Modulation of baseline behavior in rats by putative serotonergic agents in three ethoexperimental paradigms

The present study adopts an ethoexperimental approach to examine the deportment subsequent to alteration in serotonin (5-HT) neurotransmission following treatment with site-specific neuropharmacological probes. The impact of perturbation in (5-HT) neurotransmission on baseline behavior was analyzed employing three animal models of anxiety, i.e., hole-board, elevated plus maze, and bright/dark arena. Inbred male rats (Wistar strain, weighing between 150 and 200 g) were used in this study. The vivarium and the behavioral laboratory were specially designed to permit operation of reversed light-dark cycle and all experiments were performed during the dark period. Pharmacological tools selected to influence 5-HT levels include (1) a combination of tranylcypromine and tryptophan (TCP + TRYPT) (0.75 mg/kg + 40 mg/kg) which augments 5-HT biosynthesis; (2) p-chlorophenylalanine (PCPA: 200 mg/kg), an inhibitor of 5-HT biosynthesis; and (3) 5-HT reuptake blockers, namely zimelidine (ZIM) (40 mg/kg) and fluoxetine (FLU) (10 mg/kg). Rats under the influence of PCPA exhibited anxiolytic response, whereas those under treatments to raise 5-HT levels, viz., TCP + TRYPT, ZIM and FLU, displayed anxiogenic-like reactions. Several other agents known to specifically interact with 5-HT receptor subtypes were also tested. 5-HT2 receptor stimulants, such as quipazine (5 mg/kg) and MK 212 (0.5 mg/kg), were found to be anxiogenic. Buspirone (2 mg/kg), a 5-HT1 agonist, surmounted normal behavioral inhibition. However, another 5-HT1 stimulant, 8-OH-DPAT (0.025 mg/kg), had anxiogenic action. Pretreatment with 5-HT3 antagonists [zacopride (2 mg/kg) and GR 38032F (0.1 mg/kg)] and putative 5-HT1 antagonist [propranolol (10 mg/kg)] resulted in borderline disinhibition of normal behavioral inhibition to novel environments. In contrast, cyproheptadine (0.5 mg/kg), a 5-HT2 antagonist, provoked anxiogenic-like behavior. Altogether, uniform results were obtained for each probe in all the three models, suggesting that the battery of anxiety tests chosen in this study is reliable and sensitive to detect unknown pharmacological responses. The results support the hypothesis that stimulation of serotonergic neurotransmission heightens normal anxiety, whereas its blockade releases normal behavioral inhibition. Furthermore, this work establishes the validity of using the three paradigms in evaluating the involvement of multiple neurotransmitter receptors in the control of behavior of rodents under natural circumstances and also detects any aberration following exposure to novelty and stress.     

Evaluation of the interaction between D1 and D2 receptors in a drug discrimination paradigm

Recent research has suggested that there is a synergistic interaction between D1 and D2 dopamine (DA) receptors and that D1 stimulation by endogenous DA is necessary for the expression of some D2-mediated behavioral effects. The purpose of the present experiment was to examine further the interactions between D1 and D2 receptors using drug discrimination (DD), a behavioral paradigm that is sensitive and selective for D1 and D2 agonist and antagonist activity. Two groups of male Sprague-Dawley rats (N = 8/group) were trained to discriminate the D2 agonist quinpirole (QUIN; either 0.05 or 0.012 mg/kg, ip, 10 min pre-session) from saline (1.0 ml/kg, ip, 10 min pre-session) in a two-lever, food-reinforced DD paradigm. QUIN (0.0015-0.1 mg/kg) produced a dose-related increase in QUIN-appropriate responding in both groups of rats. The D1 agonist SKF 38393 (SKF; 6.4-12.8 mg/kg, ip) given alone did not substitute for QUIN in either of the two training dose groups. The administration of SKF 30 min before QUIN had no effect on the QUIN dose-response function in either group of rats. These results indicate that stimulation of D1 receptors failed to potentiate a behavioral effect mediated by D2 receptors. The D1 antagonist SCH 23390 (SCH; 0.0015-0.05 mg/kg, ip) partially substituted for QUIN in the group trained with the 0.05 dose of QUIN, and to a larger extent in the group trained with the 0.012 dose of QUIN. SCH did not alter the effect of the training dose of QUIN except at a dose high enough to virtually eliminate lever pressing in the group trained to discriminate the high dose of QUIN. The failure of SCH to block QUIN suggests that D1 receptor stimulation by endogenous DA is not necessary for this D2 effect to be expressed. These results may be accounted for by assuming a presynaptic site of action for QUIN in the QUIN discrimination. Further, they demonstrate that the interaction between D1 and D2 receptors cannot be simply characterized as synergistic.     

