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

Are (activity regulated, cytoskeleton associated protein) is an effector immediate early gene that is selectively localized in the neuronal dendrites. Elevation of brain 5-HT by the combined administration of the monoamine oxidase inhibitor, tranylcypromine (TCP, 5 mg/kg, i.p.), and the 5-HT precursor L-tryptophan (L-TP, 100 mg/kg, i.p.), increased Are mRNA abundance in the cingulate, orbital, frontal and parietal cortices as well as in the striatum 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 increased Are mRNA in the cortical and striatal areas. Depleting brain 5-HT with the tryptophan hydroxylase inhibitor, p-chlorophenylalanine (pCPA, 300 mg/kg, i.p. for two days), on the other hand, significantly attenuated the increase in Are mRNA induced by tranylcypromine and L-tryptophan (TCP/L-TP). Pretreatment with the 5-HT2 receptor antagonist ketanserin (2 mg/kg, i.p.) significantly attenuated the effect of TCP/L-TP in the cortex but only partially 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 the effect of DOI on Are expression. These data suggest that Are mRNA expression can be induced ill the cortex by increases in extracellular 5-HT and that 5-HT2 receptors play a major part in mediating such effects. Additional 5-HT receptors as well as other neurotransmitters may also be involved, particularly in the striatum and in CA1 subfield of the hippocampus. Overall, our data suggest that expression of Are mRNA is highly responsive to changes in brain 5-HT functions. and may provide a sensitive marker of postsynaptic 5-HT2(2A and 2C) receptor functions. (C) 2000 Elsevier Science Ltd. All rights reserved.