Effects of the monoamine stabilizer (−)-OSU6162 on locomotor and sensorimotor responses predictive of antipsychotic activity

Abstract

The monoamine stabilizer (3S)-3-[3-(methenesulfonyl)phenyl]-1-propylpiperidine hidrochloride [(-)-OSU6162] is a promising compound for the treatment of neurological and psychiatric disorders, such as schizophrenia. Here, we tested the hypothesis that (-)-OSU6162 prevents hyperlocomotion and sensorimotor deficits in prepulse inhibition of the startle response (PPI) induced by psychomimetic drugs. Male Swiss mice received injections of (-)-OSU6162 (1, 3, 10, or 30 mg/kg), and their motor responses were investigated in the open field and in the catalepsy tests, which predicts liability to induce sedation and extrapyramidal side effects, respectively. Next, in independent experiments, this compound was evaluated for its efficacy to prevent hyperlocomotion induced by cocaine (10 mg/kg; dopamine transporter inhibitor) or ketamine (60 mg/kg; glutamate NMDA channel blocker) in the open field. Finally, we tested if (-)-OSU6162 prevents PPI disruption induced by MK-801 (0.5 mg/kg; glutamate NMDA channel blocker). (-)-OSU6162 induced neither locomotion impairment nor catalepsy. This compound prevented cocaine-induced hyperlocomotion at the doses of 10 and 30 mg/kg and ketamine-induced hyperlocomotion at the doses of 1 and 3 mg/kg. In the sensorimotor test, (-)-OSU6162 failed to reverse MK-801-induced PPI deficits. The dopamine stabilizer (-)-OSU6162 prevents the hyperactivity induced by dopaminergic and anti-glutamatergic drugs at doses that preserve motor functions, although it failed in the PPI test. Its therapeutic potential for specific symptoms of schizophrenia warrants further investigation in both preclinical and clinical studies.

Single Low Dose of Cocaine–Structural Brain Injury Without Metabolic and Behavioral Changes

“…It is well-known that this psychostimulant increase dose dependently the locomotor activity in different mice and rat strains (3-56 mg/kg) (Thomsen and Caine, 2011). For example, cocaine doses ranging from 1 to 20 mg/kg (Barr et al, 2020;Romero-Fernandez et al, 2020) showed that 10 mg/kg of cocaine (but not lower doses including 2.5 and 5 mg/kg) increased the distance traveled by male Swiss mice in the open field (da Silveira et al, 2018). Moreover, it was further shown that the threshold dose of cocaine that significantly stimulated forward locomotion of rats in an open field arena was 10 mg/kg (Baumann et al, 2013).…”

In Silico Study of Metoclopramide as A Small Molecule of Dopamine D2 Receptor: a Quantum-Mechanical (QM) Based Molecular Docking Treatment

“…The main agonists for dopamine D2 receptor are bromocriptine [3], cabergoline [4], dihydrexidine [5], piribedil [6], pramipexole [7], quinelorane [8], quinpirole [9], ropinirole [10], sumanirole [11] and talipexole [12]. Some drugs like aplindore [13], aripiprazole [14], armodafinil [15], brexpiprazole [16], cariprazine [17], ketamine [18], GSK-789 [19], 2-phenethylamine [20], LSD [21], OSU-6162 [22], roxindole [23], RP5063 [24] and salvinorin A [25] show the partial agonistic activity in interaction with D2R binding sites. In recent years, antagonist drugs have shown better properties than agonist compounds for binding with dopamine D2 receptor.…”