Down-regulation of α2-adrenoceptors involved in growth hormone control in the hypothalamus of infant rats receiving short-term clonidine administration

Abstract In infant rats short-term administration of the α 2 -adrenoceptor agonist, clonidine (CLO), induces refractoriness to the growth hormone (GH)-releasing effect of an acute CLO challenge. CLO reportedly stimulates GH release via increased release of GH-releasing hormone (GHRH) from the hypothalamus. Based on these premises, in this study we investigated the possibility that repeated CLO administration may induce down-regulation of hypothalamic α 2 -adrenoceptors, involved in GH control, thus prohibiting the GH-releasing effect of the drug. α 2 -Adrenoceptor binding was determined in different brain regions of 10-day-old rats pretreated for 5 days with CLO (150 μg/kg, b.i.d.) and killed 14 h after last CLO administration. [ 3 H ]p- Aminoclonidine ( [ 3 H ] PAC ) was used as the specific ligand of α 2 -adrenoceptors. Treatment with CLO decreased by about 30% the maximum number of binding sites ( B max ) in areas of the mediobasal hypothalamus (MBH) involved in the stimulatory control of GH secretion, i.e. nucleus periventricularis arcuatus, nucleus ventromedialis hypothalami and nucleus lateralis hypothalami. Reduction of B max for [ 3 H]PAC binding was observed also in the nucleus periventricularis hypothalami, an area involved in the inhibitory control of GH secretion and, among extrahypothalamic areas, only in the cortex piriformis. In no brain areas was the affinity constant ( K d ) for [ 3 H ] PAC binding significantly changed after CLO pretreatment. Binding studies performed with a specific ligand of α 1 -adrenoceptors, [ 3 H ] prazosin , showed that the effect of CLO was specific since no changes in the B max or K d were present in either hypothalamic or extrahypothalamic regions. In these rats, which are refractory to the GH-releasing effect of CLO, an opioid peptide analogue, FK 33-824, which like CLO acts via release of GHRH from the hypothalamus, was still capable of eliciting a rise in plasma GH. In all, these data indicate that: (1) CLO-induced α 2 -adrenoceptor down-regulation in some hypothalamic nuclei may explain the refractoriness to the GH-releasing effect of an acute CLO challenge present in short-term CLO pretreated infant rats; (2) there is, likely, an opioidergic interneuron between α 2 -adrenergic and GHRH-secreting neurons.