INTRANASAL MGLU<SUB>5</SUB>R NANOBODY ADMINISTRATION INDUCES SUSTAINED BEHAVIOURAL CHANGES CONSISTENT WITH ANTIPSYCHOTIC‑LIKE ACTIVITY

Nanobodies (Nbs) are single‑domain antibody fragments derived from camelids that have become valuable tools in structural biology, biosensing and molecular imaging. Their capacity to pharmacologically modulate G protein‑coupled receptors (GPCRs) positions them as innovative candidates for therapeutic development. Here, we investigated Nb43, a positive allosteric modulator of the metabotropic glutamate receptor 5 (mGlu5R), with the aim of evaluating its ability to penetrate the brain and modulate dopamine‑related behaviours relevant to neuropsychiatric disorders. Molecular imaging revealed no detectable Nb43 in the central nervous system (CNS) following intravenous administration, whereas limited CNS penetration was observed after intranasal delivery. In contrast, intracerebroventricular administration produced robust central effects, including reduced locomotor activity and enhanced haloperidol‑induced catalepsy. Notably, intranasal Nb43 also potentiated haloperidol‑induced catalepsy, and this behavioural modulation persisted for up to 48 hours, indicating long‑lasting central activity. Preliminary experiments further showed that intracerebroventricular Nb43 attenuated phencyclidine‑induced hyperlocomotion, an acute pharmacological model of psychosis. Together, these findings demonstrate that Nb43 can modulate dopaminergic function in vivo and produce behavioural outcomes consistent with antipsychotic‑like activity. Moreover, the ability of intranasally delivered Nb43 to exert sustained central effects underscores its translational potential and highlights nanobody‑based targeting of mGlu5R as a promising strategy for modulating dopaminergic dysregulation in neuropsychiatric disorders.