Rationale:In the rewarded alternation model of obsessive compulsive disorder (OCD), the serotonin agonist m-chlorophenylpiperazine (mCPP) increases persistent behaviour, while chronic pretreatment with selective serotonin reuptake inhibitor (SSRI-fluoxetine) but not benzodiazepine or desipramine abolishes mCPP effects. However, we noted that acute SSRI administration also causes transient persistence increases, counteracted by mCPP pretreatment.Objectives:This studya.further explores the apparent cross-tolerance between fluoxetine and mCPP andb.extends the model by investigating its sensitivity to dopaminergic manipulations (D2,3 agonism - quinpirole).Methods:In both experiments, baseline and drug testing was carried out under daily T-maze alternation training.Exp.1:Matched group (n=8) pairs of rats received one of the following 20-day pretreatments (daily intraperitoneal administration):1.saline,2.low-dose fluoxetine (2.5mg/kg),3.low-dose mCPP (0.5mg/kg) or4.combined fluoxetine+mCPP.One group per pretreatment then received a 4-day challenge with high-dose fluoxetine (10mg/kg), the other with high-dose mCPP (2.5mg/kg).Exp.2:One group (n=12) of rats received 20-day treatment with saline, another with quinpirole (0.5 mg/kg).Results:Exp.1:Saline and low-dose mCPP- or fluoxetine-pretreated animals showed significant persistence increases under both challenges, while combined low-dose fluoxetine+mCPP pretreatment afforded full protection from either challenge.Exp.2:Quinpirole significantly increased directional persistence after 13 administration days.Conclusions:These results establish the sensitivity of the rewarded alternation OCD model to D2,3receptor activation, thereby extending its profile of pharmacological isomorphism with OCD. Furthermore, they suggest a common mechanism of action of an SSRI and a serotonin agonist in the control of directional persistence.