Bidirectional modulation of classical fear conditioning in mice by 5-HT(1A) receptor ligands with contrasting intrinsic activities.
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.
Youn
Jiun
J
Center for Neurogenomics and Cognitive Research (CNCR) and Neuroscience Campus Amsterdam, VU University Amsterdam, 1081 HV Amsterdam, The Netherlands.
Misane
Ilga
I
Eriksson
Therese M
TM
Millan
Mark J
MJ
Ogren
Sven Ove
SO
Verhage
Matthijs
M
Stiedl
Oliver
O
D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D001578:Benzopyrans / Q000494:pharmacology; D002491:Central Nervous System Agents / Q000494:pharmacology; D003214:Conditioning, Classical / Q000187:drug effects* / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D005239:Fear; D008024:Ligands; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D010879:Piperazines / Q000008:administration & dosage / Q000494:pharmacology; D017729:Presynaptic Terminals / Q000187:drug effects* / Q000502:physiology; D011725:Pyridines / Q000008:administration & dosage / Q000494:pharmacology; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism*; D058825:Serotonin 5-HT1 Receptor Agonists; D058829:Serotonin 5-HT1 Receptor Antagonists; D012702:Serotonin Antagonists / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000008:administration & dosage / Q000494:pharmacology; D013569:Synapses / Q000187:drug effects / Q000502:physiology; D013997:Time Factors
D001578:Benzopyrans; D002491:Central Nervous System Agents; D008024:Ligands; D010879:Piperazines; D011725:Pyridines; D058825:Serotonin 5-HT1 Receptor Agonists; D058829:Serotonin 5-HT1 Receptor Antagonists; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D044282:Receptor, Serotonin, 5-HT1A; C079549:4-(benzodioxan-5-yl)-1-(indan-2-yl)piperazine; C090413:N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; C108607:robalzotan