Biased 5-HT_1A receptor agonists F13714 and NLX-101 differentially affect pattern separation and neuronal plasticity in rats after acute and chronic treatment

Pattern separation is a hippocampal process in which highly similar stimuli are recognized as separate representations, and deficits could lead to memory impairments in neuropsychiatric disorders such as schizophrenia. The 5-HT^1A receptor (5-HT_1AR) is believed to be involved in these hippocampal pattern separation processes. However, in the dorsal raphe nucleus (DRN), the 5-HT_1AR is expressed as a somatodendritic autoreceptor, negatively regulates serotonergic signaling, and could thereby counteract the effects of hippocampal postsynaptic 5-HT_1A receptors. Therefore, this study aims to identify how pre- and post-synaptic 5-HT_1AR activity affects pattern separation. Object pattern separation (OPS) performance was measured in male Wistar rats after both acute and chronic treatment (i.p.) with 5-HT_1AR biased agonists F13714 (0.0025 mg/kg acutely, 0.02 mg/kg/day chronically) or NLX-101 (0.08 mg/kg acutely, 0.32 mg/kg/day chronically), which preferentially activate autoreceptors or postsynaptic receptors respectively, for 14 days. Body temperature - a functional correlate of hypothalamic 5-HT_1AR stimulation - was measured daily. Additionally, 5-HT_1AR density (DRN) and plasticity markers (hippocampus) were assessed. Acute treatment with F13714 impaired OPS performance, whereas chronic treatment normalized this, and a drop in body temperature was found from day 4 onwards. NLX-101 enhanced OPS performance acutely and chronically, and caused an acute drop in body temperature. Chronic NLX-101 treatment increased doublecortin positive neurons in the dorsal hippocampus, while chronic treatment with F13714 resulted in a downregulation of 5-HT_1A autoreceptors, which likely reversed the acute impairment in OPS performance. Chronic treatment with NLX-101 appears to have therapeutic potential to improve brain plasticity and OPS performance.