Memory of an operant response and of depressed mood retained in activation states of 5-HT(1A) receptors: evidence from rodent models.

Three series of studies were conducted to specify the role of 5-HT(1A) receptors in memory; using selective ligands that differentially activate 5-HT(1A) receptors, it was determined whether a change in the activation state of these receptors can lead to deficient retrieval, and whether a so-produced deficit can occur in an animal model of depression. First, in vitro studies of [35S]GTPgammaS binding responses identified ligands that differentially activate 5-HT(1A) receptors in rat hippocampus. WAY 100635, 8-OH-DPAT and flesinoxan induced 5-HT(1A) receptor activation that amounted to -2, +50 and +63%, respectively, of that produced by 5-HT. Second, we determined whether changes in the activation state of 5-HT(1A) receptors could impair the retrieval of an operant response in vivo. Rats treated with either a 5-HT(1A) receptor ligand or saline were trained to lever press for milk reward, and were then tested for retrieval with either the same or another treatment. Animals trained with 8-OH-DPAT retrieved the response when tested in the same state, but not when tested in the saline state, and vice versa. Rats trained with 0.16 mg/kg of 8-OH-DPAT also retrieved the response when tested with the other intermediate-efficacy ligand flesinoxan (0.63 mg/kg), but not when tested in a state of lower-magnitude activation (i.e. with 0.16 mg/kg of WAY 100635). Animals trained with 0.16 mg/kg of WAY 100635 retrieved the response when tested in this same state or with saline, but not when tested in a state of intermediate-magnitude activation (i.e. with 0.16 mg/kg of 8-OH-DPAT). Finally, studies using the forced swimming paradigm indicated that the retrieval of learned immobility was similarly dependent upon the activation state of 5-HT(1A) receptors. The findings indicate that changes in activation states of 5-HT(1A) receptors can impair the retrieval of learned responses. It is suggested that depression may in part be acquired in the course of ontogeny and may be available for retrieval in the same but not in other states; various biological rhythms conceivably define such states.