Chronic citalopram administration desensitizes prefrontal cortex but not somatodendritic α 2 -adrenoceptors in rat brain.

Selective serotonin reuptake inhibitors (SSRIs) regulate brain noradrenergic neurotransmission both at somatodendritic and nerve terminal areas. Previous studies have demonstrated that noradrenaline (NA) reuptake inhibitors are able to desensitize α2 -adrenoceptor-mediated responses. The present study was undertaken to elucidate the effects of repeated treatment with the SSRI citalopram on the α2 -adrenoceptor sensitivity in locus coeruleus (LC) and prefrontal cortex (PFC), by using in vivo microdialysis and electrophysiological techniques, and in vitro stimulation of [35 S]GTPγS binding autoradiography. Repeated, but not acute, treatment with citalopram (5 mg/kg, i.p., 14 days) increased extracellular NA concentration selectively in PFC. The α2 -adrenoceptor agonist clonidine (0.3 mg/kg, i.p.), administered to saline-treated animals (1 ml/kg i.p., 14 days) induced NA decrease in LC (Emax  = -44 ± 4%; p < 0.001) and in PFC (Emax  = -61 ± 5%, p < 0.001). In citalopram chronically-treated rats, clonidine administration exerted a lower decrease of NA (Emax  = -25 ± 7%; p < 0.001) in PFC whereas the effect in LC was not different to controls (Emax  = -36 ± 4%). Clonidine administration (0.625-20 μg/kg, i.v.) evoked a dose-dependent decrease of the firing activity of LC noradrenergic neurons in both citalopram- (ED50  = 3.2 ± 0.4 μg/kg) and saline-treated groups (ED50  = 2.6 ± 0.5 μg/kg). No significant differences between groups were found in ED50 values. The α2 -adrenoceptor agonist UK14304 stimulated specific [35 S]GTPγS binding in brain sections containing LC (144 ± 14%) and PFC (194 ± 32%) of saline-treated animals. In citalopram-treated animals, this increase did not differ from controls in LC (146 ± 22%) but was lower in PFC (141 ± 8%; p < 0.05). Taken together, long-term citalopram treatment induces a desensitization of α2 -adrenoceptors acting as axon terminal autoreceptors in PFC without changes in somatodendritic α2 -adrenoceptor sensitivity.