p-Chlorophenylalanine and fluoxetine inhibit D-fenfluramine-induced Fos expression in the paraventricular nucleus, cingulate cortex and frontal cortex but not in other forebrain and brainstem regions.

D-Fenfluramine, a putative serotonin releaser and reuptake inhibitor, is commonly prescribed for the treatment of obesity. Brain sites activated by D-fenfluramine have been mapped via the expression of the immediate early gene Fos. However, it is not clear that serotonin release in the brain mediates the effects of D-fenfluramine on Fos expression. The present study determined whether D-fenfluramine induces the expression of Fos in the brain through the release of serotonin. Rats were pretreated either with the serotonin depleting drug p-chlorophenylalanine (PCPA) or with the serotonin reuptake inhibitor fluoxetine. Both drugs inhibited D-fenfluramine-induced Fos expression in the cingulate cortex, frontal cortex, and the parvocellular subdivision of the paraventricular nucleus of the hypothalamus. Neither drug reduced D-fenfluramine-induced Fos responses in several other brain areas, including the caudate-putamen, amygdala, and brainstem regions such as the lateral parabrachial nucleus and nucleus of the solitary tract. These results indicate regional specificity of mechanisms mediating D-fenfluramine-induced Fos expression. It is likely that D-fenfluramine-induced Fos expression at various sites in the brain is mediated via a combination of serotonin release and other, as yet unidentified, neurotransmitters.