Serotonergic regulation of mRNA expression of Arc, an immediate early geneselectively localized at neuronal dendrites

Are (activity regulated, cytoskeleton associated protein) is an effector im mediate early gene that is selectively localized in the neuronal dendrites. Elevation of brain 5-HT by the combined administration of the monoamine ox idase inhibitor, tranylcypromine (TCP, 5 mg/kg, i.p.), and the 5-HT precurs or L-tryptophan (L-TP, 100 mg/kg, i.p.), increased Are mRNA abundance in th e cingulate, orbital, frontal and parietal cortices as well as in the stria tum but a reduction was observed in the CA1 region of the hippocampus. The 5-HT releasing agent p-chloroamphetamine (PCA, 5 mg/kg, s.c.) also increase d Are mRNA in the cortical and striatal areas. Depleting brain 5-HT with th e tryptophan hydroxylase inhibitor, p-chlorophenylalanine (pCPA, 300 mg/kg, i.p. for two days), on the other hand, significantly attenuated the increa se in Are mRNA induced by tranylcypromine and L-tryptophan (TCP/L-TP). Pret reatment with the 5-HT2 receptor antagonist ketanserin (2 mg/kg, i.p.) sign ificantly attenuated the effect of TCP/L-TP in the cortex but only partiall y in striatum and did not affect the reduction in the CA1 region. The 5-HT2 agonist DOI (0.2, 1 and 2 mg/kg, i.p.) dose-dependently increased Are mRNA abundance in cortical areas with a pattern similar to that of TCP/L-TP and PCA. DOI, however, had much weaker effects on Are mRNA in the striatum and did not have any significant effect in the CA1, CA3 and the dentate gyrus (DG) of the hippocampus. Pretreatment with ketanserin completely blocked th e effect of DOI on Are expression. These data suggest that Are mRNA express ion can be induced ill the cortex by increases in extracellular 5-HT and th at 5-HT2 receptors play a major part in mediating such effects. Additional 5-HT receptors as well as other neurotransmitters may also be involved, par ticularly in the striatum and in CA1 subfield of the hippocampus. Overall, our data suggest that expression of Are mRNA is highly responsive to change s in brain 5-HT functions. and may provide a sensitive marker of postsynapt ic 5-HT2(2A and 2C) receptor functions. (C) 2000 Elsevier Science Ltd. All rights reserved.