5-HT2 receptor activation in the midbrain periaqueductal grey (PAG) reduces anxiety-like behaviour in mice

It is widely acknowledged that the indoleamine neurotransmitter serotonin (5-HT) plays a dual role in the regulation of anxiety, a role that in part depends upon neuroanatomical locus of action. Thus, whereas stimulation of 5-HT1A or 5-HT2 receptors in the limbic forebrain (amygdala, hippocampus) enhances anxiety-like responding in rodents, activation of corresponding receptor populations in the midbrain periaqueductal grey (PAG) more often than not reduce anxiety-like behaviour. The present study specifically concerns the anxiety-modulating influence of 5-HT2 receptors within the mouse PAG. Experiment 1 assessed the effects of intra-PAG infusions of the 5-HT2B/2C receptor agonist mCPP (0, 0.03, 0.1 or 0.3 nmol/0.1 mu l) on the behaviour of mice exposed to the elevated plus-maze. As mCPP acts preferentially at 5-HT2B and 5-HT2C receptors, Experiment 2 investigated its effects in animals pretreated with ketanserin, a preferential 5-HT2A/2C receptor antagonist. In both cases, test sessions were videotaped and subsequently, scored for anxiety-like behaviour (e.g., percentage of open arm entries and percentage of open arm time) as well as general locomotor activity (closed arm entries). The results of Experiment I showed that mCPP microinfusions (0.03 and 0.1 nmol) into the PAG of mice decreased behavioural indices of anxiety without significantly altering general activity measures. In Experiment 2, the anxiolytic-like profile of intra-PAG mCPP (0.03 nmol) was substantially attenuated by intra-PAG pretreatment with an intrinsically inactive dose of the preferential 5-HT2A/2C receptor antagonist, ketanserin (10 nmol/0.1 mu l). Together, these data suggest that 5HT(2C) receptor populations within the midbrain PAG play an inhibitory role in plus-maze anxiety in mice. (C) 2007 Elsevier B.V. All rights reserved.

Parametric analyses of anxiety in zebrafish scototaxis

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H1 but not H2 histamine antagonist receptors mediate anxiety-related behaviors and emotional memory deficit in mice subjected to elevated plus-maze testing

This study investigated the role of H1 and H2 receptors in anxiety and the retrieval of emotional memory using a Trial 1/Trial 2 (T1/T2) protocol in an elevated plus-maze (EPM). Tests were performed on 2 consecutive days, designated T1 and T2. Before T1, the mice received intraperitoneal injections of saline (SAL), 20 mg/kg zolantidine (ZOL, an H2 receptor antagonist), or 8.0 or 16 mg/kg chlorpheniramine (CPA, an H1 receptor antagonist). After 40 min, they were subjected to the EPM test. In T2 (24 h later), each group was subdivided into two additional groups, and the animals from each group were re-injected with SAL or one of the drugs. In T1, the Student t-test showed no difference between the SAL and ZOL or 8 mg/kg CPA groups with respect to the percentages of open arm entries (%OAE) and open arm time (%OAT). However, administration of CPA at the highest dose of 16 mg/kg decreased %OAE and %OAT, but not locomotor activity, indicating anxiogenic-like behavior. Emotional memory, as revealed by a reduction in open arm exploration between the two trials, was observed in all experimental groups, indicating that ZOL and 8 mg/kg CPA did not affect emotional memory, whereas CPA at the highest dose affected acquisition and consolidation, but not retrieval of memory. Taken together, these results suggest that H1 receptor, but not H2, is implicated in anxiety-like behavior and in emotional memory acquisition and consolidation deficits in mice subjected to EPM testing.

