Relevance of the Kappa Dynorphin System to Schizophrenia and Its Therapeutics.

Anissa Abi‐Dargham

doi:10.20900/jpbs.20210015

Abstract

Multiple lines of evidence suggest a potential role for the kappa dynorphin system in schizophrenia and its therapeutics. Kappa stimulation acutely and chronically modulates dopamine in opposite ways, where acutely it decreases dopamine transmission and chronically it increases it and it can induce D2 sensitization. In addition, pharmacological evidence from studies using agonist and antagonists at KOR have indicated a therapeutic potential of KOR antagonists for psychosis. We present here a brief overview of the evidence supporting this viewpoint.

Highlights

The opiate system includes the mu, delta and kappa opioid receptors (KOR)
KOR is activated by the endogenous ligand dynorphin, a peptide neurotransmitter processed from its precursor prodynorphin [1]
KOR negatively regulate dopamine release from dopaminergic projection neurons [10] and may play an important role in maintaining dopamine homeostasis and synaptic plasticity [11,12]. Consistent with this mechanism, rodent studies in vivo have shown that systemic administration of an acute dose of selective KOR agonists reduces dopamine levels in mesolimbic and nigrostriatal pathways by acting on presynaptic KORs on dopaminergic neurons in striatal subdivisions [10,13,14,15,16,17,18,19,20,21,22]

Summary

Introduction

The opiate system includes the mu, delta and kappa opioid receptors (KOR). KOR is activated by the endogenous ligand dynorphin, a peptide neurotransmitter processed from its precursor prodynorphin [1]. KOR stimulation has differential effects on dopamine under acute vs chronic conditions. Consistent with this mechanism, rodent studies in vivo have shown that systemic administration of an acute dose of selective KOR agonists reduces dopamine levels in mesolimbic and nigrostriatal pathways by acting on presynaptic KORs on dopaminergic neurons in striatal subdivisions [10,13,14,15,16,17,18,19,20,21,22].

Results

Conclusion