The physiological importance of brain alpha 2-adrenoceptors in controlling the activity of tyrosine hydroxylase in noradrenergic regions was investigated using the accumulation of 3,4-dihydroxyphenylalanine (DOPA) after decarboxylase inhibition as a measure of the rate of tyrosine hydroxylation (and synthesis of noradrenaline) in vivo. In the hypothalamus and cerebral cortex, clonidine (0.025-1 mg/kg, i.p.) decreased (18%-43%) and idazoxan (0.1-80 mg/kg, i.p.) increased (20%-73%) the synthesis of DOPA in a dose-dependent manner. Moreover, pretreatment with idazoxan (0.1 mg/kg) antagonized the effect of clonidine (0.1 mg/kg) in the hypothalamus. After treatment with reserpine (5 mg/kg, s.c., 18 h before decapitation) and depletion of noradrenaline, clonidine (0.5 mg/kg) continued to decrease (50%-55%) but idazoxan (20 mg/kg) failed to increase the synthesis of DOPA, which suggested the involvement of an alpha-auto-receptor mechanism. Acute treatments of rats (not exposed to reserpine) with a wide variety of adrenoceptor agonists such as guanfacine 6, B-HT920, xylazine, bromoxidine (1 mg/kg) and antagonists such as yohimbine, phentolamine, prazosin (10 or 20 mg/kg) resulted in significant decreases (15%-55%) or increases (21%-99%) in the synthesis of DOPA in both brain regions. However, other agonists (oxymetazoline, azepexole, tramazoline, methoxamine) and antagonists (tolazoline, dihydroergotamine, phenoxybenzamine, propranolol) did not modify the synthesis of DOPA. In the hypothalamus and cerebral cortex the effects of the drugs were consistent with the selectivity of alpha-adrenoceptor agonists and antagonists (except prazosin) for an alpha 2-adrenoceptor. The results also suggest that the alpha 2-autoreceptor that modulates the synthesis of noradrenaline in the rat brain appears to belong to the prazosin-sensitive alpha 2B-subtype.
SUMMARY [3H]noradrenaline ([3H]NA) uptake studies were carried out in cat hypogastric nerves ligated in vivo, 2 cm distal to the inferior mesenteric ganglion, for different time periods. Atria from the same animals served as controls to determine the uptake of the amine by the U1 uptake system present in noradrenergic nerve terminals.2. The net uptake of [3H]NA by hypogastric nerves increased with time of ligation, reaching a maximum 24 h after ligation in the segment of nerve immediately proximal to the ligature (PI segment, neurosome). No further increase in uptake was observed at 48 or 72 h. Segments distal (D1) to the ligature also retained significant amounts of [3H]NA. In both cases the uptake was blocked by cocaine (3 #M).3. Reserpine pre-treatment (2 mg/kg I.M.) markedly decreased the endogenous NA content to 1-2 % ofuntreated cats and the net uptake of [3H]NA was lowered to 25 % both in cat hypogastric nerve and atria. The uptake was further decreased in the presence of cocaine (3 #M).4. 6-Hydroxydopamine (100 ,IM) did not modify the [3H]NA uptake by ligated cat hypogastric nerves but almost abolished the [3H]NA net uptake by right atria from the same animals. After collagenase pre-treatment (0 05 % for 15 min) the net uptake of [3H]NA was not altered in the atrium. However, collagenase-pre-treated ligated nerves, took up almost twice as much [3H]NA; under these conditions, 6-hydroxydopamine produced a marked decrease in [3H]NA net uptake. These data suggest the presence in the perineurium of a diffusion barrier for very polar substances, including 6-hydroxydopamine.5. In conclusion, our data demonstrate that the cat hypogastric nerve ligated in vivo has a cocaine-sensitive system for NA uptake which resembles the NA uptake mechanism (U1) present in noradrenergic nerve terminals. Our data further support the view that the ligated cat hypogastric nerve (neurosome) could be considered as a model of noradrenergic nerve terminal free of effector cell.
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