抗精神病薬によるジストニアの発現機序に関する実験的研究―σ (sigma) sites の関与について―

Recent findings have suggested that neuroleptics exhibit a strong affinity for not only dopamine receptors, but also the sigma sites. Therefore, some clinical or adverse effects of neuroleptics may be due to their action on the sigma sites. This study showed that intrarubral microinjection of 1,3-di-o-tolylguanidine (DTG) or (＋) -3- (3-hydroxyphenyl) -N-1-propyl) piperidine, sigma ligands, and several neuroleptics such as haloperidol caused dystonic reactions in rats resembling tha acute dystonic reaction in humans. The intensity and duration of the dystonia induced by these drugs showed a correlation with their affinities for the sigma sites. These findings raise the possibility that the acute dystonic reaction, one of the motor side effects of neuroleptics, might be mediated via the sigma sites. On the other hand, BMY 14802, an atypical neuroleptic, never caused dystonia after intrarubral microinjection. Furthermore, BMY 14802 still inhibited the dystonia induced by intrarubral microinjection of DTG. This reduction in DTG-induced dystonia by BMY 14802 may result its direct inhibitory effects against DTG at the sites, because BMY 14802 possesses potent sigma affinty. These findings imply that sigma ligands may be divided into two categories, dystonia-reinforcing and -reducing groups. Application of this theory should lead to the elucidation of the mechanism of neuroleptics-induced dystonia and other motor side effects.

原著