A multidisciplinary program of preparation for childbirth and motherhood: maternal anxiety and perinatal outcomes

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Effects of the essential oil from Citrus aurantium L. in experimental anxiety models in mice

Citrus aurantium L. is popularly used to treat anxiety, among other indications suggesting central nervous system action. Previous studies showed anxiolytic effect in the essential oil from peel in mice evaluated on the elevated plus maze [Carvalho-Freitas, M.I.R., Costa, M., 2002. Anxiolytic and sedative effects of extracts and essential oil from Citrus aurantium L. Biological and Pharmaceutical Bulletin 25, 1629-1633.]. In order to better characterize the activity of the essential oil, it was evaluated in two other experimental models: the light-dark box and the marble-burying test, respectively related to generalized anxiety disorder and to obsessive compulsive disorder. Mice were treated acutely by oral route 30 min (single dose) or once a day for 15 days (repeated doses) before experimental procedures. In light-dark box test, single treatment with essential oil augmented the time spent by mice in the light chamber and the number of transitions between the two compartments. There were no observed alterations in the parameters evaluated in light-dark box after repeated treatment. Otherwise, single and repeated treatments with essential oil were able to suppress marble-burying behavior. At effective doses in the behavioral tests, mice showed no impairment on rotarod procedure after both single and repeated treatments with essential oil, denoting absence of motor deficit. Results observed in marble-burying test, related to obsessive compulsive disorder, appear more consistent than those observed in light-dark box. (c) 2005 Elsevier B.V. All rights reserved.

Use of the elevated T-maze to study anxiety in mice

We have recently suggested that the elevated T-maze (ETM) is not a useful test to study different types of anxiety in mice if a procedure similar to that originally validated for rats is employed. The present study investigated whether procedural (five exposures in the enclosed arm instead of three as originally described for rats) and structural (transparent walls instead of opaque walls) changes to the ETM leads to consistent inhibitory avoidance acquisition (IAA) and low escape latencies in mice. Results showed that five exposures to the ETM provoked consistent IAA, an effect that was independent of the ETM used. However, the ETM with transparent walls (ETMt) seemed to be more suitable for the study of conditioned anxiety (i.e. IAA) and unconditioned fear (escape) in mice, since IAA (low baseline latency with a gradual increase over subsequent exposures) and escape (low latency) profiles rendered it sensitive to the effects of anxiolytic and anxiogenic drugs. In addition to evaluation of drug effects on IAA and escape, the number of line crossings in the apparatus were used to control for locomotor changes. Results showed that whereas diazepam (1.0-2.0 mg/kg) and flumazenil (10-30 mg/kg) impaired IAA, FG 7142 (10-30 mg/kg) did not provoke any behavioral change. Significantly, none of these benzodiazepine (BDZ) receptor ligands modified escape latencies. The 5-HT1A partial receptor agonist buspirone (1.0-2.0 mg/kg) and the 5-HT releaser fenfluramine (0.15-0.30 mg/kg) impaired IAA and facilitated escape, while the full 5-HT1A receptor agonist, 8-OH-DPAT (0.05-0.1 mg/kg) and the 5-HT2B/2C receptor antagonist, SER 082 (0.5-2.0 mg/kg) failed to modify either response. mCPP (0.5-2.0 mg/kg), a 5-HT2B/2C receptor agonist, facilitated IAA but did not alter escape latency. Neither antidepressant utilized in the current study, imipramine (1.0-5.0 mg/kg) and moclobemide (3.0-10 mg/kg) affected IAA or escape performance in mice. The well-known anxiogenic drugs yohimbine (2.0-8.0 mg/kg) and caffeine (10-30 mg/kg) did not selectively affect IAA, although caffeine did impair escape latencies. Present results suggest the ETMt is useful for the study of conditioned anxiety in mice. However, upon proximal threats (e.g. open arm exposure), mice do not exhibit escape behavior as an immediate defensive strategy, suggesting that latency to leave open arm is not a useful parameter to evaluate unconditioned fear in this species. (C) 2003 Elsevier B.V. All rights reserved.

