Differential Effects of Aripiprazole on Electroencephalography-Recorded Gamma-Band Auditory Steady-State Response, Spontaneous Gamma Oscillations and Behavior in a Schizophrenia Rat Model.

The available antipsychotics for schizophrenia (SZ) only reduce positive symptoms and do not significantly modify SZ neurobiology. This has raised the question of the robustness and translational value of methods employed during drug development. Electroencephalography (EEG)-based measures like evoked and spontaneous gamma oscillations are considered robust translational biomarkers as they can be recorded in both patients and animal models to probe a key mechanism underlying all SZ symptoms: the excitation/inhibition imbalance mediated by N-methyl-D-aspartate receptor (NMDAr) hypofunction. Understanding the effects of commercialized atypical antipsychotics on such measures could therefore contribute to developing better therapies for SZ. Yet, the effects of such drugs on these EEG readouts are unknown. Here, we studied the effect of the atypical antipsychotic aripiprazole on the gamma-band auditory steady-state response (ASSR), spontaneous gamma oscillations and behavioral features in a SZ rat model induced by the NMDAr antagonist MK-801. Interestingly, we found that aripiprazole could not normalize MK-801-induced abnormalities in ASSR, spontaneous gamma oscillations or social interaction while it still improved MK-801-induced hyperactivity. Suggesting that aripiprazole is unable to normalize electrophysiological features underlying SZ symptoms, our results might explain aripiprazole's inefficacy towards the social interaction deficit in our model but also its limited efficacy against social symptoms in patients.

Validation of a New Scoring Scale for Behavioral Assessment of L-Dopa-Induced Dyskinesia in the Rat: A New Tool for Early Decision-Making in Drug Development.

The 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated nonhuman primate (NHP) has been described as the most translatable model for experimental reproduction of L-dopa-induced dyskinesia (LID). However, from a drug discovery perspective, the risk associated with investment in this type of model is high due to the time and cost. The 6-hydroxydopamine (6-OHDA) rat dyskinesia model is recommended for testing compounds but relies on onerous, and nonstandard behavioral rating scales. We sought to develop a simplified and sensitive method aiming at assessing LID in the rat. The purpose was to validate a reliable tool providing earlier insight into the antidyskinetic potential of compounds in a time/cost-effective manner before further investigation in NHP models. Unilaterally 6-OHDA-lesioned rats were administered L-dopa (20 mg/kg) and benserazide (5 mg/kg) daily for 3 weeks starting 4 weeks postlesion, then coadministered with amantadine (20-30-40 mg/kg). An adapted rating scale was used to score LID frequency and a severity coefficient was applied depending on the features of the observed behavior. A gradual increase (about 3-fold) in LID score was observed over the 3 weeks of L-dopa treatment. The rating scale was sensitive enough to highlight a dose-dependent amantadine-mediated decrease (about 2.2-fold) in LID score. We validated a simplified method, able to reflect different levels of severity in the assessment of LID and, thus, provide a reliable tool for drug discovery.