to as "one trial tolerance" (OTT). Nevertheless, a possible correlation between these intriguing events remains unclear. Using maze-naive and maze-experienced (free exploration of the EPM for 5 min) rats, Experiment 1 confirmed the anxiolytic effects of midazolam (MDZ; 0.125-1.0 mg/kg) in maze-naive rats, while both increased OAA and OTT to the MDZ anxiolytic effects were observed in maze-experienced rats. However, our results from Experiment 2, designed to assess whether open, enclosed or both arms experience is involved in increased OAA and OTT, showed that MDZ retained its efficacy in rats confined either to an open or enclosed arm, where no significant changes in open arm exploration were observed when compared to the maze-naive group, therefore suggesting that prior experience in the whole apparatus may be involved in the loss of the anxiolytic MDZ effects. Results are discussed in terms of a possible correlation between increased OAA and the OTT phenomenon elicited in a subsequent exposure to the EPM.     

Aversive learning as a mechanism for lack of repeated anxiolytic-like effect in the elevated plus-maze

Rodents re-exposed to the elevated plus-maze no longer respond to anxiolytic-like drugs, such as benzodiazepines. This phenomenon is thought to be due to retrieval of aversive learning associated with the initial exploration of this potentially dangerous environment. Based on this assumption, one might expect the maintenance of the drug's anxiolytic-like effect in rodents already experienced in the elevated plus-maze if the acquisition and/or consolidation of this learning were impaired. Using male Wistar rats, we investigated whether the systemic administration of propranolol, at putative learning-impairing doses, prior to or immediately after the first (Trial 1) elevated plus-maze exposure would retain the midazolam anxiolytic-like effect on the second (Trial 2) exposure to this apparatus. There was an anxiolytic-like effect, characterized by an increase in the open-arms exploration, in response to 0.25 mg/kg of midazolam on Trial 2 only in rats administered with 20 mg/kg of propranolol before Trial 1. Although propranolol had a dose-dependent and behaviorally-selective anti-anxiety effect (significant at 20 mg/kg) on Trial 1, further minute-by-minute analysis confirmed the propranolol-induced learning acquisition deficit in this group on Trial 2. The knowledge of the environment actually contributes to the unresponsiveness to anxiolytic-like drugs observed in rats re-exposed to the elevated plus-maze.     

One-trial tolerance to midazolam is due to enhancement of fear and reduction of anxiolytic-sensitive behaviors in the elevated plus-maze retest in the rat

The anxiolytic-like effects of benzodiazepines (BZDs) in rats is reduced after a single exposure to the elevated plus-maze test (EPM). Several hypotheses have been formulated but no conclusive explanation exists for this phenomenon called "one-trial tolerance." In this study, we examined this phenomenon further by carrying out an ethopharmacological analysis of the behavior of rats submitted to the EPM in two trials. Rats injected with saline before both trials (control), treated with 1.0 mg/kg of midazolam before both trials (MM), or only before Trial 2 (SM), were exposed to the EPM. The SM group did not differ from the controls in the Trial 1 and Trial 2 conditions. The MM group showed a clear anxioselective profile in Trial 1 and no anxiolytic-like effects in Trial 2. Whereas midazolam injected before the first trial caused no significant change in immobility, there was a pronounced increase in immobility during Trial 2 for all three conditions. These data suggest that the anxiolytic-like action of midazolam in the first trial gives way to the fear-related insensitive behaviors (phobic/avoidance responses) responsible for the one-trial tolerance to BZDs in Trial 2. Furthermore, an additional experiment showed that midazolam does not seem to affect the acquisition of the learned avoidance response since it is present upon retesting even after midazolam administration in Trial 1 (MS group). Rather, the present data suggest an emotional shift from Trial 1 to Trial 2, which leads to change in the responsiveness of the animals to BZDs.     

Anxiolytic-like effects of NMDA/glycine-B receptor ligands are abolished during the elevated plus-maze trial 2 in rats

