Hippocampal 5-HT4/6 Receptor Antagonists Normalize Dopaminergic Dysfunction in a Rodent Model of Alzheimer’s Disease

Abstract Psychosis affects approximately 4 million Americans with Alzheimer’s disease (AD), yet safe and effective pharmacological treatments remain limited. The clinical utility of traditional antipsychotics is constrained by an FDA black box warning regarding increased mortality in the elderly. A potential mechanistic driver for these symptoms is hyperactivity in the ventral hippocampus (vHipp), a feature common to both AD and psychosis that has been shown in preclinical models to induce dopamine system dysregulation. This study explores the hypothesis that such hippocampal dysfunction is facilitated by aberrant serotonergic signaling. Clinical and preclinical studies suggest that activation of two serotonin-responsive G-protein-coupled receptors (GPCRs), 5-HT4R and 5-HT6R, in the hippocampus contributes to symptoms of psychosis in AD. Although targeting these receptors could provide therapeutic benefits, their widespread expression throughout the brain raises concerns about whether systemic administration would yield selective effects specifically in the hippocampus. To investigate this, we microinfused the selective 5-HT4 receptor antagonist (SB-204070) or the 5-HT6 receptor antagonist (PRX-07034) directly into the vHipp of TgWKY-AD and WKY-WT rats. Intra-vHipp blockade of either receptor reversed the pathological elevation of ventral tegmental area (VTA) dopamine neuron population activity; notably, these effects were fully recapitulated following systemic administration. We further demonstrated that 5-HT4R and 5-HT6R mRNA expressions in the vHipp and nucleus accumbens (NAc) are preserved in 12-month-old TgWKY-AD rats, suggesting that these targets remain viable as the disease progresses. Together, these findings identify systemic 5-HT4R or 5-HT6R antagonism as a viable therapeutic strategy to attenuate hippocampal hyperactivity and restore dopaminergic homeostasis, offering a mechanistically grounded and potentially safer alternative for managing psychosis in AD.