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

Abstract

KCl (16 mM) stimulated the release of [3H]noradrenaline ([3H]NA) from rat hypothalamic synaptosomes in a Ca2+-dependent manner; this release was attenuated by clonidine (0.01-100 microM). Changes in the release of [3H]NA and the functional status of alpha 2-adrenoceptors in the medial hypothalamus of rats treated acutely and chronically with clorgyline (1 mg/kg/day) or desipramine (DMI, 10 mg/kg/day) were assessed using superfused synaptosomes in which the attenuating effects of clonidine (1 microM) or the potentiating effects of yohimbine (1 microM) on K+-evoked release of [3H]NA were measured. After acute administration of DMI, significantly less [3H]NA was accumulated into synaptosomes. Although total (spontaneous + K+-evoked) [3H]NA release from these synaptosomes was unchanged, a significant reduction was apparent in the K+-evoked release from the DMI-treated tissue. Attenuation of K+-evoked release by clonidine was abolished in both these acute treatment groups. Following the chronic antidepressant drug regimens, [3H]NA uptake into DMI-treated tissue remained significantly reduced although total percent and K+-evoked [3H]NA release were unchanged. The K+-evoked release of [3H]NA in S1 was significantly enhanced (by 22%) in the clorgyline treatment group. Attenuation of K+-evoked [3H]NA release by clonidine in both chronic antidepressant-treated tissues was not significantly changed. It is concluded that the functional sensitivity of alpha 2-adrenoceptors on nerve endings in the medial hypothalamus is unchanged by these chronic antidepressant drug regimens. In synaptosomes from untreated tissue, yohimbine significantly potentiated K+-evoked release of [3H]NA; this effect was unchanged after acute regimens and reduced after chronic administration of both the antidepressants.(ABSTRACT TRUNCATED AT 250 WORDS)

Activation and desensitization by cyclic antidepressant drugs of α2-autoreceptors, α2-heteroreceptors and 5-HT1A-autoreceptors regulating monoamine synthesis in the rat brain in vivo

“…Chronic desipramine also has been shown to induce desensitization of postsynaptic α 2 -adrenoceptors mediating mydriasis in rats (Menargues et al 1990) and that of α 2A -adrenoceptors in platelets of depressed patients ). In contrast, chronic desipramine did not induce desensitization of α 2 -adrenoceptors regulating the release of noradrenaline from rat hypothalamic synaptosomes (McWilliam and Campbell 1987). The present results also demonstrate the induction of desensitization of presynaptic α 2A -heteroreceptors modulating 5-HTP/5-HT synthesis in the cerebral cortex, but not in hippocampus, since the ability of clonidine to decrease this synthesis in the cerebral cortex also was markedly attenuated after chronic treatment with desipramine.…”

Desensitization of α₂-Adrenoceptors which Regulate Noradrenaline Synthesis and Release after Chronic Treatment with Clorgyline in the Rat Brain

“…However, not all results support these findings, as in some studies there has been no desensitization of · 2 -adrenoceptors after chronic treatment with antidepressants [11][12][13][14][15].…”

“…A possible explanation for this could be that the hypothalamic · 2 -adrenoceptors either respond less to increased endogenous neurotransmitter availability or take longer to downregulate than do those from the other two regions. In this context, in another study in which the same methodology as that of ours was used, no change in the · 2 -adrenoceptor sensitivity was found after an even longer treatment with clorgyline [15].…”

“…Moreover, the few studies which have evaluated the modulation of the · 2 -adrenoceptors which regulate noradrenaline release following chronic treatment with this MAO-A inhibitor have provided conflicting results. In some studies no changes were found in the sensitivity of these adrenoceptors [14,15,22], whilst in others there was a reduction in the · 2 -adrenoceptor-mediated response in different brain regions [23,24].…”

Effects of N‐(2‐chloroethyl)‐N‐ethyl‐2‐bromobenzylamine (DSP4) on α2‐Adrenoceptors which Regulate the Synthesis and Release of Noradrenaline in the Rat Brain

“…However, it has been demonstrated that the inhibitory effect induced by the activation of a 2 -adrenoceptors does not depend on [ 3 H]NA accumulation (Schoffelmeer & Mulder 1982;Campbell & McKernan 1986;McWilliam & Campbell 1987). These findings rule out the possibility that the sensitivity of a 2 -adrenoceptors which modulate NA release is affected by the diminished uptake of [ 3 H]NA.…”