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A 53-year-old woman presented with a 25-year history of acne excoriée and prurigo excoriée. Her symptoms began in 1988 coinciding with her husband’s death from a brain tumour when she was 27. The pruritus affected her quality of life and disturbed her sleep. She had scarring on her face and body resulting from persistent scratching. The pruritus proved refractory to treatment despite a multi-modal treatment approach including multiple topicals, phototherapy and systemic agents such as isotretinoin, antibiotics, anxiolytic agents and neuromodulators. She was extremely frustrated that various treatments had been ineffective at controlling the itch-scratch cycle. She was commenced on low dose naltrexone (LDN), 3 mg nocte, and she became itch free within a few weeks. She reports that the LDN has had a beneficial impact on her quality of life.

Anxiety and stress are considered as universal psychiatric exhibitions of the present societies and lifestyles. Several experiments have been conducted to examine natural anxiolytic agents to find out an alternative to synthetic anxiolytic drugs. The present study investigated the anxiolytic effects of cinnamaldehyde (Cin) on mice behavior in the elevated plus maze (EPM) and open field (OF) tests. Sixty male Swiss mice, weighing 20-30 g, were divided into six groups including: acute stress + mazola oil; chronic stress + oil; acute stress + Cin (20 mg/kg); chronic stress + Cin; non-stress + oil; and non-stress + Cin groups. The groups were administered for seven days (once a day). The acute stress + Cin group showed a meaningful rise in the percentage of entries into the open arms compared to the acute stress + oil group (p .05). The percentage of time spent in the open arms in the chronic stress + Cin group was significantly higher compared to the chronic stress + oil group (p .01). The percentage of entries into the open arms increased significantly (p .01) in the chronic stress + Cin group in comparison with the chronic stress + oil group. The Cin treated groups showed significant increases in the time spent in the center area and in the number of entries into the center area compared with the oil treated groups in OF test. The number of entries into the arms (total activity), as well as locomotor activity was not significant among groups. The results of the present study indicated that Cin, as a natural product, might have anxiolytic effects in mice behavior in the EPM and OF tests. Lay summary The results demonstrated that the administration of cinnamaldehyde (Cin) produced anxiolytic effects in mice. Natural antioxidant products have been reported effective for anxiety. Synthetic medications have notable adverse effects. Therefore, these natural substances with broad therapeutic applicability are able to reduce anxiety-related behavior with rare side effects. According to the results, Cin could decrease anxiety-related behavior in mice.

Objective: The aim of this study was to explore the influence of short-term (2-week) exposure to social (SE) and/or physical enrichment (PE) on the anxiety-like behavior of ovariectomized (OVX) NIH Swiss mice. Method: One week after surgery, each OVX mouse was housed under one of 4 social conditions: (1) isolated, (2) accompanied by an intact female, (3) accompanied by an intact male, or (4) in a community of 10 OVX individuals. The animals in each of these environments were divided into 2 subgroups, consisting of the presence and absence of PE. Following a 2-week exposure to the respective conditions, each OVX mouse was subjected to either the light/dark exploration test (LDT) or the elevated plus maze (EPM) to examine anxiety-like behavior. Results: The LDT and EPM showed very similar patterns. Compared to an impoverished environment, PE elicited a significant anxiolytic effect for OVX mice housed alone or in companion of an intact female (F [1, 54] = 16.11, P = 0.001). By contrast, mice living in community but without PE displayed anxiogenic-like behavior, perhaps due to crowding, compared to the animals living in isolation (F [1, 36] = 5.64, P = 0.023). Conclusion: This study emphasized the importance of taking housing conditions into account during the screening of new anxiolytic agents and the critical role of OVX in the regulation of anxiety.