Rationale Drugs enhancing the GABA_A and/or reducing the NMDA/glycine-B receptor activity produce an anxiolytic effect. Regarding the former drugs (e.g. benzodiazepines), prior elevated plus-maze (EPM) test experience abolishes the trial 2 anxiolytic activity, a phenomenon referred to as "one-trial tolerance" (OTT).Objectives The present study examined whether the OTT phenomenon occurs with drugs that reduce the NMDA/glycine-B receptor activity. Methods. Maze-naive and maze-experienced (prior EPM exposure) rats were treated with (±)-HA-966 (2.0 or 4.0 mg/kg), (+)-MK-801 (0.03 or 0.06 mg/kg) or memantine (4.0 or 8.0 mg/kg) and submitted to the EPM. To investigate whether the loss of drug responsiveness was due to pharmacological tolerance, rats received memantine (8.0 mg/kg) both 48 h and 30 min before the first EPM exposure.Results All drugs increased open arms exploration, indicating an anxiolytic effect, in maze-naive but not in maze-experienced rats, in which increased open arms avoidance was observed. An anxiolytic effect was also observed after repeated memantine administration in maze-naive/drug-experienced rats. These effects were observed in the absence of changes in enclosed arms entries, an EPM general exploratory activity index.Conclusions The present findings extend the OTT phenomenon to drugs that reduce the NMDA/glycine-B-receptor activity, and emphasize the repeated test exposure rather than repeated drug administration as a critical determinant for the drug anxiolytic activity. Considering the mechanisms by which the EPM experience alters the drug effects, the present findings favor the hypothesis in which the OTT phenomenon emerge as a consequence of the development and adoption of an anxiolytic-insensitive behavioral strategy.     

Temporal analysis of the rat's behavior in the plus-maze: effect of midazolam

The aim of the present study was to carry out a temporal analysis of the midazolam (MDZ)-induced anxiolysis in rats submitted to the elevated plus-maze (EPM) test. Male Wistar rats received either MDZ (0.5, 1.0 and 1.5 mg.kg(-1)) or saline (0.9%) and were submitted to the EPM test. Temporal analysis revealed that the group receiving MDZ (1.5 mg.kg(-1)), as well as the group treated with saline, displayed low %Open arm entries, which suggests increased anxiety over the test period. Motor activity, evaluated by the enclosed arm entries, was also decreased in both experimental groups, thus suggesting locomotor habituation. The treatment with MDZ (1.5 mg. kg(-1)) induced a clear anxiolysis during the first 3 min, but not at the end of the test, since only the %Open arm time remained increased. The data are discussed with reference to the lack of the test's sensitivity to alterations in the level of anxiety over time and with respect to a qualitative shift in the experimental anxiety at the end of the session.     

Anxiolytic-Like Effect of baicalin and its additivity with other anxiolytics

Baicalin, a naturally occurring flavonoid, was previously reported to exert anxiolytic-like effects in the Vogel conflict test. In the present study, the anxiolytic effects of baicalin alone and in combination with other anxiolytics were tested in mice using the elevated plus-maze (EPM). Baicalin treatment (7.5 - 30 mg/kg) significantly increased entries into and time spent in open arms, indicative of an anxiolytic-like effect. Motor-depressive and myorelaxant side effects commonly associated with anxiolytics were not observed with baicalin at effective anxiolytic doses in the hole-board and horizontal wire tests, respectively. Co-administration of baicalin (3.75 mg/kg) with dl-tetrahydropalmatine ( dl-THP; 0.25 mg/kg), an anxiolytic-hypnotic alkaloid, both at sub-effective doses, induced an additive effect resulting in considerable anxiolysis. Similarly, an additive anxiolytic-like effect was observed with baicalin (3.75 mg/kg) and diazepam (DZ; 0.5 mg/kg). Results obtained from this study demonstrate the potential of baicalin as a candidate anxiolytic and its possible application in multidrug therapy. Abbreviations. BZS:benzodiazepine-binding site EPM:elevated plus-maze DZ:diazepam GABA (A):type A gamma-aminobutyric acid dl-THP: dl-tetrahydropalmatine.     

Chronic treatment with desipramine induces an estrous cycle-dependent anxiolytic-like action in the burying behavior, but not in the elevated plus-maze test.

The effect of chronic desipramine (DMI, 2.5 mg/kg x 21-26 days) treatment in female rats in two anxiety paradigms was assessed: the burying behavior (BB) and the elevated plus-maze (EPM) tests. In the BB test DMI produced a significant decrease in burying in ovariectomized rats, an effect considered as anxiolytic-like. In cycling females, DMI also reduced the cumulative BB most notably in proestrus rats. However, in diestrus rats no anxiolytic-like actions were observed. In addition, DMI increased BB latencies in proestrus and estrus rats. In the EPM test, DMI produced anxiolytic-like actions only in ovariectomized rats, while no significant actions were found in cycling females. Finally, the chronic treatment with DMI produced a general reduction in the ambulatory behavior of rats in all estrous cycle phases. Results are discussed on the basis of the differences between both anxiety paradigms and the probable relationship between the steroids secreted during proestrus and chronic DMI treatment.     

