Background/Aims: Extrapyramidal symptoms (EPS) are representative side effects of antipsychotics, caused by their inhibitory action on dopaminergic nerves in nigrostriatal pathways. EPS could be also caused by direct augmentation of cholinergic effects, for example, by acetylcholinesterase (AChE) inhibition. We investigated the potential inhibitory effects of 26 clinically available antipsychotics on the activity of recombinant human AChE (rhAChE) to predict the role of antipsychotic-induced AChE inhibition in EPS onset. Method: The degree of rhAChE activity inhibition was calculated using the 5,5′-dithio-bis-(2-nitrobenzoic acid) method. Results: At a concentration of 10^–5 mol/L, haloperidol, bromperidol, timiperone, nemonapride, pimozide, risperidone, blonanserin, aripiprazole, and brexpiprazole inhibited rhAChE activity by >20%. Risperidone, aripiprazole, and brexpiprazole inhibited rhAChE activity in a concentration-dependent manner, and their effects were more potent than those of other antipsychotics. The inhibitory effects of these 3 drugs were evident from 10^–6 mol/L, and their pIC₅₀ values were 4.74 ± 0.04, 4.80 ± 0.04, and 4.93 ± 0.06, respectively. Notably, the concentration range in which aripiprazole inhibited rhAChE activity (≥10^–6 mol/L) overlapped with its clinically achievable blood levels. Conclusion: Aripiprazole may cause EPS at clinical dosages by augmenting cholinergic effects via AChE inhibition, in addition to its suppressive effect on dopaminergic neurons.

Dimethyl sulfoxide (DMSO) has been used not only as an experimental solvent, but also as a therapeutic agent for interstitial cystitis. The therapeutic effects of DMSO on interstitial cystitis are presumed to involve anti-inflammatory and analgesic effects. However, the effects of DMSO on urinary bladder smooth muscle (UBSM) have not been fully investigated. Thus, in this study, we investigated the effects of DMSO on rat UBSM contractions, and these effects were compared with those of acetone, which has a structure in which the sulfur of DMSO is replaced with carbon. DMSO (0.5-5%) enhanced acetylcholine (ACh)-induced contractions, whereas acetone (3 and 5%) suppressed them. Additionally, DMSO (5%) suppressed carbacholinduced contractions. DMSO/acetone (0.5-5%) inhibited 80 mM KCl-induced contractions in a concentration-dependent manner; however, the inhibitory effects of DMSO were weaker than those of acetone. The enhancing/suppressing effects of DMSO and acetone were almost completely abolished by wash out. DMSO and acetone (0.5-5%) inhibited recombinant human acetylcholinesterase (rhAChE) activity in a concentration-dependent manner. At 0.5 and 1%, the inhibitory effects of DMSO on rhAChE activity were more potent than those of acetone. These findings suggest that DMSO can enhance ACh-induced UBSM contractions and promote urinary bladder motility by inhibiting acetylcholinesterase (AChE), although DMSO also inhibits Ca 2 influx-mediated UBSM contractions. In addition, the sulfur atom in DMSO might play an important role in its enhancing effect on ACh-induced contractions by inhibiting AChE, as acetone did not enhance these contractions.