The influence of competitive status (winner/loser) on the behavior of male rats in three models of anxiety

Studies indicate that features such as prior stressful experience, strain, gender, and age can influence the behavior of rats in animal models of anxiety. In the present study, we examined the possible influence of competitive status (winner/loser) in three such models: the elevated plus‐maze, the open field, and the social interaction test. One hundred to 135‐day‐old male Wistar rats were conditioned to traverse a straight runway tube to obtain food. Subsequently, two rats were placed at the same time in the runway tube and, being unable to pass each other, one of them pushed the other to the opposite end‐box. The rats were categorized as winners or losers in this competition. One week after the straight runway tube test, the rats were submitted to the anxiety models, where it was observed that winner rats showed greater locomotor activity than the losers in the three models studied. Furthermore, winner rats showed less immobility and higher central and total locomotor activity in the open field and a greater duration of social interaction in the social interaction test. These results suggest that competitive status has an influence on the locomotor activity of rats in animal models of anxiety. However, whether competitive status influences anxiety as assessed in these models is unclear, and further investigations are warranted. Aggr. Behav. 28:164–171, 2002. © 2002 Wiley‐Liss, Inc.     

Influence of anabolic steroid on anxiety levels in sedentary male rats

The aim of this study was to evaluate the influence of nandrolone decanoate on anxiety levels in rats. Male Wistar rats were treated with nandrolone decanoate (5mg/kg, two times per week, i.m.) or vehicle (propylene glycol--0.2 ml/kg, two times per week, IM) for 6 weeks. Control rats were subject only to procedures related to their routine husbandry. By the end of 6 weeks, all groups (24-29 rats/group) were submitted to the elevated plus maze test in order to evaluate their anxiety level. Some of these animals (12-14/group) were treated with diazepam (1 mg/kg i.p.) 30 min before the elevated plus maze test. Nandrolone decanoate significantly decreased the percentage of time spent in the open arms (1.46+/-0.49%) compared with control (3.80+/-0.97%) and vehicle (3.96+/-0.85%) groups, with no difference between control and vehicle treatments. The percentage of open arm entries was also reduced in the group treated with nandrolone decanoate in comparison with the vehicle and control. No changes in the number of closed arm entries were detected. Diazepam abolished the effects of nandrolone decanoate on the percentage of time in, and entries into the open arms. The present study showed that chronic treatment with a high dose of nandrolone decanoate increased the anxiety level in male rats.     

生命早期双酚A暴露对子代成年小鼠焦虑和抑郁行为的影响及其神经机制

双酚A (bisphenol A, BPA)对脑和行为发育的影响已引起关注, 本研究探讨围生期不同发育阶段母体BPA暴露对仔鼠成年后焦虑和抑郁行为的影响。分别在妊娠期(妊娠第7天~出生)和哺乳期(出生第1~14天) 将母鼠暴露于BPA (0.4、4 mg/kg/day), 以旷场、明暗箱、镜子迷宫、高架十字迷宫等多种模型检测生后56天(postnatal day 56)仔鼠的焦虑行为, 以强迫游泳模型检测其抑郁行为。结果显示, 妊娠期BPA暴露的成年雌性仔鼠在所有4种模型中均检测到促焦虑作用, 而哺乳期BPA暴露的雌鼠、妊娠期或哺乳期BPA暴露的雄鼠仅在2种模型中检测到促焦虑作用。妊娠期BPA暴露显著加重雌雄仔鼠的抑郁行为, 而哺乳期仅高剂量BPA加重仔鼠的抑郁行为。进一步的Western blot分析显示, 妊娠期或哺乳期BPA暴露显著下调成年后雌雄仔鼠海马和杏仁核AMPA受体GluR1亚基的表达, 但对NMDA受体NR1亚基的影响不一致。以上结果提示, 妊娠期或哺乳期BPA暴露对成年雌雄仔鼠均有不同程度的促焦虑和抑郁作用, 其中妊娠期暴露对雌鼠的作用最显著, 海马和杏仁核AMPA受体活动的减弱可能与围生期BPA暴露加重仔鼠成年后的焦虑和抑郁行为有关。     