A series of 4-phenyl-6H-imidazo[1,5-a]thieno[3,2-f][1,4]diazepine-7-carboxylate esters were synthesized and tested as central benzodiazepine receptor (CBR) ligands by the ability to displace [3H]flumazenil from rat cortical membranes. All the compounds showed high affinity with IC50 values ranging from 5.19 to 16.22 nM. In particular, compounds 12b (IC50 = 8.66 nM) and 12d (IC50 = 5.19 nM) appeared as the most effective ligands being their affinity values significantly lower than that of diazepam (IC50 = 18.52 nM). Compounds 12a-f were examined in vivo for their pharmacological effects in mice and five potential benzodiazepine (BDZ) actions were thus taken into consideration: anxiolytic, anticonvulsant, anti-amnesic, hypnotic, and locomotor activities. All the new synthesized compounds were able to induce a significant antianxiety effect and, among them, compound 12f protected pentylenetetrazole (PTZ)-induced convulsions in a dose-dependent manner reaching a 40% effect at 30 mg/kg. In addition, all the compounds were able to significantly prevent the memory impairment evoked by scopolamine, while none of them was able to interfere with pentobarbital-evoked sleep and influence motor coordination. Moreover, title compounds did not affect locomotor and exploratory activity at the same time and doses at which the anti-anxiety effect was observed. Finally, molecular docking simulations were carried out in order to assess the binding mode for compounds 12a-f. The obtained results demonstrated that these compounds bind the BDZ binding site in a similar fashion to flumazenil.

It has been reported that the use of certain stimuli can lead to anxiety-like behavior in zebrafish. Moreover, visual stimulation of zebrafish is becoming a popular tool. Here we evaluated the effects of six colors combinations and alprazolam, a benzodiazepine which is widely used in the treatment of anxiety disorders, on the behavior of adult zebrafish in a two-chambered apparatus, which chambers were illuminated by red/yellow, green/blue, red/green, green/yellow, red/blue and blue/yellow light. The following parameters were measured: time spent in the zone, number of entries to the zone, time of freezing, distance traveled and average speed in the zone. We report that the adult zebrafish spent more time in the red zone compared to yellow or green as well as in the yellow or blue compared to green. The zebrafish displayed a concomitant increase in time freezing in the red zone compared to yellow or green as well as in the yellow or blue compared to green. Moreover, average speed was decreased in the red zone compared to yellow or green and in the yellow zone compared to green. Treatment with alprazolam significantly affected the behavior of the zebrafish, e.g., following alprazolam administration time spent in the zone and time freezing were longer in the green zone than in red. Based on these observations, we suggest that light color combinations could be effective to manipulate zebrafish behavior and could be useful in neuropsychopharmacological studies, perhaps to study anxiety-like behavior and the effects of anxiolytic agents.

Objectives Anxiety diagnoses occur in 17.1% in people age 65 years and older. Individuals with anxiety may be at a higher risk of the development of probable Alzheimer's disease (AD). Previous literature has suggested that anxiolytic medications may exacerbate the risk of AD development. This study explored anxiolytic medication as a potential moderator of AD risk in older adults. Methods A secondary data analysis of the National Alzheimer's Coordinating Center Uniform Data Set was undertaken, analyzing observations from 12,083 participants with normal cognition at the first visit. Survival analysis was utilized to examine if anxiolytic medication use by those with anxiety and/or APOE ɛ4 moderates the hazard of AD and/or MCI development. Results The hazard of probable AD (HR = 3.50, [2.77 – 4.44], p

Ethnopharmacological relevance Galphimia glauca is a Mexican medicinal plant used to treat anxiety, fear, phobia and stress as it possesses sedative properties which produce a calming effect. Although some chemical and pharmacological studies have already been carried out on G. glauca, there are still new chemical entities from this plant whose anxiolytic activity should be established. Aim of the study To validate the use of G. glauca growing in Cuernavaca, Morelos, as an anti-stress agent, through the purification and structural identification of its extracts’ chemical constituents; the analysis of the biogenetic relationship of its chemical compounds, and its biological evaluation to demonstrate its traditional use as anxiolytic agents. Materials and methods The structures of all isolated compounds were established based on their spectroscopic and spectrometric data. The structure of compound 2 was corroborated through X-Ray. The anxiolytic and sedative-like activities were assessed by the open-field, hole-board and exploration cylinder test. Results The nor-triterpenes glaucacetalin E (1) and galphimidin B (2) were isolated for the first time along with seven other known compounds, one of them galphimidin (3), from the CHCl3 fraction of the aerial parts of Galphimia glauca. The biogenesis of the natural nor-triterpenes isolated from Galphimia glauca is delineated for the first time starting from the taraxasteryl cation. Oral administration of CHCl3 fraction and 1–3 compounds produced significant attenuation in the anxiety-response in cylinder activity, decrease in the ambulatory activity and in head dipping when compared to the vehicle. However, only the extract enhanced the pentobarbital-induced hypnosis. Diazepam was used as a positive control. Conclusion Our results suggest that G. glauca growing in Cuernavaca, Morelos, exerts anxiolytic-like activity due to the presence of the nor-triterpenes 1–3. These results reinforce the potential use of this species in the treatment of anxiety.

