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

Stephanie M. Perez, Daniel J. Lodge

Research output: Contribution to journalReview articlepeer-review

17 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)887-896
Number of pages10
JournalDrug Design, Development and Therapy
Volume8
DOIs
StatePublished - Jul 2 2014

Keywords

  • Dopamine
  • GABA
  • Glutamate
  • Hippocampus
  • MAM rat
  • Schizophrenia

ASJC Scopus subject areas

  • Pharmacology
  • Pharmaceutical Science
  • Drug Discovery

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