Anhedonia is frequently observed in Alzheimer's disease (AD) patients and is associated with a higher risk of cognitive decline and dementia, and it potentially serve as preclinical marker and psychopathological risk factor for AD. Current antidepressants show limited efficacy in anhedonia, highlighting a critical unmet medical need. In this study, APP/PS1 mice at 8 months of age exhibited...
bioRxivJune 3, 2026Shuo Yang, Ling-Jun Wang, Yunxiang Sun et al.
preprint
Abstract A deeper understanding of the targets and mechanisms of fast-acting antidepressants, exemplified by ketamine, remains indispensable for better therapeutic strategies and understanding depression. Beyond the canonical neuron-centric NMDAR inhibition hypothesis, brain opioid system and glia-mediated processes are increasingly implicated in ketamine’s antidepressant efficacy, yet their...
bioRxivJune 3, 2026Yanxia Liang, Lingjun Wang, Yajie Li et al.
preprint
Ketamine produces rapid antidepressant effects but is constrained by psychotomimetic properties and abuse potential. The ketamine metabolite (2R,6R)-hydroxynorketamine (HNK) shows antidepressant-like efficacy without N-methyl-D-aspartate receptor (NMDAR) blockade, yet its upstream targets remain unclear. Here we show that HNK potentiates hippocampal excitatory transmission and reverses...
Hallucinogens, including mescaline, psilocybin, and lysergic acid diethylamide (LSD), profoundly affect perception, cognition, and mood. All known drugs of this class are 5-HT(2A) receptor (2AR) agonists, yet closely related 2AR agonists such as lisuride lack comparable psychoactive properties. Why only certain 2AR agonists are hallucinogens and which neural circuits mediate their effects are...