Increased Brain Dopamine and Reduced Glutamic Acid Decarboxylase and Choline Acetyl Transferase Activity in Schizophrenia and Related Psychoses

Bird, E. D.; Barnes, Joanna; Ll, Iversen; Spokes, E.G.; Mackay, AngusV.P.; Shepherd, Michael

doi:10.1016/s0140-6736(77)91542-2

Cited by 248 publications

(64 citation statements)

References 17 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…In accordance with the hypothesis of a GABA deficit in schizophrenia, GABAergic cells and markers of GABAergic cells have usually been reported to be decreased in postmortem studies in patients with schizophrenia (Bird et al 1977;Perry et al 1979;Simpson et al 1989;Reynolds et al 1990;Benes et al 1991;Sherman et al 1991;Akbarian et al 1995b;Beasley and Reynolds 1997). However, few of these observations have been replicated (Bennett et al 1979;Cross et al 1979;Akbarian et al 1995b;Woo et al 1997).…”

Section: I]iomazenil; Spectmentioning

confidence: 76%

No Evidence of Altered In Vivo Benzodiazepine Receptor Binding in Schizophrenia

Abi‐Dargham

Laruelle

Krystal

et al. 1999

Neuropsychopharmacology

View full text Add to dashboard Cite

show abstract

Section: I]iomazenil; Spectmentioning

confidence: 76%

No Evidence of Altered In Vivo Benzodiazepine Receptor Binding in Schizophrenia

Abi‐Dargham

Laruelle

Krystal

et al. 1999

Neuropsychopharmacology

View full text Add to dashboard Cite

show abstract

“…D4 receptor proteins present in high levels in cortical layer II/III or V/VI are associated with both calbindin-and parvalbumin-containing GABA interneurons (Mezljak et al, 1996;Le Moine and Gaspar, 1998;Wedzony et al, 2000). Alterations in GABA transmission in these subclasses of GABAergic neurons have been reported in the PFC of schizophrenia brains examined post mortem (Bird et al, 1977;Akbarian et al, 1995;Lewis, 2000) and in a rat model of amphetamine sensitization (Mohila and Onn, 2005). Although D4 antagonists have not yet been reported to have antipsychotic efficacy (Lahti et al, 1998), both D4 receptor anatgonists, PNU-101387 and L-745870, were reported to prevent or improve cognitive deficits in monkeys (Arnsten et al, 2000) and in rats .…”

Section: Discussionmentioning

confidence: 99%

Dopamine D1 and D4 Receptor Subtypes Differentially Modulate Recurrent Excitatory Synapses in Prefrontal Cortical Pyramidal Neurons

Onn

Wang

Lin

et al. 2005

Neuropsychopharmacol

View full text Add to dashboard Cite

Although dopamine (DA) effects in the prefrontal cortex (PFC) have been studied extensively, the function of steady-state ambient levels of DA in the regulation of afferent excitatory transmission in PFC pyramidal neurons remains relatively unexplored. Using intracellular sharp-electrode and whole-cell recordings combined with intracellular labeling in brain slices, we found that D1/D5 receptor blockade did not alter synaptic responses in the PFC, but D1/D5 receptor activation consistently enhanced recurrent synaptic excitation in the majority of pyramidal neurons tested. In contrast, D4 receptor blockade resulted in an evoked complex multiple spike discharge pattern that contained both early and late (presumably multisynaptic) components of the evoked response that is contingent upon the preservation of axon collaterals of the neuron under study. Moreover, GABAergic interneurons were found to play a role in both responses; blockade of GABA a -mediated inhibition caused bath application of DA to convert monosynaptic excitatory postsynaptic potentials (EPSPs) to complex spike bursts riding on the late component of the EPSP. On the other hand, during the blockade of GABA amediated conductances, administration of a D4 receptor antagonist failed to facilitate evoked multiple spike discharge. Morphological analysis of axon collaterals of labeled neurons revealed that neurons in which the D4 receptor blockade induced the putative polysynaptic response had axon collaterals that were largely preserved. These data suggest that DA exerts a bidirectional modulation of PFC pyramidal neurons in brain slices provided that local network connections with interneurons are preserved, with D4 receptors under tonic stimulation by ambient low levels of DA, whereas D1/D5 receptors activated upon phasic DA input.

show abstract

“…However, the state of cholinergic signaling in different brain regions and during different tasks remains unknown in schizophrenia. Potential evidence for regional alterations in cholinergic signaling has been demonstrated in reductions of choline acetyltransferase (ChAT) activity, the catalytic enzyme involved in the synthesis of ACh, in the nucleus accumbens and pontine tegmentum of postmortem brain tissue from schizophrenic patients (Bird et al, 1977;Karson et al, 1993). Moreover, reductions in cortical and pontine tegmentum ChAT activity have been directly correlated with decreased cognitive performance in schizophrenic patients (Karson et al, 1996;Powchik et al, 1998).…”

Section: Introductionmentioning

confidence: 99%

Muscarinic and Nicotinic Acetylcholine Receptor Agonists and Allosteric Modulators for the Treatment of Schizophrenia

Jones

Byun

Bubser

2011

Neuropsychopharmacol

186

139

View full text Add to dashboard Cite

Muscarinic and nicotinic acetylcholine (ACh) receptors (mAChRs and nAChRs) are emerging as important targets for the development of novel treatments for the symptoms associated with schizophrenia. Preclinical and early proof-of-concept clinical studies have provided strong evidence that activators of specific mAChR (M 1 and M 4 ) and nAChR (a 7 and a 2 b 4 ) subtypes are effective in animal models of antipsychotic-like activity and/or cognitive enhancement, and in the treatment of positive and cognitive symptoms in patients with schizophrenia. While early attempts to develop selective mAChR and nAChR agonists provided important preliminary findings, these compounds have ultimately failed in clinical development due to a lack of true subtype selectivity and subsequent dose-limiting adverse effects. In recent years, there have been major advances in the discovery of highly selective activators for the different mAChR and nAChR subtypes with suitable properties for optimization as potential candidates for clinical trials. One novel strategy has been to identify ligands that activate a specific receptor subtype through actions at sites that are distinct from the highly conserved ACh-binding site, termed allosteric sites. These allosteric activators, both allosteric agonists and positive allosteric modulators, of mAChR and nAChR subtypes demonstrate unique mechanisms of action and high selectivity in vivo, and may provide innovative treatment strategies for schizophrenia.

show abstract

Increased Brain Dopamine and Reduced Glutamic Acid Decarboxylase and Choline Acetyl Transferase Activity in Schizophrenia and Related Psychoses

Cited by 248 publications

References 17 publications

No Evidence of Altered In Vivo Benzodiazepine Receptor Binding in Schizophrenia

No Evidence of Altered In Vivo Benzodiazepine Receptor Binding in Schizophrenia

Dopamine D1 and D4 Receptor Subtypes Differentially Modulate Recurrent Excitatory Synapses in Prefrontal Cortical Pyramidal Neurons

Muscarinic and Nicotinic Acetylcholine Receptor Agonists and Allosteric Modulators for the Treatment of Schizophrenia

Contact Info

Product

Resources

About