Effects of acute and chronic administration of fluoxetine on the activity of serotonergic neurons in the dorsal raphe nucleus of the rat.

The gradual recovery of activity of serotonergic neurons following an initial inhibition has been hypothesized to play an important role in the delayed onset of efficacy of selective serotonin reuptake inhibitors. This study explored the clinical relevance of this hypothesis by examining the effects of different doses and routes of administration of fluoxetine on the recovery of activity of serotonergic neurons over the course of a 21-day exposure. Single-unit, extracellular recordings of serotonergic neurons were made in the dorsal raphe nucleus of anesthetized male rats. Acute i.v., s.c. and i.p. administration of fluoxetine inhibited the activity of serotonergic neurons. With chronic administration of fluoxetine, at clinically relevant doses, the activity of serotonergic neurons gradually recovered to baseline levels over the course of 14-21 days. The dose of fluoxetine (5, 10 or 20 mg/kg per day) did not make a significant difference in the time course of the recovery of activity of serotonergic neurons. A significant, non-parallel shift in the dose-response curve of serotonergic neurons to the serotonin-1A (5-HT1A) agonist 8-OH-DPAT occurred over the 21 days of treatment with fluoxetine, indicating a desensitization of the 5-HT1A receptor during this period. The recovery of firing did not correlate with either plasma or cerebrospinal fluid levels of fluoxetine or norfluoxetine. These results indicate that, similar to the effects of dose on the speed of onset of the clinical effects of SSRIs, increasing the dose of fluoxetine does not hasten the recovery of firing of serotonergic neurons during chronic administration. These results support the hypothesis that desensitization of the 5-HT1A receptor and consequent recovery of firing of 5-HT cells in the dorsal raphe nucleus plays a role in the delayed therapeutic onset of fluoxetine.