Role of 5-HT in stress, anxiety, and depression

There are conflicting results on the function of 5-HT in anxiety and depression. To reconcile this evidence, Deakin and Graeff have suggested that the ascending 5-HT pathway that originates in the dorsal raphe nucleus (DRN) and innervates the amygdala and frontal cortex facilitates conditioned fear, while the DRN-periventricular pathway innervating the periventricular and periaqueductal gray matter inhibits inborn fight/flight reactions to impending danger, pain, or asphyxia. To study the role of the DRN 5-HT system in anxiety, we microinjected 8-OH-DPAT into the DRN to inhibit 5 HT release. This treatment impaired inhibitory avoidance (conditioned fear) without affecting one-way escape (unconditioned fear) in the elevated T-maze, a new animal model of anxiety. We also applied three drug treatments that increase 5-HT release from DRN terminals: 1) intra-DRN microinjection of the benzodiazepine inverse agonist FG 4172, 2) intra-DRN microinjection of the excitatory amino acid kainic acid, and 3) intraperitoneal injection of the 5-HT releaser and uptake blocker D-fenfluramine. All treatments enhanced inhibitory avoidance in the T-maze. D-Fenfluramine and intra-DRN kainate also decreased one-way escape. In healthy volunteers, D-fenfluramine and the 5-HT agonist mCPP (mainly 5-HT2C) increased, while the antagonists ritanserin (5-HT2A/(2C)) and SR 46349B (5-HT2A) decreased skin conductance responses to an aversively conditioned stimulus (tone). In addition, D-fenfluramine decreased, whereas ritanserin increased subjective anxiety induced by simulated public speaking, thought to represent unconditioned anxiety. Overall, these results are compatible with the above hypothesis. Deakin and Graeff have suggested that the pathway connecting the median raphe nucleus (MRN) to the dorsal hippocampus promotes resistance to chronic, unavoidable stress. In the present study, we found that 24 h after electrolytic lesion of the rat MRN glandular gastric ulcers occurred, and the immune response to the mitogen concanavalin A was depressed. Seven days after the same lesion, the ulcerogenic effect of restraint was enhanced. Microinjection of 8-OH-DPAT, the nonselective agonist 5-MeO-DMT, or the 5-HT uptake inhibitor zimelidine into the dorsal hippocampus immediately after 2 h of restraint reversed the deficits of open arm exploration in the elevated plus-maze, measured 24 h after restraint. The effect of the two last drugs was antagonized by WAY-100135, a selective 5-HT1A receptor antagonist. These results are compatible with the hypothesis that the MRN-dorsal hippocampus 5-HT system attenuates stress by facilitation of hippocampal 5-HT1A-mediated neurotransmission. Clinical implications of these results are discussed, especially with regard to panic disorder and depression.

Effects of erythrinian alkaloids isolated from Erythrina mulungu (Papilionaceae) in mice submitted to animal models of anxiety

The effects of acute oral administration of erythrinian alkaloids, Le. (+)-alpha-hydroxy-erysotrine, erythravine and (+)-11 alpha-hydroxy-erythravine isolated from the flowers of Erythrina mulungu were investigated in two animal models of anxiety in mice-the light-dark transition model (LDTM) and the elevated plus-maze (EPM). In the LDTM, erythravine (3, 10 mg/kg) and (+)-11 alpha-hydroxy-erythravine (10mg/kg) increased the time spent by the animals in the illuminated compartment and (+)-11 alpha-hydroxy-erythravine (3 mg/kg) increased the number of transitions between compartments of the LDTM, suggesting an anxiolytic-like effect of these erythrinian alkaloids. Nevertheless, the third alkaloid studied, (+)-alpha-hydroxy-erysotrine, did not change any behavioral response with the range of doses used (3-10 mg/kg). Since the oral administration of the crude extract of E. mulungu (EM) (100-400 mg/kg) did not modify the conventional measures of anxiety in the EPM, this animal model was not chosen to evaluate the anxiolytic properties of the isolated alkaloids. These results suggest that the alkaloids erythravine and (+)-11 alpha-hydroxy-erythravine are responsible for the anxiolytic effects of the crude extract of E. mulungu.

