Psychopharmacology (1992) 109:433-438 Psychopharmacology ~ Springer-Verlag 1992 Reversal of stress-induced anhedonia by the atypical antidepressants, fluoxetine and maprotiline Richard Muscat*, Mariusz Papp**, and Paul Willner Department of Psychology, City of London Polytechnic, Old Castle Street, London E1 7NT, UK Received February 12, 1992 / Final version May 7, 1992 Abstract. Chronic exposure to mild unpredictable stress has previously been found to depress the consumption of palatable sweet solutions. In the present study this effect was reversed by chronic (9 weeks) treatment with the atypical antidepressants, fluoxetine and maprotiline (5 mg/kg/day); the non-antidepressant chlordiazepoxide was ineffective. Stressed animals were also subsensitive to food reward in the place conditioning procedure; how- ever, fluoxetine and maprotitine treated animals showed normal place preference conditioning. Acute pretreatment with raclopride (100 lag/kg) selectively reversed the re- covery of sucrose drinking in antidepressant-treated stres- sed animals. These results extend previous reports of the efficacy of tricyclic antidepressants in this paradigm, and support the hypothesis of a dopaminergic mechanism of antidepressant action. Key words: Stress - Sucrose drinking - Place preference conditioning - Reward - Fluoxetine - Maprotiline - Chlordiazepoxide - Rats Chronic sequential exposure to mild unpredictable stress has been found to depress the consumption of, and prefer- ence for, palatable sweet solutions; these deficits, which may represent a decrease in sensitivity to rewards, are reversed by chronic administration of tricyclic antidepres- sants (Willner et al. 1987; Muscat et ak 1988, 1990; Sampson et al. 1991). As stress is implicated in the etiology of depression (Lloyd 1980; Kanner et al. 1981; Anisman and Zacharko 1982; Brown and Harris 1988), the chronic mild stress paradigm may provide a relatively realistic animal model of the decreased response to rewards (anhe- donia) that characterizes melancholia (Klein 1974; Nelson and Charney 1981; Fawcett et al. 1983; American Psych- *Present address: Department of Biomedical Sciences, Universityof Malta, Msida, Malta **Present address: Institute of Pharmacology, Polish Academy of Sciences, Krakow,Poland Correspondence to: P. Willner iatric Association 1987). The main purpose of the present study was to investigate the activity in this model of two non-tricyclic antidepressants, the specific serotonin (5HT) uptake inhibitor fluoxetine (Bremner 1984; Asberg et al. 1986) and the specific noradrenaline (NA) uptake in- hibitor maprotiline (Maitre et al. 1975; Montgomery 1980). The non-antidepressant anxiolytic drug chlordiaze- poxide was also included, as a negative control. The place conditioning paradigm, in which animals increase their preference for a distinctive environment in which the reward is administered, has been used exten- sively to study the rewarding properties of natural re- wards and of drugs of abuse (Bozarth 1987; Carr et al. 1989). In support of the interpretation that decreased sucrose consumption in animals subjected to chronic mild stress results from subsensitivity to reward, we have pre- viously reported that the suppression of sucrose intake by chronic mild stress is associated with a decrease in the rewarding properties of natural rewards (food pellets or sweet solutions) and drug rewards (amphetamine, mor- phine), as assessed by their ability to support conditioned place preferences (Papp et al. 1991, 1992). A second objec- tive of this study was to investigate whether, in addition to restoring normal sucrose consumption, antidepressant drugs also normalize place preference conditioning in chronically stressed animals. Antidepressant drugs have traditionally been assumed to exert their clinical effects through an interaction with noradrenergic or serotonergic systems. However, after chronic administration, antidepressants have also been found to potentiate the locomotor stimulant effects of dopamine (DA) D2 agonists. These effects are apparent following systemic administration (Willner and Mon- tgomery 1981; Martin-Iverson et al. 1983; Arnt et al 1984; Maj et al. 1984a, b; Maj 1988) or direct injection of D2 agonists into the nucleus accumbens (Maj and Wedzony 1985, 1988; Maj et al. 1987; Maj 1988). We have previously demonstrated that acute administration of DA receptor antagonists reduced the consumption of a sweet solution in chronically stressed rats successfully treated with imi- pramine, desmethylimipramine (DMI) or amitriptyline, but did not reduce consumption in non-stressed animals