The effects of chronic treatment with amitriptyline and MDL 72394 on the control of 5-HT release in vivo.

The purpose of the experiments reported were to determine whether chronic treatment with either a monoamine oxidase (MAO) inhibitor or an uptake inhibitor would increase extracellular levels of 5-HT in vivo and whether such treatment resulted in a down-regulation of the 5-HT1B-mediated decrease in extracellular levels of 5-HT. Rats were given either saline, (E)-beta-fluoromethyline-m-tyrosine (MDL 72394 0.25 mg/kg p.o.) or amitriptyline (10 mg/kg p.o.) once a day for 21 days. Twenty-four hr after the final injection, dialysis loops were implanted into the frontal cortices of these rats and basal extracellular levels of 5-HT were measured. The effect of the 5-HT1 receptor agonist 5-methoxy-3(1,2,3,6-tetrahydropyridin-4-yl)1H indole succinate (RU 24969 10 mg/kg i.p.) on the extracellular level of 5-HT was then studied. Basal levels of 5-HT in saline-treated rats was found to be 27.9 +/- 3.9 fmol/20 microliters perfusate. Chronic treatment with amitriptyline had no effect on extracellular levels of 5-HT but chronic treatment with MDL 72394 significantly increased extracellular levels of 5-HT. Chronic treatment with either MDL 72394 or amitriptyline had no significant effect on the ability of RU 24969 to reduce extracellular levels of 5-HT. These results suggest that 5-HT1B receptors are not down-regulated in response to chronically raised extracellular levels of 5-HT.