Autoreceptors remain functional after prolonged treatment with a serotoninreuptake inhibitor

Serotonin (5-hydroxytryptamine, 5-HT) autoreceptors may desensitize during prolonged administration of antidepressant drugs. If autoreceptors desensit ize, their inhibitory influence on extracellular 5-HT should be attenuated. To test this hypothesis, the selective serotonin reuptake inhibitor (SSRI) citalopram (10 mg kg(-1), s.c., b.i.d.) or saline was administered for 14 days to rats. After a 24-h washout period, rats were anesthetized, and impl anted with dialysis probes for determination of 5-HT in the frontal cortex (FCx) and dorsal hippocampus (DH). In response to citalopram (5 mg kg(-1), s.c.) challenge, there were moderate increases in 5-HT in the FCx and DH of both the chronic citalopram and saline pretreatment groups. After subseque nt administration of the 5-HT1A/1B autoreceptor antagonist, (-)-penbutolol, there were further increases in 5-HT in the FCx and DH of the saline pretr eatment group. Moreover, contrary to the expected effect if autoreceptors w ere desensitized, the potentiation produced by (-)-penbutolol was greater i n the FCx and DI-I of the chronic citalopram group as compared to rats pret reated with saline. These results suggest that autoreceptors still restrain the increase in 5-HT produced by an SSRI after prolonged administration. ( C) 1999 Elsevier Science B.V. All rights reserved.