Psychopharmacology (1994) 115:454462 Psychopharmacolog © Springer-Vertag 1994 Reversal of stress-induced anhedonia by the dopamine recep agonist, pramipexole Paul Willner 1, Spiros Lappas, Survjit Cheeta ~, Richard Muscat 2 Department of Psychology, City of London Polytechnic, Old Castle St, London E1 7NT, UK Received: 19 July 1993 / Final version: 16 December 1993 Abstract. Chronic exposure to mild unpredictable stress has previously been found to depress the consumption of a palatable (1%) sucrose solution, and to attenuate food° induced place preference conditioning. In this study the effects of pramipexole (SND-919), a dopamine D2 ago- nist, were studied during 7-9 weeks of chronic treatment. Pramipexole (1.0 mg/kg per day) reversed the suppres- sion of sucrose intake in stressed animals, increasing su- crose intakes above the levels seen in untreated non- stressed controls. Pramipexole also increased sucrose in- take in nonstressed animals; these effects were accompa- nied by increases in water intake and tended to correlate with weight loss. Drug-treated stressed animals also lost weight, but in this case water intake was unaffected. A second group of animalsreceived a higher dose of pramipexole (2.0 mg/kg per day). The effects of the two doses were very similar. After three weeks of treatment, these animals were switched to a lower dose of pramipex- ole (0.1 mg/kg per day). Increases in sucrose intake were maintained over three weeks of treatment at the lower dose, with significant recovery of body weight. Two fur- ther groups received the same doses of pramipexole (1.0 mg/kg for 6 weeks or 2.0 mg/kg for 3 weeks followed by 0.1 mg/kg thereafter), but received intermittent (twice- weekly) drug treatment. Intermittent pramipexole treat- ments also tended to increase sucrose intakes, but the results were less consistent from week to week. Following 6-8 weeks of pramipexole treatment, food-induced place preference conditioning was studied in all animals. Un- treated stressed animals showed no evidence of place conditioning. Normal conditioning was seen in both groups of stressed animals treated daily with pramipex- ole (at 1.0 and 0.1 mg/kg) and in the group treated twice weekly at the higher dose (1.0 mg/kg); intermittent treat- ment at the lower dose (0.1 mg/kg) was ineffective. The 1present address: Dept of Psychology, University of Wales, Swansea, Singleton Park, Swansea SA2 8PP, UK 2 Present address: Dept of Biomedical Sciences, University of Malta, Msida, Malta Correspondence to: P Willner results indicate that pramipexole exerts rapid anti-an- hedonic effects in the chronic mild stress model. This conclusion is complicated, but not undermined, by drug~ induced weight loss and by the presence of significa drug effects in nonstressed control animals. Key words: Stress Sucrose drinkingPlace preference conditioning -Reward -Pramipexole - D2 agonist - Rats Chronic sequential exposure to mild unpredictable stress (chronic mild stress: CMS) causes, in rats, a generalize decrease in responsiveness to rewards,which may provide an animal model of anhedonia, the pervasive loss of pleasure capacity characteristic of melancholic depres sions (Klein 1974; Fawcett et al. 1983). Effects of CMS include decreased consumption of, and preference for palatable sweet solutions (Willner et al. 1987; Muscat and Willner 1992), attenuation of the rewarding proper- ties of drugs (amphetamine, morphine) and natural rein- forcers (sweet solutions, food) in the place preference paradigm (Papp et al. 1991, t992), and increases in th threshold for intracranial self-stimulation (Moreau et al. t992, 1994). All of these effects may be reversed by chron ic treatment with antidepressants, including tricyclics (Willner et al. 1987; Muscat et al. 1990; Sampson et al 1991; Moreau et al. 1992), monoamine oxidase inhibitors (Moreau et al. 1994), and atypical antidepressants, suc as specific noradrenatine or serotonin reuptake inhibitors (Muscat et al. 1992a) and mianserin (Cheeta et al. 1992 CMS causes abnormalities of dopamine (DA) neuro- transmission within the nucleus accumbens (Willner et al 1991a; Stamford et al. 1991) and a decreased sensitiv to behavioural effects of DA agonists (Papp et al. 1991 1993a). A functional role for DA in the behavioural ef fects of CMS is indicated by the fact that antidepressant effects in the CMS model are reversed by acute adminis- tration of DA receptor antagonists (Muscat et al. 1990 1992a; Sampson et al. 1991), which suggests that th