Antidepressant and anxiolytic drug development has largely stalled. This article reviews novel current programs for developing depressants and anxiolytics. Biological bases are discussed for these, as are recent results. Problems encountered are reviewed. Recently announced failed programs for other antidepressants are then discussed with an eye toward uncovering possible common elements that may explain their failures. Lastly, possible solutions for improving the likelihood of the success of antidepressant/anxiolytic agents are discussed.

Pregabalin is a γ-aminobutyric acid analogue that is primarily prescribed in psychiatry for management of generalized anxiety disorder. The belief in its low potential for abuse has placed it in a superior position to other anxiolytic agents. However, more recent, concerns have been raised about the addictive potential of pregabalin. This problem has not received much attention nor has the mechanism of its development. There is also a lack of understanding of the difference in the experience of abusing pregabalin in contrast to abusing other illicit drugs. We report the case of a 55-year-old patient with a background history of multiple psychoactive substances misuse who elaborated on his own personal experience of pregabalin abuse. He consumed a month’s supply of this medication over 2 days and realized an enhancement in sexual desire and excitement. This effect should be considered when prescribing pregabalin.

Many compounds bearing a sulfonamide fragment have been used in medicinal practice for a long time, e.g., as antibacterial or hypoglycaemic agents [1, 2]. However, the interest in sulfonamides as potential medications has not decreased until now [3]. Recently, there has been a sharp increase in the number of publications concerning the synthesis and use of sultams as the cyclic analogs of sulfonamides. This is related, on one hand, to the absence of general methods for their synthesis and, on the other hand, to their potential biological activity, since several types of sultams are already well established in clinical practice as anticonvulsant [4], 1-adrenoblocking [5], and diuretic [6] agents. Oxicams can also serve as examples of a large class of nonsteroidal anti-inflammatory medications, which are widely used in clinical practice in many countries (e.g., ampiroxicam), as anxiolytic agents based on alkylated saccharin derivatives (ipsaspirone), and as sulthiame – a drug used in the treatment of epilepsy. Several sultams are used as pesticides in agriculture [7]. Finally, they are widely employed in asymmetric synthesis. Hence camphorsultams [9] have been quite recently introduced as one of the most popular chiral auxiliaries [8] in synthetic practice.

The classical benzodiazepines (Bz) constitute a well-known class of therapeutics displaying hypnotic, anxiolytic and anticonvulsant effects acting upon a specific binding site (BzR) belonging to the GABAA receptor complex. Their usefulness, however, is limited by a broad range of side effects; consequently the fact that the action of GABA with the receptor complex could be allosterically modulated by a wide variety of chemical entities, made the Bz binding site, from late eighties to nowdays, the target of extensive research programmes directed to the identification of new ligands displaying varying degrees of affinity- and efficacy-selectivity for the different GABAA/BzR-subtypes. The principal aim has been to discover ideal sedative-hypnotic agents (selective 1 agonists), anxiolytic agents (selective 2/ 3 agonists), or cognitive enhancers (selective 5 inverse agonists). In this connection, an important contribution in the field of GABAA/BzR ligands was made by the research group directed by Professor Antonio Da Settimo at the University of Pisa. The purpose of this review is therefore to describe the studies, performed from early '80s, on the several classes of BzR ligands developed featuring the indol-3-ylglyoxyl scaffold. All the compounds reported have been summarized on the basis of their main chemical structural features, focusing attention on their SARs, which determined the affinity profiles or efficacy-selectivity. Moreover, the biological studies performed within each class of compounds allowed the identification of new derivatives exhibiting an anxiolytic/nonsedative profile, either in vitro (full 2 agonism and 1 partial agonism/ antagonism) and in vivo (anxiolytic/nonsedative activity in mice).

