Rationale We have proposed rewarded T-maze alternation as a model of
obsessive-compulsive disorder (OCD): the serotonin agonist
m-chlorophenylpiperazine (mCPP) increments persistence therein, 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 increase, counteracted by mCPP pretreatment.
Objectives This study (a) further explores the cross-tolerance between
fluoxetine and mCPP and (b) extends the model by investigating its
sensitivity to dopaminergic manipulations (D-2,D- 3 agonism-quinpirole).
Materials and methods In both experiments, baseline and drug testing
were 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 (2.5 mg/kg), (3) low-dose mCPP (0.5 mg/kg) or (4)
combined fluoxetine + mCPP. One group per pretreatment then received a
4-day challenge with high-dose fluoxetine (10 mg/kg), the other with
high-dose mCPP (2.5 mg/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 D-2,D- 3 receptor 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
