Anxiolytic Substances Research Articles

Zebrafish (Danio rerio) responds differentially to stimulus fish: The effects of sympatric and allopatric predators and harmless fish

The zebrafish has been an excellent model organism of developmental biology and genetics. Studying its behavior will add to the already strong knowledge of its biology and will strengthen the use of this species in behavior genetics and neuroscience. Anxiety is one of the most problematic human psychiatric conditions. Arguably, it arises as a result of abnormally exaggerated natural fear responses. The zebrafish may be an appropriate model to investigate the biology of fear and anxiety. Fear responses are expressed by animals when exposed to predators, and these responses can be learned or innate. Here we investigated whether zebrafish respond differentially to a natural predator or other fish species upon their first exposure to these fish. Naïve zebrafish were shown four species of fish chosen based on predatory status (predatory or harmless) and geographical origin (allopatric or sympatric). Our results suggest that naïve zebrafish respond differentially to the stimulus fish. Particularly interesting is the antipredatory response elicited by the zebrafish's sympatric predator, the Indian Leaf Fish, and the fact that this latter species exhibited almost no predatory attacks. The findings obtained open a new avenue of research into what zebrafish perceive as “dangerous” or fear inducing. They will also allow us to develop fear and anxiety related behavioral test methods with which the contribution of genes to, or the effects of novel anxiolytic substances on these behaviors may be analyzed.

Magnesium-deficient diet alters depression- and anxiety-related behavior in mice—influence of desipramine and Hypericum perforatum extract

A relation between magnesium (Mg) status and mood disorders has been suggested, but evidence remains inconsistent. Therefore, we examined in mice whether Mg-depletion would alter behavior evaluated in established animal models of depression and anxiety and whether these effects would be sensitive to antidepressants. Compared to control mice fed with normal diet, mice receiving a low Mg diet (10% of daily requirement) for several weeks displayed increased immobility time in the forced swim test, indicating enhanced depression-like behavior. In addition, the partial Mg-depletion increased anxiety-related behavior in the light/dark and open field test, while locomotor activity or motor coordination was not influenced. Chronic oral administration of desipramine (30 mg/kg/day), or Hypericum extract LI160 (Hyp, 380 mg/kg/day) prevented the “pro-depression-like” forced swim behavior in Mg-depleted mice. Furthermore, the increase in anxiety-related behavior of Mg-depleted mice was abolished in both the open field and light dark test by Hyp. Taken together, we report that Mg-depletion leads to enhanced depression- and anxiety-related behavior in mice, which was further validated by the reversibility of the behavioral changes by known antidepressant and anxiolytic substances. Further, the utility of Mg-depletion as a new screening model for clinically active antidepressant and anxiolytic drugs is suggested.

Measuring fear and anxiety in the marmoset ( Callithrixpenicillata) with a novel predator confrontation model: effects of diazepam

This report describes a new experimental method for measuring fear and anxiety in Cerrado marmosets ( Callithrix penicillata). In order to test the sensitivity of the behavioral parameters to an anxiolytic substance, the effects of the benzodiazepine diazepam on the anxiety measures were examined. The strategy was to use a naturally occurring stimulus known to elicit anxiety and fear in this species. A taxidermized predator (the wild cat Felis tigrina) was chosen as the stimulus to induce anxiety-related behaviors on the basis of a preceding study in which various stimuli were systematically compared in their effectiviness to induce fear responses. The apparatus consisted of three parallel arms of equal dimensions, joining two perpendicular arms at each end, thus comprising a figure eight-like or five-arm continuous rectangular maze. The wild-cat was placed outside of one corner of the maze’s outer parallel arms. Each subject was submitted to six treatments given in random order: three drug sessions (diazepam 1, 2 and 3 mg/kg, IM), saline, sham (injection control), and a control session, involving neither manipulation nor injection. Subjects were placed into the back of the chamber, out of sight of the ‘predator’, 20 min after a treatment and given free access to the maze for 30 min. The behavioral repertoire was recorded via videocamera. The following behaviors were considered to be possible indices of emotionality relevant to exposure to the predator in the paradigm used: scratching, scent marking, exploration, frequency and time spent in each of 13 defined sections of the maze. Administration of diazepam induced a significant reduction in scratching and an increase in the time spent in the vicinity of the ‘predator’, as well as in the frequency of exploratory behaviors, indicative of an anxiolytic effect. Gender did not influence the effect of treatment. These results suggest that this new ethologically-based test may be a useful method for studying anxiety and fear-induced avoidance in non-human primates and for pre-clinical research on psychoactive drugs.

