Effect of serotonin depletion on 5-HT2A-mediated learning in the rabbit: evidence for constitutive activity of the 5-HT2A receptor in vivo

Rationale Associative learning during Pavlovian eyeblink conditioning has been shown to be regulated by 5-HT_2A receptors. The existence of inverse agonists that retard learning through an action at the 5-HT_2A receptor suggests the existence of constitutive activity at that receptor and that depletion of serotonin should have minimal effects on learning. Objectives We examined whether depletion of serotonin would impair trace eyeblink conditioning or the enhancement of conditioning produced by the agonist lysergic acid diethylamide (LSD) and the retardation of conditioning produced by the inverse agonist MDL11,939. Methods Animals received bilateral intraventricular injections of 5,7-dihydroxytryptamine (5,7-DHT) at doses of 760 or 1,140 μg/side (1.88 or 2.82 μmol/side) and were later exposed to eight daily conditioning sessions. Results Serotonin depletion produced by the lower dose of 5,7-DHT was 71 and 72% in cortex and hippocampus, respectively, with no change in 5-HT_2A receptor density, no effect on learning, and no effect on the ability of LSD to enhance and MDL11,939 to retard learning. The higher dose of 5,7-DHT produced serotonin decreases of 85 and 90% in cortex and hippocampus, respectively, accompanied by a 96% decrease in the density of the serotonin transporter, but no significant effect on learning. Conclusions Pavlovian trace eyeblink conditioning is regulated predominantly by the constitutive activity of the 5-HT_2A receptor rather than by serotonin release onto the receptor during learning. It was suggested that the 5-HT_2A receptor regulates learning by modulating the release of dopamine, acetylcholine, and glutamate, transmitters known to affect eyeblink conditioning.