A recently implemented QSAR method, whose descriptors derive from bidimensional images, is applied here to model some compounds with anxiolytic activities. A calibration set composed by 47 drug-like molecules (5-HT 2C receptor antagonists) was built and a leave-one-out cross-validation, as well as an external validation, was carried out in order to test the predictive ability of the calibration model. The results ( R 2 = 0.866 and Q 2 for the external validation set = 0.681, using 6 latent variables) were comparable to the ones obtained elsewhere, where a CoMFA model was used as 3D approach.

The syndromes described are often related to primary endocrine or development defects, but may also result from purely educational or psychological problems. Adolescents may find it difficult to seek help, particularly in the younger age range where early medical intervention is important. While psychotherapy alone is often advisable, the use of anxiolytic agents may be an effective adjunctive treatment. Benzodiazepines are particularly useful because they do not stimulate enzyme activity as do some sedative agents. Teenagers are dependent on the expectations of their parents, and as ANTHONY and RIZZO [1971] have emphasized, the administration of drugs to a member of a family demands an understanding of such expectations, as well as a subtle awareness of the dynamic homeostasis and interactional patterns prevalent in the family at the time. The expectations of parents and the physician concerning the changes due to the drugs prescribed should be synchronized by mutual discussions and questioning. The adolescent has less anxiety tolerance, fewer brakes, less facilities for elaborating his symptoms on symbolic levels, and diminished capacities for postponement of impulsive gratifications; all these factors are important in achieving results by psychological methods alone. The time factor urges us to combine psychotherapy and pharmacotherapy; a well-selected drug in moderate dosage will not necessarily impair the transference. We may take the advise of Plato, who said that the drug effect should be supplemented with parleys ("epodai") which will guieten down or cheer up the soul. The modern sex therapist dealing with adolescents might follow this direction.

Psychosomatic medicine is a way of approaching problem and health, and psychosomatic disorders in general are pathological expression of biological, psychological and socioecological parameters of human health and illness. Psychopharmacology, on the other hand, is one of the youngest and rapidly developing disciplines of treating agents and has become a widely used tool on psychosomatic medicine. The antecedents of psychopharmacology are many, such as biochemical, physiological, biophysical, psychological and, of course, clinical. These antecedents combine and run through the psychiatry and psychosomatic medicine to bind them, just like the psychosomatic medicine has become the binding force of biopsychosocioecological antecedents. Psychopharmacological agents most used in psychosomatic medicine are antidepressants, anxiolytic agents, hypnotics, antipsychotics, beta-blockers and mood stabilizers. As psychopharmacology is moving rapidly from empirical to rational, it is reflecting the path of understanding the mechanism of many psychosomatic disorders and a symbiosis is taking place between these two for bringing successful control or for curing psychosomatic sufferings. The holistic management of psychosomatic medicine requires the need to bring back suffering patients free from disorder, but with multiple modalities, including psychopharmacology, to enhance the quality of life to what it was before the illness started. Non-specific, more curative these agents will be, the more control over the abnormal biopsychosocioecological process will occur in human sufferers and the symbiosis of present will bind more firmly to psychosomatic disorder in future.

Many different practice models for radiology sedation can provide satisfactory patient care. Adherence to recognized safety standards and the training and experience of sedation providers are critical for a successful program. Pediatricians should develop an appreciation of safe practices in the radiologic environment and the requirements related to individual studies and procedures. Sedation needs in radiology are diverse. Imaging procedures such as MRI, CT, and nuclear medicine studies require hypnosis to achieve results without motion artifact. Invasive studies may require the use of analgesic and anxiolytic agents. IR procedures often require the use of multiple agents.

