Augmentation by citalopram of risperidone-induced monoamine release in rat prefrontal cortex

Rationale: Atypical antipsychotics (APDs), e.g. olanzapine and risperidone, have been reported to be effective adjunctive treatment for depression if selective serotonin (5-HT) reuptake inhibitors (SSRIs) alone are ineffective. Objectives and methods: We utilized microdialysis in awake, freely moving rats to study the effect of risperidone in combination with citalopram, an SSRI, on extracellular 5-HT, dopamine (DA), and norepinephrine (NE) efflux in rat medial prefrontal cortex (mPFC). Results: Risperidone (1.0 mg/kg, s.c.), given alone, significantly increased 5-HT, DA, and NE concentrations in the mPFC. Citalopram (10 mg/kg, s.c.), by itself, produced a significant increase in 5-HT levels only. The combination of risperidone and citalopram produced significantly greater increases in efflux of both DA and NE than risperidone alone. However, the effect of this combination on extracellular 5-HT concentrations was not significantly different than that of citalopram alone. The augmentation of DA and NE efflux induced by risperidone plus citalopram could be partially blocked by the selective 5-HT_1A antagonist, WAY 100635 (0.2 mg/kg, s.c.). Conclusions: The results suggest that the ability of atypical APDs to augment the therapeutic efficacy of SSRIs in major depression and treatment-resistant depression may be due, at least in part, to potentiation of SSRI-induced increases in cortical DA and NE. The contributions of 5-HT_1A receptor stimulation and 5-HT_2A and alpha₂ adrenergic receptor antagonism to this augmentation are discussed.