Mice lacking the cell adhesion molecule Thy-1 fail to use socially transmitted cues to direct their choice of food.

BACKGROUND: Thy-1 is a major cell-surface glycoprotein of mature neurons and certain other cells, including those of the lymphoreticular system. Despite being the simplest member of the immunoglobulin superfamily, the biological role of Thy-1 has proved elusive. Analysis of Thy-1 null mice has shown the presence of excessive GABAergic inhibition of neurotransmission in the dentate gyrus of the hippocampal formation selectively, without any neurological or behavioural effects being apparent. RESULTS: We show here that Thy-1 null mice are unable to make the appropriate dietary choice in the test for social transmission of food preference, despite showing a normal level of social interaction with the demonstrator mouse, normal neophobia, and normal learning in a T-maze using scented food as cues. The mice also performed normally in tests of anxiety, locomotor activity, exploration of a novel environment, habituation to novelty and spatial learning. This phenotype is maintained on two different strain backgrounds, is rescued by transgenic expression of Thy-1 and by administration of the GABA(A) receptor antagonist pentylenetetrazole. CONCLUSIONS: The test for social transmission of food preference is based on the normal ability of mice in a colony to learn from each other which foods are safe to eat. The lack of this key survival behaviour in Thy-1 null mice could act as an evolutionary pressure point to conserve expression of Thy-1. Furthermore, the specific cognitive defect caused by inactivation of the Thy-1 gene suggests that it would be worthwhile to determine the role of Thy-1 in certain human familial forms of mental retardation that map to chromosome 11q22-23 in the region of the Thy-1 locus rather than the nearby ataxia telangiectasia locus.

Interactions of anxiolytic and antidepressant drugs with hormones of the hypothalamic-pituitary-adrenal axis.

Changes in hormones of the hypothalamic-pituitary-adrenal (HPA) axis in patients suffering from anxiety and depressive disorders are reviewed, and the changes that occur when animals are exposed to test situations used preclinically to model anxiety or depression. The effects of exogenous administration of HPA hormones both clinically and in animal tests is discussed and the effects of clinically used anxiolytics and antidepressants on hormones of the HPA axis. The final section discusses stress-induced changes in the CNS.

The history of benzodiazepine dependence: a review of animal studies.

This article provides a historical review of the animal literature relating to the development of tolerance to the behavioral effects of benzodiazepines, and the incidence of biochemical and behavioral changes that result from termination of benzodiazepine treatment (spontaneous withdrawal responses). It charts the slow emergence of a pertinent animal literature and highlights conclusions that were prevalent in 1963 (at the introduction of diazepam), 1973 (at the introduction of lorazepam), 1980 and the present day. For 25 years the animal literature has lagged behind the clinical literature, but recent studies into the neurochemical mechanisms of benzodiazepine dependence and possible treatments for withdrawal responses suggest that, at last, animal experiments may be about to make a substantial contribution.

Tolerance to the behavioral actions of benzodiazepines.

The evidence for tolerance to the behavioral effects in animals of benzodiazepines is reviewed. Tolerance develops rapidly (within 3-5 days) to the sedative effects and from 5 days of treatment to the anticonvulsant effects. In general, tolerance has not been found to anxiolytic effects after 7-15 days of treatment, although in the social interaction test it was found after 25 days. Tolerance has not been found to the locomotor stimulant effects up to 20 days of treatment. Dispositional tolerance does not occur following treatment with low doses and nor is there clear evidence of changes in benzodiazepine binding. Such changes could not account for the very different rates of tolerance to the different behavioral effects, but these could be explained if learned adaptation were to underlie tolerance or to influence the rate at which it develops. Whether the mechanism of learned adaptation is one of instrumental conditioning, classical conditioning or habituation will depend on the formal aspects of the test. It is therefore suggested that the different rates of tolerance are a function of the detailed arrangement of the experimental situation and not of the particular behavior measured or of the clinical effect the test is meant to reflect.

What can be learned from the effects of benzodiazepines on exploratory behavior?

The purpose of this review is to assess the value of using tests of exploratory behavior to study the actions of benzodiazepines. The methods of measuring exploration and the factors influencing it are briefly described. The effects of benzodiazepines on exploratory behavior of rats and mice are reviewed; and the dangers of interpreting the results of such tests in terms of any of the clinical effects of the benzodiazepines is stressed. Finally, the interactions between benzodiazepines and other drugs acting at the GABA-benzodiazepine receptor complex are described. The results of these experiments caution against global classification of compounds as benzodiazepine "antagonists."