Made available in DSpace on 2018-12-11T16:37:27Z (GMT). No. of bitstreams: 0 Previous issue date: 2014-01-22. Added 1 bitstream(s) on 2021-07-15T15:02:03Z : No. of bitstreams: 1 S0102-86502014000100047.pdf: 271483 bytes, checksum: 88ea3d40c782415e803dcd13b8d258c4 (MD5) Purpose: To investigate the sedative and clinical effects of the pharmacopuncture with xylazine, compared to the conventional dose of a intramuscular injection in dogs. Methods: Twelve dogs were randomly distributed in two groups of six animals and treated as follows: control group (X-IM): 1mg kg-1 of xylazine given intramuscularly (IM); pharmacopuncture group (X-Yintang): 0.1mg kg-1 of xylazine diluted to 0.5 mL of saline injected into the Yin Tang acupoint. Heart rate, cardiac rhythm (ECG), systolic arterial blood pressure (SABP), respiratory rate (RR), rectal temperature (RT), blood glucose concentration, degree of sedation and adverse effects were evaluated. Results: Sedative effect was observed in both groups. The degree of sedation was greater in X-IM only at 15 min when compared with X-Yintang group. Cardiovascular established was observed in X-Yintang group, while marked reduction in the HR and increased incidence of ECG abnormalities were detected in X-IM. In both treatment groups, minimal changes were observed in relation to SABP, RR, RT and blood glucose. High incidence (66%) of vomiting was observed in X-IM, while this adverse effect was absent in X-Yintang. Conclusion: Pharmacopuncture with xylazine induced clinically relevant sedative effects in dogs, with the advantage of reduction of undesirable side effects associated with α2-agonists, including bradycardia, cardiac arrhythmias, and emesis. Department of Veterinary Surgery and Anestesiology Scholl of Veterinary Medicine Oeste Paulista University (UNOESTE), Presidente Prudente-SP Department of Clinical Veterinary Scholl of Veterinary Medicine Sao Paulo State University (UNESP), Botucatu-SP Department of Veterinary Anestesiology Scholl of Veterinary Medicine Andradina Educational Foundation (FEA), Andradina-SP Department of Veterinary Surgery and Anestesiology Scholl of Veterinary Medicine UNOESTE, Presidente Prudente-SP Department of Clinical Veterinary Scholl of Veterinary Medicine Sao Paulo State University (UNESP), Botucatu-SP

Anxiolytic potency of 1 week of treatment with alprazolam or tandospirone in psychiatric outpatients with anxiety disorders was evaluated by changes in the scores on the Hamilton Anxiety Scale and the State and Trait Anxiety Inventory and in the saliva level of free-3-methoxy-4-hydroxyphenylglycol (free-MHPG). Saliva level of free-MHPG was significantly reduced by 1 week of treatment with alprazolam but not with tandospirone. Reductions in the HAS score after 1 week of drug treatment were greater in patients treated with alprazolam than in those treated with tandospirone. These results indicate that the short-term anxiolytic potency of alprazolam is greater than that of tandospirone and that the saliva level of MHPG would be a useful marker for the evaluation of the therapeutic potency of anxiolytic agents. Copyright 2001 John Wiley & Sons, Ltd.

A variety of pyrido[1,2-a]benzimidazoles (PBIs) modified on the A-ring were prepared and evaluated for affinity to the benzodiazepine binding site on the GABA-A receptor and in animal models predictive of anxiolytic activity in humans. A-ring benzo-fused derivative 7 exhibited potent activity, as did the 6- and 7-pyrido compounds 3 and 4.

This article reviews the current classification of anxiety disorders and the frequency of these disorders in older adults. General treatment principles are discussed, and an overview of anxiolytic medications is presented. Use of these anxiolytic agents in specific disorders is then discussed, followed by a brief review of nonpharmacologic treatment approaches to anxiety disorders.

Many compounds bearing a sulfonamide fragment have been used in medicinal practice for a long time, e.g., as antibacterial or hypoglycaemic agents [1, 2]. However, the interest in sulfonamides as potential medications has not decreased until now [3]. Recently, there has been a sharp increase in the number of publications concerning the synthesis and use of sultams as the cyclic analogs of sulfonamides. This is related, on one hand, to the absence of general methods for their synthesis and, on the other hand, to their potential biological activity, since several types of sultams are already well established in clinical practice as anticonvulsant [4], 1-adrenoblocking [5], and diuretic [6] agents. Oxicams can also serve as examples of a large class of nonsteroidal anti-inflammatory medications, which are widely used in clinical practice in many countries (e.g., ampiroxicam), as anxiolytic agents based on alkylated saccharin derivatives (ipsaspirone), and as sulthiame – a drug used in the treatment of epilepsy. Several sultams are used as pesticides in agriculture [7]. Finally, they are widely employed in asymmetric synthesis. Hence camphorsultams [9] have been quite recently introduced as one of the most popular chiral auxiliaries [8] in synthetic practice.

