5-HT(1A) and 5-HT(7) 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-HT₇ receptors (5-HT₇Rs) in passive avoidance learning by assessing emotional memory in male C57BL/6J mice. Additionally, 5-HT₇R binding affinity and 5-HT₇R-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_1AR antagonist NAD-299. This facilitation was blocked by the selective 5-HT₇R antagonist SB269970, revealing excitatory effects of the SSRI via 5-HT₇Rs. The enhanced memory retention by NAD-299 was blocked by SB269970, indicating that reduced activation of 5-HT_1ARs results in enhanced 5-HT stimulation of 5-HT₇Rs. The putative 5-HT₇R 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-HT₇R-activated signaling cascades. In contrast, increasing doses of the dual 5-HT_1AR/5-HT₇R 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-HT₇R activation by 8-OH-DPAT. Dorsohippocampal infusion of 8-OH-DPAT impaired passive avoidance retention through hippocampal 5-HT_1AR activation, while 5-HT₇Rs appear to facilitate memory processes in a broader cortico-limbic network and not the hippocampus alone.