Directional Persistence in the Rewarded Alternation Model of Obsessive-compulsive Disorder is Responsive to both Dopaminergic and Serotonergic Manipulations

Abstract

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 study

1. a. further explores the apparent cross-tolerance between fluoxetine and mCPP and

2. b. extends the model by investigating its sensitivity to dopaminergic manipulations (D^2,3 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. 1. saline,

2. 2. low-dose fluoxetine (2.5mg/kg),

3. 3. low-dose mCPP (0.5mg/kg) or

4. 4. 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 D^2,3receptor 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.