title: New approaches to the management of schizophrenia: focus on aberrant hippocampal drive of dopamine pathways.
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.
authors: Department of Pharmacology and Center for Biomedical Neuroscience, University of Texas Health Science Center, San Antonio, TX, USA.
authors: Stephanie M
authors: SM
authors: Perez
authors: Department of Pharmacology and Center for Biomedical Neuroscience, University of Texas Health Science Center, San Antonio, TX, USA.
authors: Daniel J
authors: DJ
authors: Lodge
mesh_terms: D000494:Allosteric Regulation; D000818:Animals; D014150:Antipsychotic Agents / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D064987:Cell- and Tissue-Based Therapy / Q000379:methods; D046690:Deep Brain Stimulation / Q000379:methods; D004298:Dopamine / Q000378:metabolism*; D015195:Drug Design; D018698:Glutamic Acid / Q000378:metabolism; D006624:Hippocampus / Q000473:pathology; D006801:Humans; D051381:Rats; D012559:Schizophrenia / Q000503:physiopathology / Q000628:therapy*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D014150:Antipsychotic Agents; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; D004298:Dopamine
keywords: GABA; MAM rat; dopamine; glutamate; hippocampus; schizophrenia