Effects of acute and repeated administration of citalopram on extracellular levels of serotonin in rat brain

The effects of acute (2 days) and repeated (21 days) administration (50 mg/kg in the diet) of the selective serotonin (5-HT, 5-hydroxytryptamine) reuptake inhibitor, citalopram, on extracellular levels of 5-HT and their modulation by terminal autoreceptors in the hypothalamus of freely moving rats were compared in vivo by microdialysis. When studied without washout, extracellular levels of 5-HT were increased by both acute and repeated citalopram administration. In rats treated repeatedly, extracellular 5-HT levels were 43% (but not significantly) greater than in those treated acutely. Extracellular levels of 5-HT in control and citalopram-treated rats were similar when measured after 24 h washout. The enhancing effect of non-selective serotonergic autoreceptor antagonists, methiothepin (100 mu M) or 1-(1-naphthyl)piperazine (NP) (10 mu M), administered through the microdialysis probe, after 24 h washout, was similar in both control and chronically treated groups. These results suggest that repeated administration of citalopram followed by a washout of 24 h does not lead to desensitization of the terminal autoreceptor as measured in vivo in contrast to the effects we have shown previously in vitro. In rats treated chronically with citalopram without washout, methiothepin had a greater maximal effect on 5-HT outflow in comparison to rats receiving acute citalopram treatment. This finding suggests that a 5-HT autoreceptor antagonist or a combination of such a drug with a 5-HT uptake inhibitor would produce a greater increase of extracellular levels of 5-HT in hyposerotonergic states such as depression.