Elevated T-maze as an animal model of memory: effects of scopolamine

The elevated T-maze (ETM) is a putative model for the assessment of anxiety and memory in rodents. This study was designed to further evaluate the utility of the ETM in the study of memory processes. We compared the performance of rats in the ETM, the water maze (WM) and the two-way avoidance task (TWA), after pretreatment with scopolamine (SCO; 0.3 or 1.2 mg/kg i.p.). In the ETM, rats were first trained to meet the criterion of remaining inside the enclosed arm for 300 seconds. Seventy-two hours after training, a retrieval test session was performed. At the lower dose, SCO impaired performance in the retrieval session on all three tasks, whereas in the training session an effect was noted only on the WM task. At the higher dose, SCO impaired the performance of rats in the training sessions for ETM and WM, but not TWA. In a fourth experiment using the elevated plus-maze, SCO showed anxiolytic-like effects at the higher dose only. In conclusion, the effects of SCO in rats submitted to the ETM were dose dependent, with the lower dose exerting a selective effect detected only on retrieval, whereas the higher dose induced motor effects that disrupted inhibitory avoidance acquisition, resulting in impaired retrieval. The results are discussed in terms of the utility of the ETM in the study of drug effects and the neurobiological mechanisms underlying anxiety, learning and memory.     

Evaluation of the anxiolytic-like effect of NKP608, a NK1-receptor antagonist,in two rat strains that differ in anxiety-related behaviors

Rationale NKP608, a selective NK1 receptor antagonist, has been shown to produce anxiolytic-like effects in rodents tested in different anxiety models. However, most of these findings are based on social behaviors and, to our knowledge, there is no report concerning the effects of NKP608 in the elevated plus-maze (EPM) and the open field (OF), two classical models of anxiety/emotionality. Moreover, this compound has never been tested in rodent strains that display contrasting levels of anxiety-related behaviors.Objectives To investigate the anxiolytic-like effects of NKP608 in Lewis and SHR inbred rats, proposed as a genetic model of anxiety for showing high and low indices of anxiety, respectively.Methods Lewis and SHR rats of both sexes were tested in the EPM and OF tests following acute administration of NKP608 (0.003, 0.03 or 0.3 mg/kg) or chlordiazepoxide (CDZ, 5 mg/kg). Measures of approach/avoidance towards the open arms of the EPM and the central area of the OF were used as indices of anxiety.Results All doses of NKP608 produced anxiolytic-like effects, similar to those of CDZ, in SHR males tested in the OF but not in the EPM. Conversely, this compound had a partial anxiolytic effect in LEW males (and, to a lower degree, in SHR females) in the EPM, but not in the OF. LEW females were unaffected following all pharmacological treatments.Conclusions These findings indicate that the anxiety-related effects of NKP608 are strain-, sex- and test-dependent. Moreover, the present data confirm and extend the therapeutic potential of NK1 receptor antagonists for the treatment of anxiety.     

Anxiolytic-like effects of rose oil inhalation on the elevated plus-maze test in rats

The effect of rose oil inhalation (1.0%, 2.5%, and 5.0% w/w) on the elevated plus-maze (EPM) test was investigated in adult male rats and compared with the effect of diazepam (DZP) (1.0 and 2.0 mg/kg) administered intraperitoneally 30 min before testing. Exposure to rose oil produced an anxiolytic-like effect similar to DZP (anxiolytic reference drug). Thus, at some concentrations, rose oil significantly increased the number of visits to and time spent in the open arms of the EPM. Anxiolytic-like properties of rose oil were observed using the EPM, being consistent with other behavioral and clinical studies.     

Effects of rolipram on the elevated plus-maze test in rats: a preliminary study.

The objective of the present study was to assess the behavioural effects of rolipram, a specific cAMP phosphodiesterase (PDE4) inhibitor, in the elevated plus-maze (EPM) test in rats. Results showed that rolipram at the highest dose tested (0.1 mg/kg) increased the percentage of both time spent and entries into open arms, although a decrease of locomotor activity in the EPM test was also observed. In contrast, diazepam (3.0 mg/kg) exhibited the typical profile of an anxiolytic in the EPM test, increasing the percentage of time spent and entries into open arms as well as locomotor activity. A posterior statistical analysis, however, established that the effects of both rolipram and diazepam on parameters denoting anxiolytic-like activity were statistically independent from those reflecting locomotor activity reduction. Furthermore, the effects of both rolipram and diazepam were shown to be distinct from those exhibited by tricyclic antidepressant imipramine which did not show any anxiolytic-like effects in the EPM test, although a reduction of locomotor activity was also detected. Although these preliminary results suggest that rolipram may have some anxiolytic-like properties on the EPM test in rats, such an interpretation should be taken cautiously due to the observed effects on locomotor activity, which could complicate the interpretation of results from rolipram and other PDE4 inhibitors in the current test and in other anxiety animal models.     

