Alterations in the central nervous alpha 2-adrenoceptor system under chronic psychosocial stress

It has recently been shown for the tree shrew that after 10 days of psychosocial stress, when the central nervous noradrenergic and adrenergic systems are highly activated, alpha 2-adrenoceptors are down-regulated in brain regions which are involved in the regulation of autonomic functions (Flügge G. et al. (1992) Brain Res. 597, 131-137). The present study demonstrates the dynamic changes occurring in the alpha 2-adrenoceptor system during chronic psychosocial stress. Male tree shrews were submitted to psychosocial stress for two, 10, 21 and 28 days, respectively, and alpha 2-adrenoceptor binding characteristics were determined in the locus coeruleus, the prefrontal cortex, the dorsal motor nucleus of the vagus and the solitary tract nucleus by in vitro receptor autoradiography using the antagonist [3H]RX821002 as a ligand. Competition experiments have shown that the radioligand labels the alpha 2-adrenoceptor subtypes A and C in these brain regions. In the locus coeruleus, receptors were already down-regulated two days after the onset of the stress period and stayed low thereafter. In contrast, in the prefrontal cortex, which is innervated by the locus coeruleus, receptor numbers were decreased only on day 10 of psychosocial stress, then returned to control values and were up-regulated from day 28. In the solitary tract nucleus, a down-regulation of alpha 2-adrenoceptors was observed from day 21 of the stress period onwards. The time-course pattern of receptor changes in the dorsal motor nucleus of the vagus followed that of the locus coeruleus. In all cases, changes in receptor numbers did not exceed 17% of the total alpha 2-adrenoceptor number. Besides the changes in receptor numbers, there was a decrease in affinity for the subtype alpha 2A-selective agonists oxymetazoline and UK 14,304, with the strongest effects occurring on day 10 of the stress period. The time-course pattern of these alterations in receptor affinity did not match the time-course pattern in changes of receptor numbers. However, receptor affinities were more or less decreased during the whole period of psychosocial stress. The present findings demonstrate that prolonged periods of recurrent challenging situations induce dynamic changes in the alpha 2-adrenoceptor system leading to region-specific down- or up-regulation of receptors. It is discussed whether the receptor alterations are agonist-mediated or might be due to stress effects on transcription of the receptor genes. The time-dependent alterations indicate that the responsiveness of the receptor system changes with the duration of the stress period, which may have profound consequences for physiological functions subjected to regulation by alpha 2-adrenoceptors.