The treatment of anxiety disorders remains an active area of research. Behavioural tests developed in the 1960s have been augmented by specific receptor binding assays. Selective modulation of these binding sites offers the hope that the abuse liability, sedation and ethanol interaction found with earlier drugs can be removed entirely or in part. Although most anxiolytic drug discovery continues to be centred on the neurotransmitters γ-aminobutyric acid (GABA) and serotonin (5-HT), research in other areas such as those involving cholecystokinin (CCK), corticotrophin releasing factor (CRF) and neuropeptide Y (NPY) also has promise for the future. This article reviews the primary and patent literature in the anxiolytic area for 1994 to the present.

We have further explored the structure-activity relationships of pyrido[1,2- a ]benzimidazole (PBI) derivatives (viz. prototype 1 ), a novel series of central GABA-A receptor modulators, with the intent of enhancing oral efficacy. A study involving the introduction of acidic or basic groups led to the identification of RWJ-38293 ( 3a ) as a potential anxiolytic agent.

The mitochondrial translocator protein (TSPO) mediates the synthesis of neurosteroids in the CNS, which have been demonstrated to enhance the neurotransmitter GABA response, exhibiting related behavioural properties. Selective TSPO ligands are able to stimulate steroidogenesis with great efficacy, thus representing potential anxiolytic agents. This review describes the development of a class of high affinity ligands to TSPO, N,N-dialkylindol-3-ylglyoxylamides (IGA), from the initial stages of design to the pharmacological characterization of selected compounds for their anxiolytic activity. Affinity data and SARs of the new class of ligands are discussed; the potential applications of compounds characterized by the indolylglyoxylyl scaffold in diagnostic imaging are also pointed out.

A series of pyrazolo[4,3-c]pyridines has been synthesized and evaluated as potential anxiolytic agents. Selected compounds from this series show a pharmacological profile of action different from that of diazepam. A number of the compounds possess higher affinity for central benzodiazepine receptors than diazepam, yet show less anticonvulsant activity and are less sedative. The structure-activity relationships of these potential anxiolytic agents are discussed.

In continuation of the search for discovering new antipsychotic and anxiolytic agents with a reduced production of extrapyramidal side-effects, a series of N,N'-bis-aminoalkyl derivatives of bicyclo[2.2.2]oct-7-ene tetracarboxydiimide was prepared. Evaluation of these compounds in vitro revealed a very low affinity for 5-HT 1a receptor

A series of N-substituted 2-hydroxy and 2-oxo-2-(phen-1-ylpyrrol-2-yl)acetamides were synthesized and their affinity at the benzodiazepine receptor tested. Isosteric replacement of the indolyl ring in previously described derivatives by a phen-1-ylpyrrole led to the synthesis of seven compounds 8–9, 12–14, 23 and 26 with benzodiazepine affinity (Ki ≤ 0.90 μM). Among these, 26 exhibits an interesting anxiolytic activity and weak lateral effects.

A series of pyrido[1,2- a ]benzimidazoles (PBIs) with substitution on the N 5 -nitrogen has been synthesized and found to possess high affinity for the benzodiazepine (BZD) site on the GABA-A receptor. The compounds evaluated include those bearing a heteroalkyl group and heterocyclic rings. The most promising of these compounds is ethoxymethyl analogue 24 , which has an IC 50 of 0.1 nM for the BZD site on the GABA-A receptor and has been advanced to human clinical trials.

Rats shocked from an electrified probe characteristically spray bedding material toward or over the probe (i.e., “defensive burying” behavior). Antianxiety (i.e., anxiolytic) agents selectively suppress this burying response, and this suppression can be reversed by GABA/benzodiazepine receptor antagonists. Antianxiety drug effects have also been found in the elevated plus-maze, where anxiolytic agents selectively suppress rats’ normal avoidance of the open arms of the maze. An ongoing series of experiments compares these anxiolytic drug effects on rats’ defensive behavior in the plus-maze and the shock-probe tests, with the effects of septal lesions. The results thus far show a surprising degree of correspondence between the effects of septal lesions and the effects of anxiolytic drugs in these paradigms. This correspondence is consistent with Gray’s (1982a) neuropsychological theory of anxiety, in which the septum plays a key role in the modulation of “anxiety.”