The effects of anxiety on visual search, movement kinematics, and performance in table tennis: A test of Eysenck and Calvo's processing efficiency theory

Processing efficiency theory predicts that anxiety reduces the processing capacity of working memory and has detrimental effects on performance. When tasks place little demand on working memory, the negative effects of anxiety can be avoided by increasing effort. Although performance efficiency decreases, there is no change in performance effectiveness. When tasks impose a heavy demand on working memory, however, anxiety leads to decrements in efficiency and effectiveness. These presumptions were tested using a modified table tennis task that placed low (LWM) and high (HWM) demands on working memory. Cognitive anxiety was manipulated through a competitive ranking structure and prize money. Participants' accuracy in hitting concentric circle targets in predetermined sequences was taken as a measure of performance effectiveness, while probe reaction time (PRT), perceived mental effort (RSME), visual search data, and arm kinematics were recorded as measures of efficiency. Anxiety had a negative effect on performance effectiveness in both LWM and HWM tasks. There was an increase in frequency of gaze and in PRT and RSME values in both tasks under high vs. low anxiety conditions, implying decrements in performance efficiency. However, participants spent more time tracking the ball in the HWM task and employed a shorter tau margin when anxious. Although anxiety impaired performance effectiveness and efficiency, decrements in efficiency were more pronounced in the HWM task than in the LWM task, providing support for processing efficiency theory.

Anxiety levels and wild running susceptibility in rats: assessment with elevated plus maze test and predator odor exposure

It is reported in the literature that nearly 20% of rats are susceptible to displays of wild running (WR) behavior when submitted to high intensity acoustic stimulation. Some characteristics of WR suggest that it can be viewed as a panic-like reaction. This work aimed to test whether WR-sensitive rats show higher levels of anxiety in elevated-plus-maze (EPM) and predator-odor exposure paradigms in comparison with WR-resistant ones. Male adult Wistar rats were submitted to two trials of acoustic stimulation (104 dB, 60 s) in order to assess WR susceptibility. Seven WR-sensitive and 15 WR-resistant rats were evaluated by the EPM test. Other 13 WR-sensitive and 18 WR-resistant animals were submitted to the predator-odor exposure test which consisted of a 10 min-session of free exploration in a specific apparatus containing two odoriferous stimuli: cotton swab imbedded with snake cloacal gland secretion or with iguana feces (control). WR-sensitive rats presented a significantly higher closed-to open-ann-entry ratio in the EPM test. All rats responded with anxiety-like behaviors to the predator odor exposure, although the WR-sensitive ones showed a marked behavioral inhibition regardless of the odor condition. We conclude that WR-sensitive rats present elevated levels of anxiety manifested by means of passive behavioral strategies. (C) 2004 Elsevier B.V. All rights reserved.

Effect of electrolytic and neurotoxic lesions of the median raphe nucleus on anxiety and stress

To study the role played by 5-HT mechanisms of the MRN, behavioural and physiological parameters were presently measured in rats having either electrolytic or 5,7-dihydroxytryptamine (5,7-DHT) lesion of the MRN made 7 days before testing. Half the animals were submitted to 2-h restraint 24 h before the test. In the elevated plus-maze, the electrolytic lesion increased the percentage of open-arm entries and of time spent on open arms - an anxiolytic effect - in both restrained and nonrestrained rats. The neurotoxic lesion had a similar effect, but only on restrained rats. Restraint had anxiogenic effect. The electrolytic lesion increased transitions between the light and dark compartments and the time spent in the bright compartment of the light-dark box in both restrained and nonrestrained rats. The neurotoxic lesion only increased bright time in restrained rats. The incidence, number and size of gastric ulcers were increased by either the electrolytic or the neurotoxic lesion in both restrained and nonrestrained animals. Both types of lesion depleted 5-HT in the hippocampus in restrained and nonrestrained rats. Restraint increased 5-HT levels. These results implicate 5-HT mechanisms of the median raphe nucleus in the regulation of anxiety and in the genesis of gastric stress ulcers. (C) 2001 Elsevier B.V. All rights reserved.