Chronic citalopram administration desensitizes prefrontal cortex but not somatodendritic α2-adrenoceptors in rat brain

Abstract

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 [³⁵S]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 (E_max = -44 ± 4%; p < 0.001) and in PFC (E_max = -61 ± 5%, p < 0.001). In citalopram chronically-treated rats, clonidine administration exerted a lower decrease of NA (E_max = -25 ± 7%; p < 0.001) in PFC whereas the effect in LC was not different to controls (E_max = -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 [³⁵S]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.

Keywords: Chloral hydrate (PubChem CID 2707); Citalopram; Citalopram hydrobromide (PubChem CID 77995); Clonidine hydrocloride (PubChem CID 20179); Locus coeruleus; Microdialysis; Noradrenaline; Prefrontal cortex; RX821002 (PubChem CID 108094); UK14304 (PubChem CID 2435); α(2)-adenoceptor.