Effects of anandamide and morphine combinations on memory consolidation in cd1 mice: involvement of dopaminergic mechanisms

In the present research the interaction between the endogenous ligand for the cannabinoid CB1 receptor anandamide (arachidonylethanolamide) and morphine in memory consolidation was investigated. Four sets of experiments were carried out with CD1 mice tested in a one-trial inhibitory avoidance task. The drugs were administered intraperitoneally after training of the animals in the apparatus. In the first set of experiments morphine (0.3 or 0.5, but not 0.15mg/kg) or anandamide (3 or 6 but not 1.5mg/kg) dose-dependently impaired memory consolidation. In the second set of experiments the administration of an otherwise ineffective dose of anandamide (1.5mg/kg) enhanced the memory impairment exerted by morphine (0.3 and 0.5mg/kg) when the drugs were injected immediately after training. In the third set of experiments the combined treatments of anandamide (1.5mg/kg) and morphine (0.5mg/kg) 2h after training were ineffective showing that the effects observed on performance following immediate posttraining administration of anandamide and morphine combinations were reflecting direct influences on memory consolidation. In the fourth set of experiments otherwise ineffective doses of the D1 DA receptor agonist SKF 38393 or the D2 DA receptor agonist LY 171555 antagonized the memory impairment produced by anandamide and morphine in combination, suggesting a possible involvement of dopaminergic mechanisms.     

Differential sensitivity to the effects of nicotine and bupropion in adolescent and adult male OF1 mice during social interaction tests

Few studies have compared the action of both nicotine (NIC) and bupropion (BUP), an antidepressant used to treat NIC dependence, on social and aggressive behavior at different ages. This study aims to determine whether these drugs produce differential effects in adolescent (postnatal day: 36-37) and adult (postnatal day: 65-66) mice that have been housed individually for 2 weeks in order to induce aggressive behavior. Mice received BUP (40, 20, or 10 mg/kg), NIC (1, 0.5, and 0.25 mg/kg as base), or vehicle earlier to a social interaction test. BUP (40 mg/kg) decreased social investigation and increased nonsocial exploration in both adolescent and adult mice. The same effects were also observed in adult mice administered with a lower dose of the same drug (20 mg/kg). In adolescents, NIC (1 mg/kg) decreased social investigation, but this effect did not reach statistical significance in adults. In conclusion, a differential sensitivity to the effects of NIC or BUP emerged in some of the behavioral categories when the two age groups were compared.     

Modulation of recognition and temporal order memory retrieval by dopamine D1 receptor in rats

The present study examines the effects of SKF 81297, a selective D1 agonist, on information retrieval in recognition and temporal order memory for objects, using three different tasks. Separate groups of rats were trained in each task and then given an intraperitoneal injection of saline or the D1 agonist (0.03, 0.3 mg/kg), before the memory testing trial in an object recognition, object location, and object temporal order memory tasks. We show that SKF 81297, at high dose (0.3 mg/kg), facilitates information retrieval after a long delay (4 h) in the three memory tasks whereas both high and low doses of D1 agonist impair recognition memory after a short delay (15 min). These results indicate a significant role of dopamine D1 receptors in recognition memory for both familiarity and place of objects in addition to object temporal order memory.     

