Title: 

α2-Adrenoceptor Binding in Depression and Antidepressant Therapies:
Lessons from the Flinders Rat Model

Electroconvulsive therapy (ECT) remains the most effective treatment of severe depression, but the exact therapeutic mechanism is still unresolved. In this study, we test the hypothesis that decreased α2-adrenoceptor level contributes to the therapeutic effect of ECT. Dysfunction in noradrenergic neurotransmission is thought to be involved in depression and alterations in α2-adrenoceptor binding are implicated in the neurobiology of depression and in the mechanisms of antidepressant therapies.

Depressed Flinders sensitive line (FSL) rats and control Flinders resistant line (FRL) and Sprague-Dawley (SD) rats were treated with electroconvulsive stimulations (ECS), an animal model of ECT, or sham for 10 days before the brains were removed and sliced into sections. The density of α2- adrenoceptors was measured by quantitative autoradiography in different brain regions implicated in depression using the α2-adrenoceptor antagonist, [3H]RX 821002. In the first study, we found 10% increased α2-adrenoceptor density in most brain regions of the sham treated FSL rats when compared to sham treated SD rats. Surprisingly, α2-adrenoceptor density was even further increased in the sham treated FRL rats compared to both sham treated FSL (10% across regions) and SD rats (24% across regions). In the second study, we found that ECS decreased α2-adrenoceptor density in most regions in the FSL and FRL rats, while no significant change was observed in the control SD rats.

Increased binding in FSL sham compared to SD sham supports the hypothesis that elevated number of inhibitory α2-adrenoceptors causes a deficiency in noradrenaline, which is found in depression. Moreover, ECS decreased the levels of α2-adrenoceptors in most regions of the FSL and FRL rats, which suggests down-regulation of α2-adrenoceptors as a potential therapeutic pathway of ECS. The studies also demonstrated that in the small sample of female rats, FRL and SD control animals did not show similar levels of α2-adrenoceptor binding in the sham condition or a similar response to ECS and therefore further studies in a larger cohort of animals of both sexes are warranted.

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