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  • Title: Bidirectional modulation of classical fear conditioning in mice by 5-HT(1A) receptor ligands with contrasting intrinsic activities.
    Author: Youn J, Misane I, Eriksson TM, Millan MJ, Ogren SO, Verhage M, Stiedl O.
    Journal: Neuropharmacology; 2009; 57(5-6):567-76. PubMed ID: 19607850.
    Abstract:
    5-HT(1A) receptors are implicated in the modulation of cognitive processes including encoding of fear learning. However, their exact role has remained unclear due to contrasting contributions of pre- vs. postsynaptic 5-HT(1A) receptors. Therefore, their role in fear conditioning was studied in mice using the selective ligand S15535, which fully activates 5-HT(1A) autoreceptors, yet only weakly stimulates their postsynaptic counterparts. The effects of S15535 were compared to those of the full agonist 8-OH-DPAT and the selective antagonist NAD-299. 8-OH-DPAT dose-dependently (0.01-0.5 mg/kg) and markedly impaired both context- and tone-dependent fear conditioning, as determined by complementary measures of inactivity and freezing. 8-OH-DPAT-mediated impairments were blocked by pre-injection of the selective 5-HT(1A) antagonist WAY100635. S15535 (0.01-5.0 mg/kg) mimicked 8-OH-DPAT in predominantly impairing conditioned contextual fear, though with smaller effect size than 8-OH-DPAT, consistent with lower efficacy at postsynaptic 5-HT(1A) receptors. Furthermore, S15535 (1.0 mg/kg) tended to attenuate the impairment of fear conditioning by 8-OH-DPAT (0.3 mg/kg). In contrast, NAD-299 (0.3 and 1 mg/kg) facilitated contextual freezing. WAY100635 (0.3 mg/kg) prevented the impairment of contextual fear by S15535 (1 and 5 mg/kg), underpinning the role of 5-HT(1A) receptors in the actions of S15535. Collectively, these data indicate that 5-HT(1A) receptor ligands modulate fear conditioning in a bidirectional manner: activation of postsynaptic 5-HT(1A) sites exerts an inhibitory influence, whereas their blockade promote facilitation of fear conditioning. The results with S15535 underscore the importance of ligand efficacy in determining the actions of 5-HT(1A) receptor ligands in fear conditioning and other models of cognitive function.
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