Many animal species exhibit approach-avoidance responses upon the novel placement of a mirror into an individual animal's environment. With a view toward identifying new behavioral measures with qualitatively or quantitatively different responses to anxiolytic agents, we developed a mirrored chamber apparatus for which adult male BALB/cByJ mice showed an extended latency to enter. Administration of diazepam significantly reduced this latency to enter a mirrored chamber in a dosage-dependent manner. The psychomotor stimulant, methylphenidate, had no effect on latency to enter the mirrored chamber at a dose which stimulated locomotor activity to the same extent as diazepam. Thus, the decreased latency to enter the mirrored chamber brought about by diazepam seems unlikely to reflect the motor effects of this benzodiazepine. The potency of diazepam was significantly lower in the mirrored chamber assay than it was on three other measures of exploratory activity--"head-dipping" performance, plus-maze performance and locomotor activity stimulation. The findings of our study indicate that the mirrored chamber method is simple to carry out, nonpunishing, rapid and quantitative and that it possesses pharmacological attributes which distinguish its response to anxiolytics from other assays of exploratory behavior.

The present study was design to examine the effect of tautomerism upon the CoMFA results. Three selected data sets involving protropic tautomerism, which are 21 p -hydroxyphenylpyruvate dioxygenase (HPPD) inhibitors, 35 inhibitors of puromycin-sensitive aminopeptidase (PSA), and 67 anxiolytic agents, were used for this purpose. Atom-by-atom alignment technique was adopted to superimpose the molecules in the data sets onto a template. The structural alignments using different tautomeric forms had no significant difference except the atoms involved in tautomerism, which ensures, to a great extent, that the differences of the CoMFA results result primarily from the tautomerism. All-orientation and all-placement search (AOS-APS) based CoMFA models, in addition to the conventional ones, were derived for each system and proved to be capable of yielding much improved statistical results. In the cases of the data sets of HPPD inhibitors and PSA inhibitors, excellent AOS-APS CoMFA models ( q 2 > 0.8 with four components for the former and q 2 > 0.7 with seven components for the latter) were obtained, and almost no significant difference in statistical quality was observed when using different tautomeric forms to derive the models. However, it was not the case when treating the data set of anxiolytic agents. The keto tautomer, which was the active form of the PBI type inhibitors, produced measurably better results ( q 2 = 0.54 with eight components) than that the enol one ( q 2 = 0.37 with five components), indicating the importance of selecting proper tautomer in the CoMFA studies. Furthermore, there existed some substantial differences of the electrostatic field contours between the two different tautomeric forms for all of the three systems considered, whereas the differences in the steric field contour maps were limited. This implies that the resulting new potent ligands may be quite different if one utilizes the CoMFA models of different tautomeric forms for guiding further structural refinements.

In three experiments, we studied the consequences of ejaculation upon the frustrative or contrast response of male rats exposed to reward downshift situations (i.e., surprising changes from 32% to 4% sucrose solutions). Similar to what has been found after treatment with anxiolytic agents, consummatory suppression was partially reversed by previous ejaculations in a second postshift trial (Experiments 2 and 3), such a result not having been obtained in a first postshift trial (Experiment 1). Moreover, the effect of ejaculations upon males' behavior during a second postshift trial was transitory, disappearing when assessed during the third and fourth postshift trials (Experiment 3). These results are in accordance with both Amsel's (1958, 1992) frustration theory and Flaherty's (1996) multistage hypothesis of successive negative contrast; the diverse factors that are known to modulate contrast effects are considered, including an interpretation of the present data in terms of the anxiolytic-like effect of the ejaculation.

New synthesis approaches that have led to a series of novel tetrahydrodibenzo[b,f]furo[2,3-d]oxepine derivatives are described. A systematic synthetic approach for the introduction of small carbon substituents (methyl groups) around the tetrahydrofuran moiety of tetrahydrodibenzo[b,f]furo[2,3-d]oxepine derivatives is reported. Preliminary pharmacological data of the newly synthesised compounds are also communicated.