5-HT1A and 5-HT7 receptor crosstalk in the regulation of emotional memory: implications for effects of selective serotonin reuptake inhibitors.
This study utilized pharmacological manipulations to analyze the role of direct and indirect activation of 5-HT(7) receptors (5-HT(7)Rs) in passive avoidance learning by assessing emotional memory in male C57BL/6J mice. Additionally, 5-HT(7)R binding affinity and 5-HT(7)R-mediated protein phosphorylation of downstream signaling targets were determined. Elevation of 5-HT by the selective serotonin reuptake inhibitor (SSRI) fluoxetine had no effect by itself, but facilitated emotional memory performance when combined with the 5-HT(1A)R antagonist NAD-299. This facilitation was blocked by the selective 5-HT(7)R antagonist SB269970, revealing excitatory effects of the SSRI via 5-HT(7)Rs. The enhanced memory retention by NAD-299 was blocked by SB269970, indicating that reduced activation of 5-HT(1A)Rs results in enhanced 5-HT stimulation of 5-HT(7)Rs. The putative 5-HT(7)R agonists LP-44 when administered systemically and AS19 when administered both systemically and into the dorsal hippocampus failed to facilitate memory. This finding is consistent with the low efficacy of LP-44 and AS19 to stimulate protein phosphorylation of 5-HT(7)R-activated signaling cascades. In contrast, increasing doses of the dual 5-HT(1A)R/5-HT(7)R agonist 8-OH-DPAT impaired memory, while co-administration with NAD-299 facilitated of emotional memory in a dose-dependent manner. This facilitation was blocked by SB269970 indicating 5-HT(7)R activation by 8-OH-DPAT. Dorsohippocampal infusion of 8-OH-DPAT impaired passive avoidance retention through hippocampal 5-HT(1A)R activation, while 5-HT(7)Rs appear to facilitate memory processes in a broader cortico-limbic network and not the hippocampus alone.
Laboratory of Translational Neuropharmacology, Center of Molecular Medicine, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
Therese M
TM
Eriksson
Sarah
S
Holst
Tiberiu L
TL
Stan
Torben
T
Hager
Benita
B
Sjögren
Sven Öve
SÖ
Ogren
Per
P
Svenningsson
Oliver
O
Stiedl
D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects; D051926:Basigin / Q000187:drug effects / Q000502:physiology*; D015153:Blotting, Western; D004644:Emotions / Q000187:drug effects / Q000502:physiology*; D005239:Fear / Q000187:drug effects / Q000502:physiology; D005473:Fluoxetine / Q000494:pharmacology; D006367:HeLa Cells; D006339:Heart Rate / Q000187:drug effects; D006624:Hippocampus / Q000378:metabolism / Q000502:physiology; D006801:Humans; D008297:Male; D008568:Memory / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D010766:Phosphorylation; D011869:Radioligand Assay; D020239:Receptor Cross-Talk / Q000187:drug effects / Q000502:physiology*; D044282:Receptor, Serotonin, 5-HT1A / Q000187:drug effects / Q000502:physiology*; D012701:Serotonin / Q000378:metabolism; D012702:Serotonin Antagonists / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*; D013238:Stereotaxic Techniques; D013379:Substrate Specificity
D051926:Basigin; D005473:Fluoxetine; D044282:Receptor, Serotonin, 5-HT1A; D012701:Serotonin; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D017367:Selective Serotonin Reuptake Inhibitors; C497887:Bsg protein, mouse