Regulation of serotonin₂ (5-HT₂) receptors labeled with [³H]spiroperidol by chronic treatment with the antidepressant amitriptyline

Recently, we reported that chronic administration of several antidepressants of different classes produced larger reductions in numbers of serotonin₂ (5-HT₂) receptors in rat brain labeled by [³H]spiroperidol than in beta adrenergic receptors. In the present study, we examine detailed properties of 5-HT₂ receptor regulation by chronic treatment with amitriptyline. Chronic but not acute treatment with the tricyclic antidepressant amitriptyline reduces binding to 5-HT₂ receptors by [³H]spiroperidol and beta adrenergic receptor binding of [³H]dihydroalprenolol in brain membranes. The decrease is time-dependent, gradually reversible and represents a change in the number of binding sites with no alteration in drug affinites for 5-HT₂ receptors. The effect can be observed at daily doses of 2.5 mg/kg, similar to clinically effective doses in humans. At all doses and time intervals, the decrease in 5-HT₂ receptors is more marked than the concurrent change in total beta adrenergic receptor binding. The properties of 5-HT₂ receptor reduction after chronic antidepressant treatment indicate that this alteration could be associated with therapeutic response.