The GABAergic effect of low doses of lorazepam on social behavior

The aim of this work was to test the antiaggressive effects of lorazepam and to determine whether these effects were mediated by benzodiazepine receptors. In a first experiment, male mice were injected with lorazepam in a range of low doses (0.05, 0.1, 0.2, and 0.6 mg/kg) or saline solution. In a second experiment, 1 mg/kg of Ro 15‐1788, a benzodiazepine receptor antagonist, and a saline solution were injected before the behavioral test. Results showed that 0.6 mg/kg of lorazepam was the only dose that decreased the total duration of threat (P < .01) and social investigation (P < .05) and that 1 mg/kg of Ro 15‐1788 had no effects. In the third experiment, animals received two injections: 0.6 mg/kg of lorazepam plus 1 mg/kg of Ro 15‐1788, 0.6 mg/kg of lorazepam plus saline solution, or saline solution plus saline solution. Those treated with lorazepam and saline solution spent less time digging (P < .001), threatening (P < .001), and attacking (P < .05) and more time avoiding the opponent (P < .01) or being immobile (P < .001) than the controls. Ro 15‐1788 was successful in completely antagonizing the behavior modulated by lorazepam. Aggr. Behav. 28:248–256, 2002. © 2002 Wiley‐Liss, Inc.     

Involvement of 5-HT1A receptors in animal tests of anxiety and depression: evidence from genetic models

Clinical studies have suggested the involvement of 5-HT1A receptors in anxiety and depressive disorders because partial 5-HT1A receptor agonists such as buspirone are therapeutic. The present review considers evidence from genetic animal models that support a role for 5-HT1A receptors in anxiety-like and depressed-like behavior in animals. Selective breeding for differential hypothermic responses to a selective 5-HT1A receptor agonist led to the development of the high DPAT sensitive (HDS) and low DPAT sensitive (LDS) lines of rats. The HDS rats differ from the LDS rats on several behavioral measures reflective of anxiety or depression, including reduced social interaction, reduced responding in a conflict task and exaggerated immobility in the forced swim test. However, they do not differ from the LDS rats in the elevated plus maze task, which is a commonly used test of anxiety. Nor do the HDS rats exhibit a typical anxiogenic response to the hippocampal administration of the 5-HT1A agonist. Although the HDS rats do exhibit elevations in 5-HT1A receptors in regions of the limbic cortex, it is not clear whether these increases account for the behavioral differences. Paradoxically, 5-HT1A receptor knockout mice also exhibit anxiety-like behavior in the plus maze, open field and conflict tests compared to wild type mice. However, the knockouts exhibited less immobility in the forced swim test than wild type control mice. Recent studies using selective regional reinstatement of the receptor have implicated the postsynaptic 5-HT1A receptors in these changes in anxiety-like behavior. Thus, preliminary evidence from two different types of genetic animal models suggests that anxiety-like behavior can arise if the 5-HT1A receptor function is eliminated or overexpressed. Further study with additional tests of anxiety are needed to confirm this intriguing relationship.     

Modulatory influence of dopamine receptors on consolidation of object recognition memory

The role of dopamine receptors in regulating the formation of recognition memory remains poorly understood. Here we show the effects of systemic administration of dopamine receptor agonists and antagonists on the formation of memory for novel object recognition in rats. In Experiment I, rats received an intraperitoneal (i.p.) injection of vehicle, the selective D1 receptor agonist SKF38393 (1.0 and 5.0mg/kg), or the D2 receptor agonist quinpirole (1.0 and 5.0mg/kg) immediately after training. In Experiment II, rats received an injection of vehicle, the dopamine receptor antagonist SCH23390 (0.1 and 0.05 mg/kg), or the D2 receptor antagonist raclopride (0.5 and 0.1mg/kg) before training, followed by an injection of vehicle or the nonselective dopamine receptor agonist apomorphine (0.05 mg/kg) immediately after training. SKF38393 at 5mg/kg produced an enhancement of novel object recognition memory measured at both 24 and 72 h after training, whereas the dose of 10mg/kg impaired 24-h retention. Posttraining administration of quinpirole did not affect 24-h retention. Apomorphine enhanced memory in rats given pretraining raclopride, suggesting that the effect was mediated by selective activation of D1 receptors. The results indicate that activation of D1 receptors can enhance recognition memory consolidation. Importantly, pharmacological activation of D1 receptors enhanced novel object recognition memory even under conditions in which control rats showed significant retention.     

