Studies on the Role of α2‐Adrenoceptors in the Control of Synaptosomal [3H]5‐Hydroxytryptamine Release: Effects of Antidepressant Drugs

Abstract

The sensitivity of α₂-adrenoceptors on 5-hydroxytryptamine (5-HT) nerve endings obtained from rat cerebral cortex was investigated following treatment with the antidepressant drugs desipramine (10 mg/kg/day for 21–28 days) or clorgyline (1 mg/kg/day for 21–28 days). [³H]5-HT (100 nM) was used to load cortical synaptosomes (P₂) after experiments with uptake inhibitors confirmed that this concentration of amine ensured exclusive uptake into 5-HT nerve terminals. The sensitivity of K⁺-stimulated release of [³H]5-HT to α₂-adrenoceptor occupancy was assessed in a superfusion system by means of the dose-dependent inhibition of [³H]5-HT release by clonidine. This is blocked by yohimbine (1 μM), which, when administered alone, enhances release, suggesting that endogenous catecholamines released from other synaptosomes act on these α₂-heteroreceptors. The effect of addition of citalopram (1 μM) to superfusates suggests that some reuptake of [³H]5-HT occurs during superfusion. Of the tritium released into superfusates during “background” and K⁺-stimulated release, 17 and 90%, respectively is [³H]5-HT. The attenuation of K⁺-stimulated release by clonidine is apparently diminished by the chronic clorgyline regimen but not by desipramine. However, clorgyline elevates catecholamine levels, and this might increase endogenous noradrenaline (NA) efflux, which by competition with clonidine could appear to alter α₂-adrenoceptor sensitivity. This possibility was investigated by depleting NA with the neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP4). These studies showed that the apparent effect of chronic clorgyline on α₂-adrenoceptor sensitivity to clonidine was due to competition with increased levels of endogenous NA. A significant decrease in sensitivity to clonidine occurred with DSP4 alone. This study with drugs from the two major classes of antidepressants suggests that antidepressant drugs do not alter α₂-heteroreceptors on serotonergic neurones.