Long-term treatment with clonidine and alpha-receptors in the brain of normotensive rats.
The aim of the present study was to investigate whether or not changes in rat brain alpha-adrenoceptors take place during chronic treatment with a low dose of clonidine. Male Wistar normotensive rats were treated with clonidine (0.1 mg/kg)i.p. twice daily for 12 days. This treatment caused a significant increase in [3H]clonidine and in [3H]WB4101 binding, respectively, to alpha 2- and to alpha 1-adrenoceptors of the frontal cortex; the levels were 30% for [3H]clonidine and 20% for [3H]WB4101. The Scatchard analysis of data obtained in binding studies indicated that the enhanced binding of two ligands to membranes prepared from chronically clonidine-treated animals, was due to an apparent increase in the number of binding sites. These changes were seen 4 h after administration of the last treatment, before the appearance of the withdrawal syndrome. However, noradrenergic alpha 2-autoreceptors of synaptosomes, from the frontal cortex and hypothalamus of treated animals, were sensitive to the regulatory action of clonidine or of noradrenaline on the [3H]noradrenaline overflow elicited by high K+ as well as on the control animals. On the contrary, the alpha 2-receptors on the serotoninergic nerve terminals from the frontal cortex of treated animals were more sensitive than those of control animals to the action of clonidine or of noradrenaline in counteracting the [3H]5-hydroxytryptamine overflow elicited by high K+. These results suggest that during treatment with clonidine no autoreceptor hyposensitivity to the regulatory action of clonidine or noradrenaline on [3H]noradrenaline overflow elicited by high K+ takes place, but, as a consequence of the diminished noradrenaline availability at the synaptic cleft, the binding of [3H]WBA101 to alpha 1-receptors and of [3H]clonidine to pre- and postsynaptic alpha 2-receptors were significantly elevated in the frontal cortex, a brain areas where the alpha-2-receptors are mainly postsynaptic. Thus, the neurotransmitter concentration in the synaptic cleft may be responsible for the trans-synaptic modulation of the alpha 2-adrenoceptor postsynaptic population. In fact, the alpha 2-adrenoceptors which are presynaptically located on the serotoninergic terminals, but are postsynaptic in relation to the noradrenergic neurons, also show increased sensitivity after chronic clonidine treatment.
D000818:Animals; D003000:Clonidine / Q000494:pharmacology*; D004146:Dioxanes / Q000378:metabolism; D005625:Frontal Lobe / Q000187:drug effects*; D007031:Hypothalamus / Q000187:drug effects*; D008297:Male; D009638:Norepinephrine / Q000502:physiology; D051381:Rats; D011919:Rats, Inbred Strains; D011942:Receptors, Adrenergic, alpha / Q000187:drug effects* / Q000378:metabolism; D012701:Serotonin / Q000502:physiology; D009435:Synaptic Transmission / Q000187:drug effects; D013574:Synaptosomes / Q000378:metabolism
D004146:Dioxanes; D011942:Receptors, Adrenergic, alpha; D012701:Serotonin; C010654:(2-(2',6'-dimethoxy)phenoxyethylamino)methylbenzo-1,4-dioxane; D003000:Clonidine; D009638:Norepinephrine