The effects of tricyclic and 'atypical' antidepressants on spontaneous locomotor activity in rodents.

With the exception of amineptin, buproprion and nomifensine all tricyclic and 'atypical' antidepressants have been reported to reduce spontaneous motor activity in rodents, after both acute and chronic administration. However, with the diversity of chemical actions of these drugs it is unlikely that a single neurochemical mechanism is underlying this one behavioral effect. These widespread sedative effects have implications for interpreting behavioral changes in other test situations, since sedation generally occurs at doses that fall within the dose-range effective in other tests. We also review the effects on spontaneous motor activity of withdrawal from chronic antidepressant treatment.

Is tofisopam an atypical anxiolytic?

This review describes the behavioural and biochemical profile of tofisopam, a 3,4-benzodiazepine that differs considerably in its effects and mechanisms of action from classical 1,4-benzodiazepines. In man tofisopam appears to possess anxiolytic activity without appreciable sedative and muscle relaxant side effects; in animals, however, tofisopam totally lacks anxiolytic and anticonvulsant properties in tests sensitive to the effects of 1,4-benzodiazepines. Tofisopam also has mixed dopamine agonist and antagonist-like properties in several in vivo and in vitro tests in animals. The possible relevance of the latter effects to the unusual behavioural profile of tofisopam are discussed, and its effects compared with those of buspirone, a novel anxiolytic that has similar activity at benzodiazepine and dopamine systems. It is proposed that these two drugs may represent a novel class of compounds that reduce anxiety by increasing the ability of patients to cope with daily tasks, rather than classical anxiolytics, that reduce anxiety by tranquilization.

Behavioral consequences of antidepressant treatment in rodents.

This review discusses the effects of antidepressant drugs on behaviors that are changed during the clinical treatment of depression. We first consider whether there is a similar subjective state produced by antidepressant drugs that might be akin to the mood changes caused clinically by these drugs. We thus review the evidence that antidepressant drugs can produce a distinctive enough subjective state to serve as a discriminative stimulus, and then discuss the nature of the cue produced. Secondly, we discuss whether there is any evidence that antidepressants enhance the rewarding aspects of stimuli since this aspect of behavior is reported to change during the successful treatment of depression. In this section we review the effects on electrical brain stimulation, water and food intake, exploratory and social behaviors. Finally, because of the proposed role of stress in the aetiology of depression, we review the effects of antidepressants on the responses to acute and chronic stress.

Characteristics of an atypical benzodiazepine, Ro 5-4864.

Ro 5-4864 is a 1,4 benzodiazepine which, atypically, does not bind to the classical CNS benzodiazepine receptors, but has high affinity for the peripheral type of binding site found both in the periphery and in the brain. Biochemical evidence for alternative sites of action for this compound is discussed. We review the behavioral profile of Ro 5-4864 (sedative, convulsant and anxiogenic in rodents) and also describe the behavioral effects of combining Ro 5-4864 treatment with benzodiazepines (e.g., diazepam, chlordiazepoxide) and with other drugs that modify the activity of benzodiazepines (Ro 15-1788, CGS 8216, picrotoxin, PK 11195, phenytoin). In the light of these interactions and electrophysiological evidence we conclude that the actions of Ro 5-4864 are most likely to be mediated at the GABA-benzodiazepine receptor complex in the CNS.

Benzodiazepines and behavior.

This article sets the background for the following series of articles on the behavioral actions of drugs acting at the GABA-benzodiazepine receptor complex. The articles provide detailed analyses of particular behaviors and emphasise the danger of interpreting all behavioral effects in terms of anxiety. What also emerges clearly from several of the articles is that any agonist/inverse agonist classification is test-dependent and that global categorisation is not possible for many of the novel compounds.

Benzodiazepine withdrawal: behavioural pharmacology and neurochemical changes.

This paper describes pharmacological treatments that can reverse the anxiogenic response detected in animal tests when rats are withdrawn from chronic treatment with diazepam. Concurrent treatment with the calcium channel antagonist verapamil prevented this withdrawal response and the benzodiazepine-receptor antagonist flumazenil reversed the anxiogenic response and restored the system to a drug-naive state. Other treatments that reversed the anxiogenic response were the GABAB agonist baclofen, the 5-HT1A receptor agonist buspirone, and the 5-HT3 receptor antagonist (R,S)-zacopride (GABA = gamma-aminobutyric acid; 5-HT = 5-hydroxytryptamine). Both the enantiomers of zacopride contributed to this reversal. These behavioural reversals are interpreted in the light of biochemical studies showing increased 45Ca2+ flux and [3H]5-HT release from the hippocampus, during benzodiazepine withdrawal (Fig. 1).

