Functional pathology of neuroleptic-induced dystonia based on the striatal striosome-matrix dopamine system in humans.

Abstract

Neuroleptic-induced dystonia is a source of great concern in clinical practice because of its iatrogenic nature which can potentially lead to life-threatening conditions. Since all neuroleptics (antipsychotics) share the ability to block the dopamine D₂-type receptors (D₂Rs) that are highly enriched in the striatum, this drug-induced dystonia is thought to be caused by decreased striatal D₂R activity. However, how associations of striatal D₂R inactivation with dystonia are formed remains elusive.A growing body of evidence suggests that imbalanced activities between D₁R-expressing medium spiny neurons and D₂R-expressing medium spiny neurons (D₁-MSNs and D₂-MSNs) in the striatal striosome-matrix system underlie the pathophysiology of various basal ganglia disorders including dystonia. Given the specificity of the striatal dopamine D₁ system in 'humans', this article highlights the striatal striosome hypothesis in causing 'repetitive' and 'stereotyped' motor symptoms which are key clinical features of dystonia. It is suggested that exposure to neuroleptics may reduce striosomal D₁-MSN activity and thereby cause dystonia symptoms. This may occur through an increase in the striatal cholinergic activity and the collateral inhibitory action of D₂-MSNs onto neighbouring D₁-MSNs within the striosome subfields. The article proposes a functional pathology of the striosome-matrix dopamine system for neuroleptic-induced acute dystonia or neuroleptic-withdrawal dystonia. A rationale for the effectiveness of dopaminergic or cholinergic pharmacotherapy is also provided for treating dystonias. This narrative review covers various aspects of the relevant field and provides a detailed discussion of the mechanisms of neuroleptic-induced dystonia.