Agonist-induced internalization of serotonin-1A receptors in the dorsal raphe nucleus (Autoreceptors) but not hippocampus (Heteroreceptors)

Serotonin-1A (5-HT1A) receptors in the CNS are a major target for psychotro pic drugs. In nucleus raphe dorsalis (NRD) and hippocampus (CA3), the selec tive 5-HT1A agonist (+)-8-hydroxy- 2-(di-N-propylamino) tetralin (8-OH-DPAT ) reduces the firing activity of serotoninergic (5-HT) and pyramidal neuron s, respectively. When located on 5-HT (autoreceptors), but not on non-5-HT (heteroreceptors) neurons, 5-HT1A receptors are known to be subject to dese nsitization. Using quantitative electron microscopy after pre-embedding imm unogold labeling with specific antibodies, we examined the subcellular dist ribution of these receptors after acute administration of 8-OH-DPAT (0.5 mg /kg, i.v.). Silver-intensified immunogold particles associated with the pla sma membrane or the cytoplasm were counted in somata and dendrites within t he NRD, 15 min, 1 hr and 24 hr after 8-OH-DPAT injection, and in hippocampa l dendrites 1 hr after the same treatment. Significant decrease in the dens ity of membrane labeling and concomitant increase of cytoplasmic labeling w ere demonstrated in the NRD, 15 min and 1 hr after 8-OH-DPAT administration , with a return to baseline level at 24 hr. Internalization was blocked by previous administration of the 5-HT1A antagonist N-[2-[4-(2-methoxyphenyl)- 1-piperazinyl]ethyl]-N-(2-pyridinyl) cyclohexane-carboxamide (WAY 100635), which, by itself, was without apparent effect. In hippocampus (CA3), there were no apparent changes in the distribution of the receptor after 8-OH-DP AT administration. These findings are in line with earlier results showing a desensitization of 5-HT1A autoreceptors but not heteroreceptors after tre atment with 5-HT1A receptor agonist. They suggest that this desensitization is the result of autoreceptor internalization.