Role of the dorsomedial hypothalamus in mediating the response to benzodiazepines on trial 2 in the elevated plus-maze test of anxiety.

Trial 2 in the elevated plus-maze provides an animal model of specific phobia (fear of heights). On this trial, rats no longer respond to benzodiazepines. The present experiment examined the role of the dorsomedial hypothalamus in mediating insensitivity to chlordiazepoxide on trial 2. Rats received a 5 min exposure to the maze, undrugged. Forty-eight hours later, rats injected with control infusions into the dorsomedial hypothalamus showed the usual lack of response to chlordiazepoxide (5 mg/kg, i.p.). However, those receiving lidocaine injections (40 micrograms/microliter in a volume of 0.2 microliter) in the dorsomedial hypothalamus (producing functional inactivation), immediately before trial 2, responded with an anxiolytic response to chlordiazepoxide, characterised by an increased percentage of time on the open arms and by an increased number of entries into, and time spent on, the distal portions of the open arms. Since the lidocaine injections were without anxiolytic effects, our results suggest that this region of the hypothalamus regulates the functional state of benzodiazepine receptors in other brain regions.

Role of the basolateral nucleus of the amygdala in the formation of a phobia.

Specific phobia is an anxiety disorder that does not respond to benzodiazepines. The elevated plus-maze test of anxiety is sensitive to benzodiazepines on trial 1, but during the first 5-min trial the nature of the anxiety generated changes to a specific fear of heights, and, as a result, on trial 2 the rats no longer respond to benzodiazepines. However, rats that received reversible bilateral lesions of the basolateral amygdala (by lidocaine injection) immediately after trial 1 responded with an anxiolytic response to chlordiazepoxide when tested 48 h later on trial 2. Those that received vehicle injections after trial 1 showed the usual lack of response to chlordiazepoxide on trial 2. Thus, the basolateral amygdala plays a crucial role in the consolidation of information that leads to the formation of a specific phobia and subsequent insensitivity to benzodiazepines.

In adolescence, female rats are more sensitive to the anxiolytic effect of nicotine than are male rats.

Anxiety may play an important role in the onset of smoking, particularly in young girls. This study examined whether there were sex differences in the effects of nicotine on anxiety in adolescent rats and whether social isolation modified these effects. Male and female adolescent rats were housed in groups of the same sex or in social isolation for seven days prior to testing in the social interaction test of anxiety. Nicotine increased social interaction in both males and females, and because there was no concomitant change in locomotor activity, this indicated anxiolytic effects. However, there was a 5-fold sex difference in the lowest dose required to enhance social interaction, with an anxiolytic effect in females at 0.05 mg/kg, but in males only at 0.25mg/kg. Furthermore, in males the anxiolytic effect was seen only in socially isolated animals, whereas in the females it was present in both housing conditions. The depressant effect of nicotine on locomotor activity also depended on both the sex of the animal and on their housing conditions, with greater effects in singly housed animals and in males. This sex difference in sensitivity to nicotine's anxiolytic effects suggests there may be sex differences in the factors initiating and maintaining teenage smoking.

The contribution of behavioural studies to the neuropharmacology of anxiety.

This article reviews animal tests of anxiety and charts the contribution of behavioural studies to the neuropharmacology of anxiety. In particular it has been possible to distinguish several sites of action for anxiogenic drugs. Whilst great progress has been made to knowledge of the functioning of the GABA-benzodiazepine receptor complex, there has been little advance in the understanding of the other neurochemical pathways concerned with mediating changes in anxiety. The claim to have a drug that is a non-sedative anxiolytic should be based on firm behavioural evidence. The extent to which this has been realised for the existing candidates is reviewed.

Regional differences in rat benzodiazepine binding in response to novelty and cat odour.

Laboratory rats exhibit innate behavioural and corticosterone responses when exposed to cat odour. However, not all are responsive and differences in benzodiazepine receptor binding between responders and non-responders were explored. Rats were exposed to cat odour for 5 min and based on time spent sheltering were divided into responders (n = 21; mean +/- SEM = 244 +/- 8.2 sec) or non-responders (n = 20; 43.9 +/- 4.8 sec). Four days later, both groups were randomly allocated among 3 experimental conditions: home-cage, neutral or cat odour, and killed 30 min after exposure. [3H]flunitrazepam binding was performed at two ligand concentrations (2 and 10 nM); where significant differences in single point binding were found, Scatchard analysis was performed on pooled samples. In hippocampus and frontal cortex responders had significantly lower binding than non-responders. In hippocampus this was most apparent when the rats were exposed to the novel test situation, i.e. neutral odour and was due to a reduction in affinity (Kd = 0.4 and 1.2 nM non-responders and responders). In frontal cortex, differences were significant only following exposure to cat odour (Bmax = 2663 and 1501 fmol/mg protein in non-responders and responders). The changes in amygdala were not significant.

