Selective remodeling of rabbit frontal cortex:: relationship between 5-HT2A receptor density and associative learning

Rationale. Associative learning during classical trace eyeblink conditioning has been shown to be regulated by serotonin 5-HT2A receptors and to be critically dependent on the integrity of frontal cortex. Chronic administration of 5-HT2A ligands has been shown to produce a selective up- or down-regulation of 5-HT2A receptors in frontal cortex. Objectives. We examined whether alterations in 5-HT2A receptor density had a functional significance with respect to associative learning. Methods. Animals received chronic injections of LSD, BOL or MDL11,939 and 1 day later began classical trace conditioning of the eyeblink response. Results. The density of 5-HT2A receptors in frontal cortex was significantly increased at 1-4 days after the cessation of chronic injections of the selective 5-HT2A receptor ligand MDL11,939. Rabbits demonstrated an enhancement of associative learning when training began at 1 day after cessation of chronic MDL11,939 injections, but acquired at the same rate as controls when training began at 8 days after cessation of injections, a time when receptor density had returned to control levels. Animals that began training 1 day after chronic injections of BOL or LSD, drugs that produce decreases in 5-HT2A receptor density, demonstrated normal rates of acquisition. Conclusions. These results indicate that increases in the density of 5-HT2A receptors in frontal cortex are associated with increases in the rate of associative learning, and further support an important role for this receptor in cortical circuitry that mediates learning. More generally, these results suggest an approach for functional remodeling of brain regions in the adult animal.