When Adolescents Experience Co-Occurring Social Anxiety and ADHD Symptoms: Links With Social Skills When Interacting With Unfamiliar Peer Confederates

Adolescents with elevated social anxiety commonly experience peer-related impairments – particularly with same-age, unfamiliar peers – stemming from their avoidant behaviors. Yet, peer-related impairments are not unique to social anxiety. For example, adolescents who experience social anxiety may also experience symptoms of attention deficit/hyperactivity disorder (ADHD), which also increase risk for peer-related impairments. Relative to social anxiety, peer-related impairments linked to ADHD symptoms more likely stem from hyperactivity (i.e., approach behaviors). These distinct pathways point to adolescents with elevated social anxiety and ADHD symptoms (i.e., social anxiety + ADHD) experiencing particularly high peer-related impairments, which commonly manifest as behavioral displays of low social skills when interacting with unfamiliar peers. We tested this notion in a mixed-clinical/community sample of 134 14- to 15-year-old adolescents and their parents. Adolescents participated in a series of social interaction tasks designed to simulate how adolescents interact with same-age, unfamiliar peers. Trained observers independently rated adolescents on observed social skills within these interactions. Both parents and adolescents completed parallel surveys of social anxiety and ADHD symptoms, which we used to identify social anxiety + ADHD adolescents as well as other combinations of social anxiety and ADHD symptoms (i.e., neither, elevated on one but not the other). Adolescents with social anxiety + ADHD displayed significantly lower social skills, relative to all other groups. Among adolescents, social anxiety + ADHD may have a compounding effect on social skills. As such, therapists working with social anxiety + ADHD adolescents should probe for peer-related impairments and factors implicated in the development and maintenance of these impairments.     

Perception of control over anxiety mediates the relation between catastrophic thinking and social anxiety in social phobia

Cognitive models of social phobia (social anxiety disorder) assume that individuals with social phobia experience anxiety in social situations in part because they overestimate the social cost associated with a potentially negative outcome of a social interaction. Some emotion theorists, on the other hand, point to the perception of control over anxiety-related symptoms as a determinant of social anxiety. In order to examine the relationship between perceived emotional control (PEC), estimated social cost (ESC), and subjective anxiety, we compared three alternative structural equation models: Model 1 assumes that PEC and ESC independently predict social anxiety; Model 2 assumes that ESC partially mediates the relationship between PEC and anxiety, and Model 3 assumes that PEC partially mediates the relationship between ESC and anxiety. We recruited 144 participants with social phobia and administered self-report measures of estimated social cost, perceived anxiety control, and social anxiety. The results support Model 3 and suggest that "costly" social situations are anxiety provoking in part because social phobic individuals perceive their anxiety symptoms as being out of control.     

Pharmacological evidence for a role of D2 dopamine receptors in the defensive behavior of the mouse

In this study the role of the DA system in the expression of defensive behavior of the mouse was investigated. C57BL/6 mice subjected to three daily defeat experiences (24 h apart) exhibited an increase of defensive behaviors (upright and sideways postures and escape) as well as a decrease of activity and a decrease of social investigation compared with undefeated mice (controls) when confronted with nonaggressive Swiss mice 24 h after the last aggressive confrontation. The selective D2 DA receptor antagonist (-)-sulpiride administered before confrontation with nonaggressive opponents (fourth day) dramatically decreased defensive behaviors and produced an increase of social investigation. The selective D1 DA receptor antagonist SCH 23390 did not affect either defence or social investigation. In further experiments the behavioral effects of the selective D1 agonist SKF 38393 and of the selective D2 agonist LY171555 on naive C57BL/6 mice interacting with nonaggressive opponents of the same strain were assessed. SKF 38393 in doses up to 30 mg/kg did not produce any significant behavioral changes while LY171555 produced a clear-cut dose-dependent increase of defensive behavior as well as a decrease of social investigation and activity and an increase of immobility. The behavioral profile produced by the D2 agonist did not differ from that produced by defeat experiences. These results indicate that D2 receptors play a major role in the expression of defensive behavior in the mouse. The hypothesis that alteration in D2 receptor functioning may produce hyperdefensiveness possibly due to altered perceptive processes is discussed.     