Nicotine-induced anxiogenic-like behaviours of rats in the elevated plus-maze: possible role of NMDA receptors of the central amygdala

The objective of the present study was to investigate the possible role of the N-methyl-D-aspartate (NMDA) receptor system of the central amygdala (CeA) in the anxiogenic-like effect of nicotine. Male Wistar rats with cannulas aimed to the CeA were submitted to the elevated plus-maze (EPM). Intraperitoneal (i.p.) injections of nicotine (0.6 and 0.8 mg/kg) decreased percentage open arm time spent (%OAT) and percentage open arm entries (%OAE), but not locomotor activity, indicating an anxiogenic-like response. Bilateral intra-CeA microinjection of NMDA (0.005-0.1 μ g/rat) decreased %OAT, but not %OAE and locomotor activity. Moreover, intra-CeA microinjection of NMDA (0.05 μ g) with an ineffective dose of nicotine (0.4 mg/kg, i.p.) reduced %OAT and %OAE without effect on locomotor activity. On the other hand, intra-CeA microinjection of the NMDA receptor antagonist D-AP5 (0.05-0.5 μ g/rat) increased both %OAT and %OAE, showing an anxiolytic-like effect of the drug. Co-administration of the same doses of D-AP5 with nicotine (0.6 mg/kg, i.p.) increased %OAT and %OAE, but not locomotor activity. Intra-CeA microinjection of D-AP5 reversed the response induced by NMDA (0.1 μ g/rat) in the EPM. The results may support the possible involvement of glutamate transmission, through NMDA receptors of central amygdala in the anxiogenic-like effect of nicotine in the EPM task.     

Antagonism of AMPA receptors produces anxiolytic-like behavior in rodents: Effects of GYKI 52466 and its novel analogues

Rationale Although emerging number of data supports the role of glutamate receptors and the potential of their antagonists in anxiety disorders, the involvement of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate receptors in anxiety is less well characterized. Objective To evaluate the anxiolytic potential of 2,3-benzodiazepine (2,3BDZ) type AMPA receptor antagonists in various models of anxiety. Materials and methods Whole-cell currents, hippocampal field potentials, elevated plus maze (EPM), meta-chlorophenylpiperazine (mCPP)-induced anxiety model, Vogel test in rats and light–dark test (LD) in mice were used to determine AMPA/kainite receptor properties and anxiolytic-like activity of a series of 2,3BDZ-type compounds. Results The reference compound GYKI 52466 was proved active in two anxiety models in non-sedative doses: minimal effective dose (MED) was especially low in EPM (0.01 mg/kg) GYKI 53405 and GYKI 53655 showed anxiolytic-like activity in two tests (EPM and mCPP). EGIS-8332 was active in EPM and LD while EGIS-9637 showed anxiolytic-like potency in EPM, mCPP and Vogel model. EGIS-10608 was the most effective compound among 2,3BDZs tested in EPM and Vogel models (MEDs are 0.01 and 2.5 mg/kg, respectively). 2,3BDZs were active in anxiety models at doses lower than those produced sedative effects. NBQX showed anxiolytic-like activity in EPM only (3 mg/kg). Conclusions The results show that non-competitive AMPA receptor antagonists can profoundly block anxiety-like behavior in rodents independently from their motor depressant activity. However, the sedative properties at higher doses might limit their therapeutic utility as new anxiolytic drugs.     

Combined beta-adrenergic and cholinergic antagonism produces behavioral and cognitive impairments in the water maze: implications for Alzheimer disease and pharmacotherapy with beta-adrenergic antagonists.

This study examined the effects of beta-adrenergic and muscarinic blockade on spatial learning and strategy use in the water maze. Male Long-Evans rats received systemic injections of propranolol (PRO; 10 or 20 mg/kg) or scopolamine (SCO; 0.3 or 1.0 mg/kg) either singly or in combination. To separate strategies learning from spatial learning approximately half of the rats underwent water maze strategies pretraining prior to drug administration and spatial training. PRO did not impair performance in any group. SCO impaired naive but not pretrained rats. PRO and SCO given together in high doses impaired all aspects of behavior in both naive and pretrained rats, and caused sensorimotor disturbances in some groups. PRO (10 mg/kg) and SCO (0.3 mg/kg) together caused a specific spatial reversal learning impairment in pretrained rats without causing strategies impairments or sensorimotor disturbances. Nadolol administered with SCO failed to produce the same impairments as PRO, suggesting that PRO produced its effects by acting on central nervous system sites. These results point to a greater than additive impairing effect of PRO and SCO on adaptive behavior, and a specific role for beta-adrenergic and cholinergic systems working in conjunction in spatial learning. They also suggest that some of the behavioral and cognitive impairments seen in Alzheimer patients or patients receiving pharmacotherapy with beta-adrenergic antagonists in which cholinergic activity is also compromised may result from the combined impairment of beta-adrenergic and cholinergic systems.     

