Induction of c-fos in rat forebrain by pharmacological manipulation of 5-hydroxytryptamine levels.
The immunocytochemical localization of the immediate-early gene c-fos has been used to map sites of neuronal activity in the rat brain associated with 5-hydroxytryptamine function. Behavioural studies have shown that brain 5-hydroxytryptamine function is increased by treatment of animals with a combination of the 5-hydroxytryptamine precursor L-tryptophan (100 mg/kg) and the monoamine inhibitor tranylcypromine (20 mg/kg). We now report that such treatment induces a specific anatomical pattern of expression of c-fos in rat forebrain in many limbic, striatal and cortical areas which corresponds well with the distribution of 5-hydroxytryptamine-immunoreactive terminals. To investigate further the involvement of 5-hydroxytryptamine in this response, we pretreated animals with the tryptophan hydroxylase inhibitor p-chlorophenylalanine and observed the effects on Fos-like immunoreactivity after L-tryptophan and tranylcypromine challenge. Two-day pretreatment with p-chlorophenylalanine (300 mg/kg) prior to tranylcypromine and L-tryptophan resulted in a significant attenuation of Fos-like immunoreactivity in specific brain areas, including the piriform and frontal cortices, nucleus accumbens, caudate-putamen, paraventricular hypothalamus and paraventricular thalamic nucleus. A marked reduction of the hyperactivity syndrome was also seen, as has been reported in earlier studies. The results of this study suggest that the elevation in Fos-like immunoreactivity following treatment with tryptophan and a monoamine oxidase inhibitor is mainly due to increased 5-hydroxytryptamine synthesis and release. It is well known that 5-hydroxytryptamine mediates mood and affect, and this study indicates potential brain loci of action of serotonergic drugs.
Oxford University-SmithKline Beecham Centre for Applied Neuropsychobiology, U.K.
J M
JM
Moorman
A
A
Jackson
D G
DG
Grahame-Smith
R A
RA
Leslie
D000818:Animals; D007150:Immunohistochemistry; D008297:Male; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology; D016548:Prosencephalon / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000378:metabolism*; D014191:Tranylcypromine / Q000494:pharmacology; D014364:Tryptophan / Q000494:pharmacology; D014365:Tryptophan Hydroxylase / Q000037:antagonists & inhibitors
D008996:Monoamine Oxidase Inhibitors; D016760:Proto-Oncogene Proteins c-fos; D012701:Serotonin; D014191:Tranylcypromine; D014364:Tryptophan; D014365:Tryptophan Hydroxylase