Amitriptyline administered after consolidation of inhibitory avoidance does not affect memory retrieval

In Experiment 1, the effect of the administration of the antidepressant amitriptyline (30 mg/kg) for 21 days on the acquisition and consolidation of the inhibitory avoidance task was studied in male and female mice. In Experiment 2, it was evaluated whether amitriptyline administered after the consolidation of this task would block the memory retrieval. Anxiety and spontaneous activity in the elevated plus maze were also assessed. When amitriptyline was given before the training phase of inhibitory avoidance it blocked learning in males and there was a tendency in the same direction in females. However, the drug administered between training and test phases did not affect conditioning. These effects of amitriptyline seem to be independent of its actions on anxiety and locomotor activity. It may be that the effects observed are related to the therapeutic effects of antidepressants.     

AF-DX 116, a Presynaptic Muscarinic Receptor Antagonist, Potentiates the Effects of Glucose and Reverses the Effects of Insulin on Memory

Male Swiss mice were tested 24 h after training in a one-trial step-through inhibitory avoidance task. Low subeffective doses of -(+)-glucose (10 mg/kg, ip), but not its stereoisomer -(−)-glucose (30 mg/kg, ip), administered immediately after training, and AF-DX 116 (0.3 mg/kg, ip), a presynaptic muscarinic receptor antagonist, given 10 min after training, interact to improve retention. Insulin (8 IU/kg, ip) impaired retention when injected immediately after training, and the effects were reversed, in a dose-related manner, by AF-DX 116 (0.3, 1.0, or 3.0 mg/kg, ip) administered 10 min following insulin. Since AF-DX 116 possibly blocks autoreceptors mediating the inhibition of acetylcholine release from cholinergic nerve terminals, the present data support the view that changes in the central nervous system glucose availability, subsequent to modification of circulating glucose levels, influence the activity of central cholinergic mechanisms involved in memory storage of an inhibitory avoidance response in mice.     

Establishment of a schizophrenic animal model through chronic administration of MK-801 in infancy and social isolation in childhood

BackgroundAlthough an increasing amount of evidence supports a “two-hit” hypothesis for the neurodevelopmental model of schizophrenia, there has been no development in animal models to test this hypothesis.MethodsAn animal model was established by chronic administration of 0.1, 0.3, and 0.5 mg/kg MK-801 in P7-P21 rats followed by four weeks of social isolation in childhood and then five days of social housing. Animal behaviors were measured by the open field (OF) test, the novel object recognition (NOR) test, the prepulse inhibition (PPI) test, and the elevated plus maze (EPM) test.ResultsWe found a significant decrease in the NOR index in adolescent rats compared to saline control rats when administering 0.5 mg/kg of MK-801 (P = 0.02). We found that social isolation had no significant effect on NOR index, though social isolation significantly increased the total distance traveled and significantly decreased the resting time in adolescent rats in the OF test (P < 0.001 and P = 0.003, respectively). In contrast, we observed that MK-801 administration showed no significant effects on either total distance traveled or resting time. Both MK-801 administration and social isolation had no significant effect on the percent of PPI and startle amplitudes in adolescent rats. Social isolation significantly reduced the open arm entries in adolescent rats in the EPM test (P = 0.023), but it did not reduce the ratio to enter the open arms and the stay time in open arm. Administration of MK-801 showed no significant effect on the indexes of entering the open arms in the EPM test on adolescent rats.ConclusionMK-801 intervention in infancy is associated with the damage of long-term visual memory, whereas social isolation in childhood is associated with the increased spontaneous activity and anxiety levels. Administration of MK-801 in infancy and social isolation in childhood are two independent factors on the neurodevelopmental defects.     

