Abstract Rationale: Social isolation is anxiogenic and may change the effects of anxiolytic drugs. These effects are generally attributed to “isolation stress”. However, isolation does not affect basal corticosterone levels; thus, it cannot be considered stressful. On the contrary, isola- tion deprives animals of mild daily stressors that are in- herent to social life. Since mild stressors were shown to be anxiolytic in rats, it was postulated that short-term, re- peated stressors may abolish the effects of isolation. Ob- jectives: The aim of the present study was to investigate whether short-term, repeated, mild social stress can abol- ish the consequences of isolation on anxiety and on the effects of chlordiazepoxide. Methods: Rats were housed in groups or in individual cages for 5 days (isolates). Half of isolates were daily submitted to the attacks of a resident rat for 30 min per day, on 4 consecutive days (stressed isolates). On day 5, rats were treated either with vehicle or with chlordiazepoxide and submitted to the el- evated plus-maze test. Endocrinological consequences of experimental manipulations were assessed in a different set of rats. Results: Plasma ACTH and corticosterone levels were similar in the three groups. Weight gain was higher, while plasma growth hormone was lower in stressed isolates, both effects being consistent with a mild stress. Isolation had a clear anxiogenic effect. This effect was completely abolished by the daily experience of social stress. Chlordiazepoxide had a significant anxi- olytic effect in all three groups. Its effects on classical plus-maze variables did not differentiate the three groups. However, chlordiazepoxide decreased risk as- sessment activity only in isolates. Conclusions: The lack of appropriate endocrinological changes challenges the concept of “isolation stress”. However, isolation was an- xiogenic in our study and it also induced subtle changes in the effects of chlordiazepoxide. It appears that mild daily stressors have a protective effect against the effects of isolation. Key words Anxiety · ACTH · Corticosterone · GH · Stress · Anxiolytic · Chlordiazepoxide · Rat Introduction Individual housing of rats is often termed as “isolation stress”, and is listed among factors that enhance anxious- ness. While the anxiogenic effect of isolation in rats ap- pears established (Holson et al. 1991; Maisonette et al. 1993), the stressfulness of isolation is questionable, since individual housing per se does not elevate basal cortico- sterone levels (Benton and Brain 1981; Misslin et al. 1982; Holson et al. 1991); moreover, isolation decreased basal corticosterone levels in a few studies (Jessop and Bayer 1989; Miachon et al. 1993; Sanchez et al. 1998). Important changes were noticed, however, in stress reac- tivity: it appears that isolated animals show a blunted corticosterone response to acute stressors (Viveros et al. 1988; Sanchez et al. 1998). Thus, one can postulate that behavioral changes noticed after individual housing can- not derive from a chronic stress state but from the changed stress reactivity of animals which is triggered by the artificial stress-free state of isolation. This hy- pothesis is also supported by the reinforcing properties of corticosterone (Piazza et al. 1993) that may render stress-free animals less prone to an active behavioral re- sponse. If indeed, daily stressors exert a “protective” effect in terms of anxiousness, repeated exposure of isolated ani- mals to mild stressors should abolish the anxiogenic ef- fects of isolation. Although chronic stress has a well es- tablished anxiogenic action, there are a few studies which show that acute or repeated exposure of rats to mild stressors decrease anxiety (Roth and Katz 1979; D’Aquila et al. 1994; Morato and Brandao 1997). Some- what similar phenomena may be valid for humans as well, since it was shown that the intensity of the acute J. Haller ( ✉ ) · J. Halász Institute of Experimental Medicine, Hungarian Academy of Science, P.O. Box 67, H-1450 Budapest, Hungary e-mail: haller@koki.hu Fax: +36-12100811 Psychopharmacology (1999) 144:311–315 © Springer-Verlag 1999 ORIGINAL INVESTIGATION József Haller · József Halász Mild social stress abolishes the effects of isolation on anxiety and chlordiazepoxide reactivity Received: 23 May 1998 / Final version: 3 December 1998