New approaches to the management of schizophrenia: focus on aberrant hippocampal drive of dopamine pathways

Drug Des Devel Ther. 2014 Jul 2;8:887-96. doi: 10.2147/DDDT.S42708. eCollection 2014.

Abstract

Schizophrenia is a disease affecting up to 1% of the population. Current therapies are based on the efficacy of chlorpromazine, discovered over 50 years ago. These drugs block dopamine D2-like receptors and are effective at primarily treating positive symptoms in a subset of patients. Unfortunately, current therapies are far from adequate, and novel treatments require a better understanding of disease pathophysiology. Here we review the dopamine, gamma-aminobutyric acid (GABA), and glutamate hypotheses of schizophrenia and describe a pathway whereby a loss of inhibitory signaling in ventral regions of the hippocampus actually drives a dopamine hyperfunction. Moreover, we discuss novel therapeutic approaches aimed at attenuating ventral hippocampal activity in a preclinical model of schizophrenia, namely the MAM GD17 rat. Specifically, pharmacological (allosteric modulators of the α5 GABAA receptor), neurosurgical (deep brain stimulation), and cell-based (GABAergic precursor transplants) therapies are discussed. By better understanding the underlying circuit level dysfunctions in schizophrenia, novel treatments can be advanced that may provide better efficacy and a superior side effect profile to conventional antipsychotic medications.

Keywords: GABA; MAM rat; dopamine; glutamate; hippocampus; schizophrenia.

Publication types

  • Review

MeSH terms

  • Allosteric Regulation
  • Animals
  • Antipsychotic Agents / adverse effects
  • Antipsychotic Agents / pharmacology
  • Antipsychotic Agents / therapeutic use*
  • Cell- and Tissue-Based Therapy / methods
  • Deep Brain Stimulation / methods
  • Dopamine / metabolism*
  • Drug Design
  • Glutamic Acid / metabolism
  • Hippocampus / pathology
  • Humans
  • Rats
  • Schizophrenia / physiopathology
  • Schizophrenia / therapy*
  • gamma-Aminobutyric Acid / metabolism

Substances

  • Antipsychotic Agents
  • Glutamic Acid
  • gamma-Aminobutyric Acid
  • Dopamine