Chronic fluoxetine reverses the effects of chronic corticosterone treatment on α-adrenoceptors in the rat frontal cortex but not locus coeruleus.

Disruption of the hypothalamic-pituitary-adrenal axis is an established finding in patients with anxiety and/or depression. Chronic corticosterone administration in animals has been proposed as a model for the study of these stress-related disorders and the antidepressant action. Alterations of the central noradrenergic system and specifically of inhibitory α-adrenoceptors seem to be part of the pathophysiology of depression and contribute to the antidepressant activity. The present study evaluates in male rats the effect of chronic corticosterone treatment during 35 days (16-20 mg kg day) on the sensitivity of α-adrenoceptors expressed in the somatodendritic and terminal noradrenergic areas locus coeruleus (LC) and prefrontal cortex (PFC), respectively. Further, the effect of chronic fluoxetine treatment (5 mg kg, i.p., since the 15th day) on the sensitivity of α-adrenoceptors was examined under control conditions and in corticosterone-treated rats. The α-adrenoceptor functionality was analysed in vitro by agonist-mediated [S]GTPγS binding stimulation and in vivo through the modulation of noradrenaline (NA) release evaluated by dual-probe microdialysis. The concentration-effect curves of the [S]GTPγS binding stimulation by the agonist UK14304 (5-bromo-N-(4,5-dihydro-1H-imidazol-2-yl)-6-quinoxalinamine) demonstrated a desensitization of cortical α-adrenoceptors induced by corticosterone (-logEC = 6.7 ± 0.2 vs 8.2 ± 0.3 in controls) that was reverted by fluoxetine treatment (-logEC = 7.5 ± 0.3). Local administration of the α-adrenoceptor antagonist RS79948 ((8aR,12aS,13aS)-5,8,8a,9,10,11,12,12a,13,13a-decahydro-3-methoxy-12-(ethylsulfonyl)-6H-isoquino[2,1-g][1,6]naphthyridine) (0.1-100 μmol L) into the LC induced a concentration-dependent NA increase in the PFC of the control group (E = 191 ± 30%) but non-significant effect was observed in corticosterone-treated rats (E = 133 ± 46%), reflecting a desensitization of α-adrenoceptors that control the firing of noradrenergic neurons. Fluoxetine treatment did not alter the corticosterone-induced desensitization in this area (E = 136 ± 19%). No effect of fluoxetine on α-adrenoceptor functionality was observed in control animals (E = 223 ± 30%). In PFC, the local administration of RS79948 increased NA in controls (E = 226 ± 27%) without effect in the corticosterone group (E = 115 ± 26%), suggesting a corticosterone-induced desensitization of terminal α-adrenoceptors. Fluoxetine administration prevented the desensitization induced by corticosterone in the PFC (E = 233 ± 33%) whereas desensitized α-adrenoceptors in control animals (E = -24 ± 10%). These data indicate that chronic corticosterone increases noradrenergic activity by acting at different α-adrenoceptor subpopulations. Treatment with the antidepressant fluoxetine seems to counteract these changes by acting mainly on presynaptic α-adrenoceptors expressed in terminal areas.