Adraoui_2026_Neuropharmacol__110929

Treating schizophrenia (SZ) still represents a major remains highly challengeing for drug developmersnt companies. While available antipsychotics mostly reduce positive symptoms of SZ, their effects on cognitive deficits and their underlying pathophysiology remain insufficient and ill-defined. Disinhibition in SZ patients' cortex is considered a key player in the genesis of these symptoms and would result from N-methyl-D-aspartate receptor (NMDAr) hypofunction on interneurons. Besides, electroencephalography-based biomarkers of these mechanisms including spontaneous and evoked gamma oscillations have been highlighted. These strongly depend on NMDAr function, associate with symptoms and therefore represent relevant translational tools forSZ drug development. However, reversing these circuit abnormalities is challenging for the field and finding drugs engaging them recovering these parameters would therefore constitute a milestonemajor advancement. Here, we have tested three different pharmacologically distinct drugs whose mechanisms of action features attract scientists for restoration of excitation/inhibition balance: cariprazine (D2/D3 receptor partial agonist and 5-HT(2A) receptor antagonist), LY379268 (mGlur2/3 receptor agonist) and donepezil (acetylcholinesterase inhibitor). We investigated their effects on spontaneous oscillations and auditory steady-state responses (ASSR, measuring evoked gamma oscillations) in a rat model of SZ induced by MK-801, a selective NMDAr blocker. As expected,MK-801 increased locomotor activity, impaired spontaneous and evoked gamma oscillations and even altered spontaneous oscillations in delta, alpha and beta frequencies of male Sprague Dawley rats. Remarkably, both cariprazine and LY379268 normalized spontaneous gamma oscillations. Moreover,In addition, cariprazine also normalized alpha and beta waves and LY37926 selectively normalized corrected delta activity. Interestingly, only cariprazine mitigated produced a robust and partial normalization of the ASSR deficit. These results highlight shed new lights on potential pharmacological strategies focused on circuits dysfunction andsymptoms in SZ. These differential normalization profiles, including cariprazine's unique broad-spectrum signature, reveal distinct patterns of circuit engagement and provide a translational pharmaco-EEG framework for circuit-level target engagement in SZ drug development.