Memory of an operant response and of depressed mood retained in activationstates of 5-HT1A receptors: evidence from rodent models

Three series of studies were conducted to specify the role of 5-HT1A recept ors in memory; using selective ligands that differentially activate 5-HT1A receptors, it was determined whether a change in the activation state of th ese receptors can lead to deficient retrieval, and whether a so-produced de ficit can occur in an animal model of depression. First, in vitro studies o f [S-35]GTP gammaS binding responses identified ligands that differentially activate 5-HT1A receptors in rat hippocampus. WAY 100635, 8-OH-DPAT and fl esinoxan induced 5-HT1A receptor activation that amounted to - 2, + 50 and + 63%, respectively, of that produced by 5-HT. Second, we determined whethe r changes in the activation state of 5-HT1A receptors could impair the retr ieval of an operant response in vivo. Rats treated with either a 5-HT1A rec eptor ligand or saline were trained to lever press for milk reward, and wer e then tested for retrieval with either the same or another treatment. Anim als trained with 8-OH-DPAT retrieved the response when tested in the same s tate, 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 whe n 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 re sponse when tested in this same state or with saline, but not when tested i n a state of intermediate-magnitude activation (i.e. with 0.16 mg/kg of 8-O H-DPAT). Finally, studies using the forced swimming paradigm indicated that the retrieval of learned immobility was similarly dependent upon the activ ation state of 5-HT1A receptors. The findings indicate that changes in acti vation states of 5-HT1A receptors can impair the retrieval of learned respo nses. 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 othe r states; various biological rhythms conceivably define such states. (C) 20 00 Elsevier Science B.V. All rights reserved.