Behavioral, Physiological, and Neuroendocrine Stress Responses and Differential Sensitivity to Diazepam in Two Wistar Rat Lines Selectively Bred for High- and Low-Anxiety–Related Behavior

Two Wistar rat lines, selectively bred for high-anxiety–related behavior (HAB) and low-anxiety–related behavior (LAB) in the elevated plus-maze test, were tested for the susceptibility of their behavioral characteristics to anxiolytic treatment and for their endocrine and physiological reactivity to different stressors. Injection of 1mg/kg diazepam failed to affect line differences in coping strategy but resulted in a marked (20-fold) decrease in plus-maze anxiety in HAB rats; whereas, the anxiolytic effect was less pronounced in LAB animals. Biotelemetrical measurements revealed that HAB and LAB rats do not significantly differ in their baseline body temperature, locomotor activity, food and water intake, or in stress-induced alterations of the diurnal rhythms in these parameters. However, line differences were found in acute changes in body temperature and locomotor activity following stress exposure, LAB rats responding with a greater, albeit shorter, increase in body temperature and activity than HAB animals. Basal ACTH and corticosterone plasma levels as well as pituitary reactivity to intravenously administered CRH (40 ng/kg) were similar in both lines, although, especially in response to plus-maze exposure, HAB rats tended toward higher ACTH secretion than LAB rats. These data confirm that animals with high or low basal levels of anxiety may be a promising model for studying the mechanisms of action of anxiolytic substances. Nevertheless, the endocrine findings support the notion that the reactivity of the hypothalamo-pituitary-adrenocortical system and anxiety-related behavior can be regulated independently.

Alcoholism and panic disorder: co-occurrence and co-transmission in families.

The co-occurrence of alcoholism and anxiety disorders in epidemiological and clinical samples is well established. Self-medication of anxiety disorder probands with the anxiolytic substance alcohol might be one reason for this association. Common susceptibility factors of both disorders might be alternative explanations. Controlled family studies recruiting probands with panic disorder and alcoholism are powerful tools to answer this question. A family study of this kind, however, is not available. The present study investigated 113 families of probands with either panic disorder or alcoholism or both (but without affective or psychotic disorders) and 80 families of healthy controls in order to estimate the degree of co-occurrence of the two disorders in non-treated samples of relatives and to explore the magnitude of overlap between susceptibility factors of the two disorders. The co-occurrence of the two disorders was relatively rare in all samples of families under study. Overlap of susceptibility factors was demonstrated by an elevated risk of alcoholism in relatives of probands with panic disorder.

Conditional attenuation of the antipentylenetetrazol activity of chlordiazepoxide

In a study of drug-drug conditioning, chlordiazepoxide (CDP) was administered to rats 30 min before chlorpromazine (CPZ) every 3–4 days for 5 weeks. Thereafter, CDP was tested for its ability to a) increase animals' exploration of the normally avoided “exposed” arms of a plus-maze (a screening method for anxiolytic substances) and b) protect against induced by pentylenetetrazol (PTZ). The CDP-CPZ conditioning procedure potentiated the usual increase in open-arm activity seen in CDP-injected rats but attenuated the anti-PTZ effect. When injected with CDP 60 min prior to PTZ, rats with a previous history of CDP-CPZ pairing had shorter latencies to seizures onset and showed a greater likelihood of progression to the most severe behavioral indices of a maximal seizure relative to control subjects with a history of backward drug pairings (CPZ-CDP) or pairings of CDP with isotonic saline.

Automatic quantification of withdrawal from 5-day diazepam in rats: ultrasonic distress vocalizations and hyperreflexia to acoustic startle stimuli.

