Psychopharmacology (1987) 93:358-364 Psychopharmacology © Springer-Verlag 1987 Reduction of sucrose preference by chronic unpredictable mild stress, and its restoration by a tricyclic antidepressant P. Willner, A. Towell, D. Sampson, S. Sophokleous, and R. Muscat Psychology Department, City of London Polytechnic, Old Castle Street, London, UK Abstract. Rats exposed chronically (5 9 weeks) to a variety of mild unpredictable stressors showed a reduced consump- tion of and preference for saccharin or sucrose solutions. Preference deficits took at least 2 weeks to develop and were maintained for more than 2 weeks after termination of the stress regime. Sucrose preference was unaffected by 1 week of treatment with the tricyclic antidepressant DMI but returned to normal after 24 weeks of DMI treatment. DMI did not alter sucrose preference in unstressed animals. No significant changes were seen in saline preference either during stress or following drug treatment. DMI reduced blood corticosterone and glucose levels, but stress did not significantly alter either measure. The results are discussed in terms of an animal model of endogenous depression. Key words: Animal model of depression - DMI Stress - Saccharin - Sucrose Saline Preference Anhedonia - Corticosterone Glucose - Rat Although a large number of behavioural paradigms have been proposed as animal models of depression, only a small minority can lay claim to a degree of validity sufficient for them to be considered as potentially useful research tools (Willner 1984). One of these is a paradigm described by Katz and co-workers, in which rats were subjected chronically and unpredictably to a variety of stressors, in- cluding electric shocks, immersion in cold water, tail pinch and others. Following a week of such treatment, deficits in open field performance and hormonal changes were ap- parent, which could be prevented by the concurrent admin- istration of a wide range of antidepressant drugs, but not by drugs of other classes (Katz 1981, 1984; Katz and Hersh 1981 ; Katz et al. 1981 a, b; Roth and Katz 1981 ; Katz and Baldrighi 1982; Katz and Sibel 1982a, b; Soblosky and Thurmond 1986). In addition to the changes in open field behaviour, it was observed in one study that animals ex- posed to the chronic stress regime failed to increase their fluid consumption when saccharin or sucrose were added to their drinking water (Katz 1982). This is a particularly significant finding, as it implies a defective reward system, and models the anhedonia which is a central feature of endogenous depression (Willner 1985). Evidence is accumu- lating that chronic low grade stress (" strain") may be an important factor in the etiology of depression (Brown and Offprint requests to ."P. Willner Harris 1978 ; Jahoda 1979; Kanner et al. 1981 ; Aneshensel and Stone 1982; Billings et al. 1983; Feather and Barber 1983), and a specific relationship to endogenous depression has been postulated (Willner 1985, 1987). The experiments described in this paper were intended to replicate Katz's (1982) observation of stress-induced an- hedonia and its prevention by a tricyclic antidepressant. We were also concerned to extend this observation, in five ways by: (i) Substantially reducing the severity of the stressors used, to give a more realistic analogue of the strains encountered in everyday life; (ii) using two-bottle tests to examine the preference deficit, rather than the less sensitive one-bottle test (Grote and Brown 1971); (iii) testing at weekly intervals during exposure to the stress regime to establish the time course of the effect; (iv) administering an antidepressant to reverse an estab- lished preference deficit; (v) examining whether the observed changes in sucrose consumption could be explained by changes in blood glucose levels. The first experiment examined the effects of chronic mild stress on saccharin consumption and preference. The second experiment, using a modified stress regime, exam- ined preference for sucrose and saline, and the effects of the tricyclic antidepressant desmethylimipramine (DMI). (Sucrose was used rather than saccharin in order to estab- lish the generality of the stress effect.) The third experiment replicated the effects of stress and DMI on sucrose prefer- ence, and also examined their effects on blood levels of corticosterone and glucose. A final experiment examined the effect of DMI on a weaker, and therefore less preferred, sucrose solution. Materials and methods Subjects. Adult male hooded Lister rats (NIMR, Mill Hill, London) weighing 310 350 g were used in all experiments; with some exceptions described below, they were singly housed in perspex cages (26x 19x38 cm; North Kent Cages) and maintained on a 12 h light/dark cycle, with food (Dixon, Ware, Herts in experiments 1 and 2; Special Diet Services, Witham, Essex in experiments 3 and 4) and water freely available.