National High Blood Pressure Education Program.

Ethologically-based animal models of anxiety disorders.

The use of social interaction as a method for detecting anxiolytic activity of chlordiazepoxide-like drugs.

Exploratory behavior models of anxiety in mice

The gamma-aminobutyric acid(B) (GABA(B)) receptor was first demonstrated on presynaptic terminals where it serves as an autoreceptor and also as a heteroreceptor to influence transmitter release by suppressing neuronal Ca(2+) conductance. Subsequent studies showed the presence of the receptor on postsynaptic neurones where activation produces an increase in membrane K(+) conductance and associated neuronal hyperpolarization. (-)-Baclofen is a highly selective agonist for GABA(B) receptors, whereas the established GABA(A) receptor antagonists, bicuculline and picrotoxin, do not block GABA(B) receptors. The receptor is G(i)/G(o) protein-coupled with mixed effects on adenylate cyclase activity. The receptor comprises a heterodimer with similar subunits currently designated 1 and 2. These subunits are coupled via coiled-coil domains at their C termini. The evidence for splice variants is critically reviewed. Thus far, no unique pharmacological or functional properties have been assigned to either subunit or the variants. The emergence of high-affinity antagonists for GABA(B) receptors has enabled a synaptic role to be established. However, the antagonists have generally failed to establish the existence of pharmacologically distinct receptor types within the GABA(B) receptor class. The advent of GABA(B1) knockout mice has also failed to provide support for multiple receptor types.

https://pharmrev.aspetjournals.org/content/pharmrev/54/2/247.full.pdf

International Union of Pharmacology. XXXIII. Mammalian γ-Aminobutyric AcidB Receptors: Structure and Function

Various minor tranquilizers (benzodiazepines, barbiturates and meprobamate) induced an increase in the food intake of rats or mice. Drugs were injected i.p. 30 min before testing and the amount of food consumed during 30 min was recorded. The enhanced food consumption occurred when the animals were in a novel situation, in a situation which they had previously experienced, or in their home cage, in which they were used to eating in the daytime within 30 min. Studies with two benzodiazepines showed this effect to be maximal between 10 to 30 min after injection and to disappear 4 hrs after injection. Moreover, minor tranquilizers reduce the latency before eating of rats and mice tested in a new situation. These results and the observation of anti-anxiety drugs-induced hyperphagia in satiated animals suggest that: 1. The enhanced food consumption of a non familiar food in a novel situation induced by the minor tranquilizers could hardly be related only to their anti-anxiety action. 2. The existence of some inhibitory controls (endogenous satiety in daytime or satiety after recent absorption) is not essential for the action of the minor tranquilizers. 3. An increased motivation and a disruption in the food related behavior could possibly be an explanation for all the observed effects.

[Effects of antianxiety drugs on the water intake in trained and untrained rats and mice (author's transl)]

In water-deprived rats and mice, animals trained to the test situation spent more time in drinking than naive animals (first exposure to the test situation). The time spent in drinking, either during 5 min or during 10 min was recorded. As compared to controls, benzodiazepines, phenobarbital, meprobamate, and mecloqualone increased drinking time whether the experiments were run on naive or on experienced animals [5 or 10 (in mice) and 9 (in rats) exposures in the test situation]. All drugs were injected i.p. 30 min before testing. This release of the drinking behavior was more pronounced during the last 5 min than during the first 5 min of the 10 min test session. These results suggest that:

Effets des anxiolytiques sur la prise de boisson en situation nouvelle et familière

The “staircase” is a simple and rapid test and was used to study two components of exploratory behaviour in the rat. The scores of rearing and the number of steps climbed during three minutes were recorded. Various psychotropic drugs were tested, which modified these two parameters. Neuroleptic induced a parallel decrease of both, while benzodiazepines, meprobamate, amobarbitone and ethanol decreased the rearing at doses which left the steps climbed unchanged. At high doses, there was a parallel decrease of both parameters. Amphetamine, at lower doses, increased the rearing score alone. The comparison of the studied psychotropic drug effects with those of two muscle relaxants (by a comparison of the slopes of regression lines) suggests that either the observed benzodiazepine effects were only partly due to their myorelaxant action, or, that both myorelaxants have some anxiolytic action. The effect of amphetamine at low doses can be viewed as a demonstration of increased anxiety.

Dissociation de deux composantes du comportement chez le rat sous l'effet de psychotropes

24 depressed inpatients received a standardized treatment by imipramine, 6 among them receiving also levomepromazine. Plasma concentrations of imipramine and DMI were controlled weekly during the study, and standardized assessment of clinical state were made by a psychiatrist who was unaware of biochemical findings. Interaction between the antidepressant and neuroleptic metabolism is shown by a significant increase of DMI levels, though the clinical effect of the drug association could not be asserted. The therapeutic effect seems mainly dependant of etiology of depression. Endogeneous depressions improve more than other types. Among endogeneous depressions a significant correlation was found between the degree of clinical improvement after three weeks and DMI level, sum of imipramine + DMI level, but not with concentration of imipramine alone.

[Plasma levels of imipramine and desmethylimipramine and antidepressant effect during controlled therapy(author's transl)].

The following behavioral modifications were observed after a single i.p. administration of T.R.H. (thyreo-tropin-releasing hormone) in mice or rats at doses higher than 4mg · kg−1: I. an increased reactivity to stimuli, II. periods of excitation alternating with periods of aggressivity, III. unusual movements (“tail-rattling” and “wet-dog”), IV. the reserpine- or oxotremorine-induced hypothermia was antagonized in mice by T.R.H. in doses of 1 mg · kg−1 and higher, but only a few other symptoms were influenced. The prochlorperazine-induced catalepsy in rats was antagonized by T.R.H.; under the experimental conditions, sudden hyperkinetic episodes were observed. The toxicity of pargyline-l-Dopa association was slightly increased, amphetamine- or apomorphine-induced stereotyped behavior was unchanged. This spectrum of activity is different from other known psychotropic drugs.

J. R. Boissier

Papers

[Effects of antianxiety drugs on the water intake in trained and untrained rats and mice (author's transl)]

Effets des anxiolytiques sur la prise de boisson en situation nouvelle et familière

Dissociation de deux composantes du comportement chez le rat sous l'effet de psychotropes

[Plasma levels of imipramine and desmethylimipramine and antidepressant effect during controlled therapy(author's transl)].

Profil de la T.R.H. en psychopharmacologie expérimentale