Intraseptal Flumazenil Enhances, while Diazepam Binding Inhibitor Impairs, Performance in a Working Memory Task

GABA_A/benzodiazepine receptors in the medial septum modulate the activity of cholinergic neurons that innervate the hippocampus. Injection of benzodiazepine (BDZ) agonists into the medial septum impairs working memory performance and decreases high-affinity choline transport (HAChT) in the hippocampus. In contrast, intraseptal injection of the BDZ antagonist flumazenil increases HAChT and prevents the memory deficits induced by systemic BDZs. The present studies attempted to further characterize the behavioral effects of medial septal injections of flumazenil to an endogenous negative modulator of the GABA_A/BDZ receptor complex, diazepam binding inhibitor (DBI). Male Sprague–Dawley rats were cannulated to study the effects of intraseptal injections of these BDZ ligands on spatial working memory, anxiety-related behaviors in the elevated plus maze, and on general locomotor activity. Intraseptal flumazenil (10 nmol/0.5 μl) produced a delay-dependent enhancement of DNMTS performance after an 8-h, but not a 4-h, delay interval. This promnestic dose of flumazenil had no effect on locomotor activity and did not produce changes in measures of anxiety on the plus maze. Intraseptal injection of DBI had no effect (8 nmol/0.5 μl) or slightly impaired (4 nmol/0.5 μl) DNMTS radial maze performance following an 8-h delay, without producing changes in locomotion or plus maze behavior. These data demonstrate that flumazenil has a unique profile of activity in enhancing working memory following intraseptal injection.     

Anxiolytic-like activity of SB-205384 in the elevated plus-maze test in mice

Recent studies point to a major role for alpha2-containing GABA-A receptors in modulating anxiety. However, the possible implication of GABA-A receptors containing the alpha3 subunit on anxiety is less known. The aim of this study was to examine the effects of SB-205384 (0.5-4 mg/kg, i.p.), an alpha3 subunit positive modulator of GABA-A receptor, on anxiety tested in the elevated plus-maze in male mice, using classical and ethological parameters. Mice treated with SB-205384 showed an increase in the frequency of entries and the time spent in open arms, as well as a reduction in the time spent in closed arms, as compared with the control group. A notable increase of "head-dipping" unprotected and a reduction of "stretched-attend posture" protected was also evident. These findings indicate that SB-205384 exhibits an anxiolytic-like profile in the elevated plus-maze test, suggesting that GABA-A receptors which contain the alpha3 subunit might be involved in regulation of anxiety.     

LY354740, an mGlu2/3 receptor agonist as a novel approach to treat anxiety/stress

Metabotropic glutamate (mGlu) receptors, which include mGlu1-8 receptors, are a heterogeneous family of G-protein coupled receptors (GPCRs) that function to modulate neuronal excitation and plasticity via pre-synaptic, post-synaptic and glial mechanisms. Agonists for group II mGlu receptors (mGlu2 and mGlu3), such as LY354740, have been shown to suppress enhanced glutamatergic excitations in brain synapses known to be involved in the expression of fear/anxiety in animals and humans. Systemic administration of LY354740 increases open-arm time in the elevated plus maze in mice under conditions of moderate to severe stress, blocks the expression but not development of fear-potentiated startle in rats, prevents lactate-induced panic-like responses in panic-prone rats, and attenuates certain physiological, behavioral, and neurochemical consequences of acute stress in rodents. In these preclinical models, LY354740 does not produce the side-effects (e.g. sedation) that are associated with other anxiolytic agents such as benzodiazepines. Early clinical results with LY354740 have demonstrated safety and efficacy in a human anxiety model (panic provocation induced by CO2 challenge). Collectively, these data indicate mGlu2/3 receptor agonists such as LY354740 represent a promising new approach for treatment of anxiety and stress-related disorders in humans.