Social interaction (SI) between two unfamiliar male rats in a dimly lit, familiar environment has been investigated as a model of anxiety, where novelty of the partner remains as the principal anxiogenic stimulus. A range of centrally acting drugs have been tested in this situation. Chlordiazepoxide, nitrazepam, flunitrazepam, and flurazepam all increase SI, as does buspirone, CL 218872, suriclone, sodium valproate, and nicotinamide in the model described. Anxiogenic agents FG 7142 and yohimbine reduced SI without significant modification of motor activities. However, the stimulant amphetamine increased all behaviours in this condition. Amphetamine also increased all behaviours when rats were tested with their cagemates, when the desire for SI is largely satiated. CL 218872 also increased SI in this second situation, and it is suggested that this agent may have a non-specific component in its action in this test. Additionally, caffeine, theophylline, and piracetam may also have non-specific behavioural actions in this model.

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Gardner, C.R., and A.P. Guy: A social interaction model of anxiety sensitive to acutely administered benzodiazepines. Drug Dev. Res. 4207-216, 1984. Active social interaction (SI) and aggression (AGG) were recorded separately during 5-min observation periods of pairs of male Wistar rats. There was little difference between the levels of S I in undrugged animals across ten different experimental conditions, involving the manipulation of environmental and social stimuli. When animals were housed and tested together, no increases in S I were observed with acute administration of chlordiazepoxide (CDZP, 8 mglkg PO) irrespective of other environmental changes. When the only potentially anxiogenic stimulus used was a novel partner, a large increase in SI was observed with CDZP. With the exception of strong lighting, combinations of this and other stimuli resulted in smaller increases. When animals were housed and familiarized together but tested with a novel partner, the large increase in S I induced by CDZP was not associated with changes in locomotor activity and was maintained after subacute dosing when decreases in motor activity were absent. Furthermore, similar increases were observed with other benzodiazepines after acute administration in this protocol. This modified method of S I in the rat is more sensitive to the anxiolytic activity of benzodiazepines leading to their detection after acute administration.

Guy, A.P., and C.R. Gardner: Agents enhancing y-aminobutyric acid receptor-coupled chloride ionophore function. Effects in a social interaction model of anxiety in the rat. Drug Dev. Res. 19:13-21, 1990. A recently described social interaction (SI) model which is sensitive to single doses of benzodiazepines and novel non-sedative anxiolytic agents has been used. Activities of drugs were compared in both an anxious (animals housed in pairs, tested with a novel partner) and a non-anxious (animals housed in pairs, tested with the cage mate) condition. Diazepam displays a typical anxiolytic response, increasing SI in the anxious but not in the non-anxious condition. This was associated with a decrease in aggression (AGG) and in locomotion (LOCO) at higher doses. Seven agents were tested which are thought to enhance central nervous system y-aminobutyric acid (GABA)-mediated neurotransmission by increasing the activity of a receptor-coupled chloride ionophore system as a major component of their action. Tracazolate, RL348, methaqualone, etomidate, LY81067, and pentobarbitone all significantly increased SI in the anxious but not the non-anxious condition. In the anxious condition tracazolate and RL348 reduced AGG and all of these compounds except LY81067 reduced LOCO. Methaqualone and etomidate also reduced LOCO in the non-anxious condition. In addition, an agent which reduces GABA function (picrotoxin) significantly reduced SI in already-anxious animals, consistent with its known anxiogenic properties. Picrotoxin also reduced LOCO in both conditions. Phenobarbitone induced a non-specific effect on SI (increased SI in both anxious and non-anxious conditions), as well as reducing AGG in the anxious condition and LOCO in both conditions. These data suggest that agents enhancing GABA receptor-coupled chloride ionophore function possess anxiolytic properties which may be attributed to this activity.

A group of imidazopyrimidine ligands of benzodiazepine receptors has been shown to produce anti-conflict effects in a punished rat operant task, at comparable doses to classical benzodiazepine agonists such as diazepam. Most were able to attenuate the convulsant effects of pentylenetetrazole and electroshock in the mouse, although with reduced potency compared with the reference classical benzodiazepines. Their activity in tests of functional central nervous system impairment (rotating drum and potentiation of phenobarbitone in the mouse, potentiation of chloral hydrate and pull-up test in the rat) was also markedly less than the classical agonists. These data are consistent with these imidazopyrimidines being partial agonists at the benzodiazepine receptor.