Release of [³H]‐amezinium from cortical noradrenergic axons: a model for the study of the α‐autoreceptor hypothesis

Abstract

[3H]-amezinium is taken up selectively into noradrenergic axons and their transmitter-storing vesicles and is released from these axons by action potentials. We used it as a non-a-adrenergic marker in order to study the a-adrenergic autoinhibition of noradrenaline release.2 Rat occipitocortical slices were preincubated with [3H]-amezinium 0.03 tLM and then superfused and stimulated electrically (3 Hz for 3 min). The stimulation-evoked overflow of tritium was measured in six groups of slices: from saline-pretreated rats; from saline-pretreated rats, the slices being exposed to exogenous noradrenaline before preincubation with [3H]-amezinium; from saline-treated rats, slices from which were exposed simultaneously to noradrenaline and cocaine before preincubation with [3H]-amezinium; from rats in which noradrenaline stores had been depleted by pretreatment with a-methyltyrosine (a-NMT); from a-MT-treated rats, the slices being exposed to noradrenaline before preincubation with [3H]-amezinium; and from a-MT-treated rats, slices from which were exposed to noradrenaline plus cocaine before preincubation with [3H]-amezinium. 3 The stimulation-evoked overflow of tritium, expressed as a percentage of the tritium content of the tissue, was 1.15% in slices from saline-pretreated rats, and was similar in slices from salinepretreated rats after exposure to noradrenaline or noradrenaline plus cocaine. It was 2.56 % in slices from a-MT-treated rats, 1.20% from a-MT-treated rats after exposure to noradrenaline, and 2.88% from a-MT-treated rats after exposure to noradrenaline plus cocaine. 4 Yohimbine 0.1 and 1 piM increased the stimulation-evoked overflow of tritium in slices from all groups of saline-pretreated rats and in those slices from a-MT rats that had been in contact with exogenous noradrenaline. Yohimbine did not change the evoked overflow in slices from a-MT rats that had not been exposed to noradrenaline, or had been exposed to noradrenaline plus cocaine. 5 Clonidine 0.01-1 LM decreased the stimulation-evoked overflow of tritium moderately in slices from saline-pretreated rats, markedly in slices from a-MT-treated rats, and moderately again when the latter slices had been exposed to noradrenaline.6 It is concluded that the action potential-evoked release of [3H]-amezinium as well as the modulation of this release by yohimbine and clonidine depend on the presence or absence of a-adrenergic autoinhibition caused by the co-secretion of noradrenaline. When there is co-secretion of noradrenaline, the evoked release of [3H]-amezinium is relatively small, yohimbine increases the release, and clonidine can cause only moderate inhibition. When there is no or very little cosecretion of noradrenaline, the evoked release of [3H]-amezinium is at least doubled, yohimbine causes no further increase and clonidine produces strong inhibition.

Effects of Antidepressant Drug Treatments on α2‐Adrenoceptor Control of [3H]Noradrenaline Release from Hypothalamic Synaptosomes

“…Potentiation of [3H]NA release by yohimbine suggests that released NA and [3H]NA present in the vicinity of the a2-adrenoceptors create a tonic background autoinhibition. The insensitivity of K+evoked release of ['HINA to yohimbine after chronic, but not acute, antidepressant treatment may indicate that changes in the composition ofbiophase NA levels are occumng during the course of drug administration: Hedler et al (1983) have demonstrated that a reduction in endogenous NA release abolishes the potentiating effects of yohimbine on 'H-amine release. The effect of chronic antidepressant drug regimens on the evoked release of endogenous NA is not known and requires investigation.…”

Role of Adenylate Cyclase in Presynaptic α2‐Adrenoceptor‐ and μ‐Opioid Receptor‐Mediated Inhibition of [3H]Noradrenaline Release from Rat Brain Cortex Slices

“…Accordingly, as observed previously with potassium-and veratrine-induced ['Hlnoradrenaline release from rat brain cortex slices (Wemer et al, 1982;Schoffelmeer and Mulder, 19836), the maximal (relative) inhibitory effect of the a,-adrenoceptor agonist clonidine on the electrically evoked release was strongly reduced upon exposure of the slices to 8bromo-cyclic AMP. Moreover, the maximal (relative) effect of phentolamine, which enhanced the electrically evoked release by antagonizing the inhibitory effect of released endogenous noradrenaline (Wemer et al, 1979;Hedler et al, 1983), was also strongly reduced. Apparently, presynaptic a,adrenoceptor efficacy is strongly reduced when the intracellular cyclic AMP concentration is raised in .…”