The 5-HT 2A receptor inverse agonist/antagonist volinanserin modulates motor outcomes and regulates lateral septum-prefrontal and lateral septum-hippocampal functional connectivity
Year: 2026
Type: article
Abstract: Background: Volinanserin is a 5-HT 2A receptor (5-HT 2A R) inverse agonist/antagonist with potential therapeutic value for schizophrenia. While there is evidence for efficacy of 5-HT 2A R targeting drugs in schizophrenia and other disorders, the impact of volinanserin on circuit-level brain function and connectivity remains unknown. Methods: Here, we test the impact of volinanserin on behaviours in mice relevant to a range of symptom domains in schizophrenia. To elucidate the brain networks regulated by volinanserin, and their relationship to behavioural outcomes, we also assess the impact on brain function, brain functional connectivity and the relationships between brain activity and behaviour. Results: Volinanserin selectively altered motor outcomes, decreasing locomotor activity, without affecting anxiety-like behaviour, compulsive-like repetitive behaviours and reward processing in mice. Moreover, no effect on learning and memory was detected. In terms of brain activity, volinanserin increased activity in the lateral septum (LS), dorsal raphé and nucleus accumbens, while reducing activity in the prefrontal cortex (PFC). Volinanserin also reduced LS functional connectivity with the PFC, hippocampus and amygdala. In volinanserin-treated animals, but not vehicle controls, LS activity was related to motor outcomes. Conclusions: These data show that volinanserin selectively modifies motor outcomes in mice that have translational relevance to the positive symptoms present in patients with schizophrenia, with these behavioural effects being associated with altered LS function and connectivity. These data highlight the LS as a key locus of action for volinanserin’s putative antipsychotic effects and support a role for this region in mediating the behavioural impact of 5-HT 2A R targeting drugs.
Source: Journal of Psychopharmacology
Institution: Lancaster University
Language: English
Subfield: Psychiatry and Mental health
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $4,400
OpenAlex ID: W7225751076