The anxiogenic-like and anxiolytic-like effects of MDMA on mice in the elevated plus-maze: a comparison with amphetamine

Many abused substances have been found to possess anxiogenic-like or/and anxiolytic-like properties. Discrepancies about the effects of MDMA, one of the most popular recreational drugs in recent years, on anxiety have been seen in the literature, and almost all of the data in this respect were derived from retrospective studies. The present study was thus designed to examine the drug's actions by using an animal model of anxiety, the elevated plus-maze test in male mice. Intraperitoneal MDMA at 1 mg/kg was ineffective, at 4 mg/kg decreased the percent of open arm entries (p < 0.01), and increased enclosed entries (p < 0.05), at 12 mg/kg had no significant effect, and at 20 mg/kg induced an increase of percent of open time (p < 0.01). As control drugs, amphetamine (0.5-4 mg/kg, i.p.) produced a dose-dependent, anxiogenic-like effect and diazepam (1 mg/kg, i.p.) induced an anxiolytic-like effect in the test. The results indicate that MDMA has anxiogenic-like properties at lower doses and anxiolytic-like at higher doses. The effects of MDMA and amphetamine on the mouse's responses to the plus-maze are compared. These findings provide a possible explanation for the controversies over MDMA's effects on anxiety in the literature.     

Antagonism of Soman-Induced Convulsions by Midazolam,Diazepam and Scopolamine

ABSTRACT

The effects of midazolam (MDZ), diazepam (DZ) and scopolamine (SCP) therapies on soman-induced electrocorticogram (ECoG) and biceps femoris electromyogram (EMG) activities and brain lesions were assessed in male rats. Animals received pyridostigmine (26 μg/kg, im) 30 min before soman (87.1 μg/kg, im) followed by therapy consisting of atropine (1.5 mg/kg) admixed with 2-PAM (25 mg/kg, im) 1 min later; MDZ (0.5 mg/kg), DZ (1.77 mg/kg) or SCP (0.43 mg/kg) was administered im at 1 min after the onset of convulsions (CVs). Typically, within 5 min after soman the ECoG profile changed to a fullblown, spike-and-dome epileptiform (SDE) pattern followed by CVs and increased amplitude of EMG activity. Treatment with SCP restored ECoG and EMG profiles by 30 min. At 2 hr after exposure only 1 animal demonstrated a slight abnormality in ECoG activity which was normal at 24 hr. Similarly, DZ and MDZ restored EcoG and EMG profiles by 30 min; however, in contrast to SCP, 83% of the animals demonstrated reappearance of SDE 2 hrs after soman. SCP therapy also enabled rats to move about in their cages by 30 min post treatment. In contrast, DZ- and MDZ-treated rats remained incapacitated as late as 2 hr post-exposure. Animals were euthanized at 24 hr, and the extent of soman-induced brain lesions was determined by light microscopic analysis. When present, brain lesions were minimal in SCP-treated rats. The mean brain lesion scores across all experimental conditions ranked as follows: soman control > MDZ > DZ≥ SCP = saline control. These observations suggest that SCP may be highly effective in severe soman intoxication.     

Protective effect of Withania somnifera dunal root extract against protracted social isolation induced behavior in rats

This study investigated the effect of Withania somnifera Dunal (WS) root extract and diazepam in social isolation induced behavior such as anxiety and depression in rats. Rats were isolated for 6 weeks and the assessment of changed behavior were done on elevated plus maze (EPM) and forced swim test (FST). Isolation reared rats spent less time into the open arms on EPM and significantly increased immobility time in FST compared to group housed rats. WS (100, 200 or 500 mg/kg, oral) and diazepam (1 or 2 mg/kg, ip) dose dependently increased the time spent and entries into the open arms on EPM test and showed the anxiolytic activity. Subeffective dose of WS (50 mg/kg, oral) potentiated the anxiolytic action of diazepam (0.5, 1 or 2 mg/kg, ip). WS (100, 200 or 500 mg/kg, oral) also reduced the immobility time in FST, thus showed antidepressant effect in both group housed and social isolates. The investigations support the use of WS as a mood stabilizer in socially isolation behavior in Ayurveda.