The purpose of the present work was to develop an objective and precise method to quantify withdrawal responses from anxiolytics relying on ethologically valid responses. Behavioral effects of diazepam withdrawal in rats are automatically measured that appear to correspond to clinically relevant disturbances in affective and sensory-motor functions. Ultrasonic vocalizations and startle reflexes in response to acoustic stimuli were measured as indices of withdrawal 24 h after 5 days of 2.5, 5 or 10 mg/kg diazepam, b.i.d., IP in male Long-Evans rats. About 60% of male rats emit 22-26 kHz ultrasonic calls when exposed to acoustic startle stimuli (18 presentations, 9 at 105 dB and 9 at 115 dB, each 30 s apart on average). Diazepam-withdrawn rats exhibited startle responses with larger maximal and average amplitude and emitted more frequent 22-26 kHz ultrasonic vocalizations than vehicle-treated control animals. The magnitude of the withdrawal changes in ultrasonic calls and in startle reflex amplitude increased significantly already at the low 2.5 mg/kg diazepam dose in spite of considerable individual variability. The increased ultrasound rates during diazepam withdrawal contrast with the suppressive effects of acutely administered diazepam in drug-naive rats. The current methodology offers the opportunity to more adequately characterize withdrawal from anxiolytic substances in a quantitative, objective and automated manner.

Anxiety, anxiolytics and brain stimulation reinforcement

The premise of this review is that neuronal substrates of anxiety are amenable to investigation using brain stimulation techniques. Anxiolytics such as meprobamate and the benzodiazepines may enhance intracranial self-stimulation (ICSS) behavior. Although demonstrated by numerous investigators, this effect shows considerable variability between and within laboratories. Some of this variability is explained by sedative/muscle relaxant effects, which are dissociable from drug-induced increases in ICSS and which may mask these increases. The anticonvulsant actions of anxiolytic drugs are unlikely to account for the increases in ICSS. Rather, anxiolytics appear to increase ICSS by attenuating concurrent aversive properties of stimulation. Consistent with this explanation, anxiolytic drugs attenuate escape from aversive dorsal tegmental stimulation. The neuronal substrates of this centrally mediated escape behavior differ from those mediating footshock-induced escape. Barbiturates also enhance ICSS, possibly due in part to an excitatory component that is not involved in benzodiazepine action. Inverse benzodiazepine agonists attenuate ICSS behavior in a manner that cannot be explained by nonspecific performance impairment. These substances, however, may not necessarily enhance stimulation-induced aversiveness. A strategy is proposed to integrate brain stimulation studies with molecular approaches to anxiety. Specifically, stimulation of sites associated with fear induction or fear reduction may selectively alter the release of endogeneous anxiogens or anxiolytic substances.

Anxiety- an approach to defining terms and formulating a methodological concept for measuring anxiety states within the framework of clinical trials with anxiolytic substances (author's transl)

A methodological concept for measuring anxiety states and changes in anxiety states in clinical studies with anxiolytic substances is presented: Effectivity should be evaluated on several levels which include emotions, objects of anxiety, psychophysiology, biochemistry, and observed behavior. This test concept is based on new knowledge from behavior psychology, learning theory, psychology of testing, psychophysiology, biochemistry, neuroendocrinology, and psychiatry. In diagrams, important mechanisms of thr origin of experimental, stress-induced and pathological anxiety states are depicted. The point is stressed that anxiety is situational and fluctuates.

Total alcohol consumption as an index of anxiety among urbanised Africans.

SummaryA relationship exists between anxiety and alcoholism; and as alcohol is an anxiolytic substance, any increase in prevailing alcoholism in a racial or national group is an index of anxiety in such a group.The increase in prevailing alcoholism based on total consumption has been noted on two occasions in respect of an influx controlled African population group, living in an African township in the South Western area of Johannesburg.On the first occasion, in 1969, 5 in this racial group there was an increase of total Bantu beer (3 per cent concentration] consumption from 15 million gallons per annum to nearly 30 million gallons per annum. Over a period of seven years the total consumption had doubled. On a second occasion recently we noticed a most significant drop in total Bantu beer consumption with a significant rise in total European type liquor consumption (40 per cent concentration), 12 in this same population controlled African group.In 19695 with the rise in the total Bantu beer consumption, we indicated that anxiety was present and its level was high, a situation confirmed by social workers and ministers of religion in close contact with, these people; presently on the second occasion, we have sufficient evidence (Table 2) to indicate that there has been compute change in the drinking pattern in this same African race group. The fact that this group has changed over from relatively mild traditional alcoholic beverage,1 to the use of high alcohol content loquor, with a rising total consumption, is indicative of the fact that anxiety is present and is maximal.