Beware the builders: construction noise changes [14C]GABA release and uptake from amygdaloid and hippocampal slices in the rat.

The effects of exposure to chronic noise and vibration, produced by construction work, on the release and uptake of [3H]5-hydroxytryptamine ([3H]5-HT) and [14C]gamma-aminobutyric acid ([14C]GABA) from rat amygdaloid and hippocampal slices were investigated. Noise-exposure resulted in increased release, with no significant change in uptake, of [14C]GABA from amygdaloid slices. In hippocampal slices, [14C]GABA release was also increased, but the changes in release were dependent upon the marked decrease in uptake of [14C]GABA into these slices. There was an increase in peak K(+)-evoked release of [3H]5-HT from hippocampal slices, but no other changes in [3H]5-HT release or uptake in either region were observed following noise-exposure. These findings may have important practical implications for the research carried out in laboratories exposed to construction noise and vibrations.

Sodium phenobarbitone reverses the anxiogenic effects of compounds acting at three different central sites.

Sodium phenobarbitone was tested for its ability to antagonise the anxiogenic effects of compounds acting at three different central sites. These compounds were: FG 7142, a beta-carboline which acts at the benzodiazepine binding site on the GABA-benzodiazepine receptor complex; pentylenetetrazole, which acts at the picrotoxinin site on the GABA-benzodiazepine receptor complex; and yohimbine which is an antagonist at the alpha 2-adrenoceptor. The experiments were carried out in two tests of anxiety using rats. In the social interaction test (the test arena was familiar and dimly lit), FG 7142 (5 mg/kg) and pentylenetetrazole (15 mg/kg) reduced the time spent in social interaction (indicating anxiogenic activity); these effects were reversed by sodium phenobarbitone (35 mg/kg). Sodium phenobarbitone (35 mg/kg) alone decreased locomotor activity as measured in the social interaction test, which was reversed by pentylenetetrazole (15 mg/kg). In the elevated plus-maze, FG 7142 (6.7 mg/kg) pentylenetetrazole (20 mg/kg) and yohimbine (4 mg/kg) reduced the percentage of open-arm entries and the percentage of time spent on the open arms (indicating anxiogenic activity); these effects were reversed by sodium phenobarbitone (35 mg/kg). Sodium phenobarbitone (35 mg/kg) alone significantly increased the percentage of open-arm entries and the percentage of time spent on the open arms (indicating anxiolytic activity). This study, together with previous studies using other clinically-effective anxiolytic drugs, suggests that the ability of a compound to antagonise the effects of anxiogenic agents may be a useful indirect means of predicting anxiolytic activity.

Repeated electroconvulsive shock has no specific anxiolytic effect but reduces social interaction and exploration in rats.

Administration of repeated electroconvulsive shock (ECS) to rats did not result in a specific anxiolytic profile in the social interaction test, but did significantly reduce several spontaneous behaviours: social interaction, locomotor activity, exploratory head-dipping and rearing. None of these behavioural changes was reversed by the administration of pentylenetetrazol prior to each seizure, a treatment that abolishes ECS-induced changes in GABA and 5-HT in the brain.

Do the reductions in social interaction produced by picrotoxin and pentylenetetrazole indicate anxiogenic actions?

The effects of picrotoxin (2 and 4 mg/kg) and of pentylenetetrazole (PTZ 5, 10 and 20 mg/kg) were examined in a social-interaction test of anxiety. Picrotoxin (2 mg/kg) caused a significant reduction in active social interaction, without a concomitant reduction in motor activity, indicating an anxiogenic action. Picrotoxin (4 mg/kg) and pentylenetrazole (20 mg/kg) reduced social interaction by more than 75% and motor activity by 40%. Although it is likely that the reduction in motor activity is secondary to the very low levels of social interaction, an unambiguous interpretation of an anxiogenic effect is not possible. Increased concentrations of corticosterone in plasma following administration of picrotoxin were consistent with the drug being anxiogenic. Chlordiazepoxide (5 mg/kg) significantly reversed the reductions in social interaction and locomotor activity following injection of picrotoxin (4 mg/kg) and PTZ (20 mg/kg).