Article

Beyond the dopamine receptor: novel therapeutic targets for treating schizophrenia.

Department of Psychiatry, Harvard Medical School, McLean Hospital, Belmont, MA 02478, USA.
Dialogues in clinical neuroscience 01/2010; 12(3):359-82.
Source: PubMed

ABSTRACT All current drugs approved to treat schizophrenia appear to exert their antipsychotic effects through blocking the dopamine D2 receptor. Recent meta-analyses and comparative efficacy studies indicate marginal differences in efficacy of newer atypical antipsychotics and the older drugs, and little effects on negative and cognitive symptoms. This review integrates findings from postmortem, imaging, and drug-challenge studies to elucidate a corticolimbic "pathologic circuit" in schizophrenia that may be particularly relevant to the negative symptoms and cognitive impairments of schizophrenia. Potential sites for pharmacologic intervention targeting glutatatergic, GABAergic, and cholinergic neurotransmission to treat these symptoms of schizophrenia are discussed.

0 Bookmarks
 · 
154 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Computational modeling of functional brain networks in fMRI data has advanced the understanding of higher cognitive function. It is hypothesized that functional networks mediating higher cognitive processes are disrupted in people with schizophrenia. In this article, we review studies that applied measures of functional and effective connectivity to fMRI data during cognitive tasks, in particular working memory fMRI studies. We provide a conceptual summary of the main findings in fMRI data and their relationship with neurotransmitter systems, which are known to be altered in individuals with schizophrenia. We consider possible developments in computational neuropsychiatry, which are likely to further our understanding of how key functional networks are altered in schizophrenia.
    Frontiers in Psychiatry 01/2014; 5:30.
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Glycine transporters are endogenous regulators of the dual functions of glycine, which acts as a classical inhibitory neurotransmitter at glycinergic synapses and as a modulator of neuronal excitation mediated by NMDA (N-methyl-D-aspartate) receptors at glutamatergic synapses. The two major subtypes of glycine transporters, GlyT1 and GlyT2, have been linked to the pathogenesis and/or treatment of central and peripheral nervous system disorders, including schizophrenia and related affective and cognitive disturbances, alcohol dependence, pain, epilepsy, breathing disorders and startle disease (also known as hyperekplexia). This Review examines the rationale for the therapeutic potential of GlyT1 and GlyT2 inhibition, and surveys the latest advances in the biology of glycine reuptake and transport as well as the drug discovery and clinical development of compounds that block glycine transporters.
    dressNature Reviews Drug Discovery 10/2013; 12(11):866-85. · 33.08 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Microglial dysfunction and neuroinflammation are thought to contribute to the pathogenesis of schizophrenia. Some antipsychotic drugs have anti-inflammatory activity and can reduce the secretion of pro-inflammatory cytokines and reactive oxygen species from activated microglial cells. Voltage-gated proton channels on the microglial cells participate in the generation of reactive oxygen species and neuronal toxicity by supporting NADPH oxidase activity. In the present study, we examined the effects of two typical antipsychotics, chlorpromazine and haloperidol, on proton currents in microglial BV2 cells using the whole-cell patch clamp method. Chlorpromazine and haloperidol potently inhibited proton currents with IC50 values of 2.2 μM and 8.4 μM, respectively. Chlorpromazine and haloperidol are weak bases that can increase the intracellular pH, whereby they reduce the proton gradient and affect channel gating. Although the drugs caused a marginal positive shift of the activation voltage, they did not change the reversal potential. This suggested that proton current inhibition was not due to an alteration of the intracellular pH. Chlorpromazine and haloperidol are strong blockers of dopamine receptors. While dopamine itself did not affect proton currents, it also did not alter proton current inhibition by the two antipsychotics, indicating dopamine receptors are not likely to mediate the proton current inhibition. Given that proton channels are important for the production of reactive oxygen species and possibly pro-inflammatory cytokines, the anti-inflammatory and antipsychotic activities of chlorpromazine and haloperidol may be partly derived from their ability to inhibit microglial proton currents.
    European Journal of Pharmacology 09/2014; 738:256–262. · 2.59 Impact Factor

Full-text (2 Sources)

Download
4 Downloads
Available from
Nov 6, 2014