High- Dose Agomelatine Combined to Haloperidol Decanoate Improves Cognition, Downregulating MT2 , Against Upregulating D5 , Maintaining Krüppel- Like Factor 9 , Though Alters Cardiac Electrophysiology.

Haloperidol decanoate (HD) was implicated in cognitive impairment. Agomelatine (AGO) was claimed to improve cognition. We aimed at investigating the effects of HD + low- or high- dose AGO on cognition, verifying the melatonergic/dopaminergic-to-the cholinergic hypothesis of cognition and exploring relevant cardiovascular issues in adult male Wistar albino rats. HD + high- dose AGO prolonged the step through latency by +61.47% ( ρ < 0.0001), increased the time spent in bright light by +439.49% ( ρ < 0.0001) , reduced the time spent in dim light by -66.25% ( ρ < 0.0001) , and increased the percent of alternations by +71.25% ( ρ < 0.0001), despite the reductions in brain acetylcholine level by -10.67%, ( ρ < 0.0001) Neurodegeneration was minimal, while the mean power frequency of source wave was reduced by -23.39% ( ρ < 0.05). Concurrently, the relative expression of brain melatonin type-2 receptors was reduced by -18.75% (ρ < 0.05) , against increased expressions of dopamine type- 5 receptors by +22.22% ( ρ < 0.0001 ) and angiopoietin-like 4 by +119.18% ( ρ < 0.0001 ). Meanwhile, ECG demonstrated inverted P wave and reduced P wave duration by -36.15% ( ρ < 0.0001) and PR interval by -19.91% ( ρ < 0.0001) , prolonged RR interval by +27.97% ( ρ < 0.05) , increased R wave amplitude by +523.15% ( ρ < 0.0001) , a depressed ST segment and inverted T wave. In rats administered AGO, HD, or HD+ low- dose AGO, Alzheimer's disease-like neuropathologic features were more evident, accompanied by extensive ECG and neurochemical alterations. HD + high- dose AGO enhances cognition but alters cardiac electrophysiology. Significance Statement Given the issue of cognitive impairment associated with haloperidol decanoate (HD) and the claimed cognitive enhancing activity of agomelatine (AGO), combined high- dose AGO to HD improved cognition of adult male rats, and exhibited minimal neurodegenerative changes. HD+ high- dose AGO was relatively safe regarding triggering epileptogenesis, while altered cardiac electrophysiology. In presence of low ACh, the melatonergic/dopaminergic hypothesis, added to ANGPTL4 and KLF9, could have some clue, thus, offering novel targets for pharmacologic manipulation of cognition.