Increased sensitivity to antidepressants of D3 dopamine receptor-deficient mice in the forced swim test (FST)

Evidence exists for a dopaminergic system dysregulation in mood disorders. In particular, depression may be accompanied by a relative fall of brain dopamine (DA) availability, while the increase of dopamine D2/D3 receptors (D2R/D3R) binding may reflect a compensatory change following primary reduction of mesolimbic DA levels. It is well established that D(3)Rs, acting as autoreceptors, inhibit DA synthesis and release, although lack of selective compounds have limited the progress in understanding D(3)Rs role in mood disorders. Aim of this study was to assess the behavioral responses of D3R-deficient (D-3(-/-)) mice tested in the forced swim test (FST) and to evaluate their sensitivity to the treatment with different antidepressant drugs. Different groups of mice received one injection of the tricyclic compound, clomipramine (1, 5 and 10 mg/kg) or of one the selective serotonin reuptake inhibitors (SSRIs), paroxetine, sertraline or citalopram (1, 4 and 16 mg/kg), 30 min prior the behavioral test. Vehicle-injected wild type (V,/T) mice and D-3(-/-) animals were used as controls and submitted to the same experimental procedure. In a preliminary experiment, vehicle- injected D-3(-/-) mice, but not their littermates, failed to show an increased immobility time in FST as compared to intact controls, suggesting an increased resistance to injection-induced stress in the former. Clomipramine 1 mg/kg failed to affect behavioral responses of both D-3(-/-) mice and WT animals. After the 5 mg/kg dose, D-3(-/-) and WT mice showed a better performance in FST than vehicle-injected controls, with a lower immobility time exhibited by D-3(-/-) mice than that shown by WT animals. No difference was found between WT mice treated with the highest dose of clomipramine (10 mg/kg) and the respective controls, although D-3(-/-) mice exhibited a decreased immobility time as compared to vehicle-injected controls. In contrast to WT animals, when treated with 1 mg/kg sertraline and the 4 mg/kg dose of every SSRI D-3(-/-) mice exhibited a decreased immobility time in FST in comparison to vehicle-injected controls. Furthermore, 16 mg/kg doses of citalopram, paroxetine or sertraline induced a greater reduction of immobility time in D-3(-/-) mice than in WT-treated animals as compared to their respective controls. These data suggest that D-3(-/-) mice, as being more resistant to stressful procedure than WT littermates, are more sensitive to antidepressants in FST paradigm than the former. Although the present data do not allow any conclusion on the neurochemical base of this difference, it might be possible that the greater sensitivity to antidepressants depends on a higher DA levels in mesolimbic pathways following the tack of D3Rs. (c) 2007 Elsevier B.V. and ECNP. All rights reserved.