Abstract
The aim of this study was to quantitate the turnover of alpha 2-adrenoceptors in different regions of the rat brain and its modulation during desipramine (a cyclic antidepressant drug)-induced receptor down-regulation. The recovery of [3H]clonidine (a mixed alpha 2A/B-adrenoceptor agonist) binding after irreversible inactivation by N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) (an alkylating agent for both alpha 2-adrenoceptor subtypes) was assessed in control and desipramine-treated (3 mg/kg, intraperitoneally, every 12 hr for 7-35 days) rats to study the process of alpha 2-adrenoceptor repopulation and to calculate receptor turnover parameters. In control rats, the turnover of brain alpha 2-adrenoceptors showed marked regional differences. The fastest receptor turnover rate was found in the hypothalamus and corpus striatum (receptor half-life, t1/2 = 2.1 days), compared with that in the brainstem (t1/2 = 2.6 days), cerebral cortex (t1/2 = 3.9 days), and hippocampus (t1/2 = 4.3 days). In the cerebral cortex and other brain regions, desipramine induced a time-dependent modulation of alpha 2-adrenoceptors, with significant decreases in the number of receptors (40-71%; p < 0.01) during the first 7-14 days of treatment and regulation to base-line values by 21-35 days. In the cerebral cortex, alpha 2-adrenoceptor turnover evaluated during desipramine-induced receptor down-regulation (phase of 7-14 days of treatment) revealed an increase in both the disappearance (degradation) (delta k = 122%; p < 0.05; t1/2 = 1.7 days) and appearance (synthesis) (delta r = 68%; p < 0.05) rates of the receptor. In other noradrenergic brain regions (hippocampus, brainstem, and hypothalamus) but not in the corpus striatum, desipramine (7-14 days) also increased alpha 2-adrenoceptor degradation (delta k = 97-144%) and shortened the half-life of the receptor, and it tended to increase the rate of synthesis (delta r = 51-83%). Similar results, but with a higher appearance rate, were obtained in the cerebral cortex during the phase of treatment (21-35 days) without apparent receptor down-regulation (delta k = 160%; p < 0.01; t1/2 = 1.5 days; delta r = 128%; p < 0.001). It is proposed that sustained stimulation of alpha 2-adrenoceptors by endogenous norepinephrine, after inhibition of neuronal uptake, increases their disappearance rate (degradation), leading to a reduction in receptor number. The increase in the appearance (synthesis) rate could be viewed as a later compensatory mechanism that would lead to restoration of brain alpha 2-adrenoceptor density.
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