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 language | English (US) |
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Pages (from-to) | 887-896 |
Number of pages | 10 |
Journal | Drug Design, Development and Therapy |
Volume | 8 |
DOIs | |
State | Published - Jul 2 2014 |
Keywords
- Dopamine
- GABA
- Glutamate
- Hippocampus
- MAM rat
- Schizophrenia
ASJC Scopus subject areas
- Pharmacology
- Pharmaceutical Science
- Drug Discovery