Interactions Between Monoamines, Glutamate, and GABA in Schizophrenia: New Evidence

Abstract

In spite of its proven heuristic value, the dopamine hypothesis of schizophrenia is now yielding to a multifactorial view, in which the other monoamines as well as glutamate and GABA are included, with a focus on neurotransmitter interactions in complex neurocircuits. The primary lesion(s) in schizophrenia does not necessarily involve any of these neurotransmitters directly but could deal with a more general defect, such as a faulty connectivity of developmental origin. Nevertheless, a precise identification of neurotransmitter aberrations in schizophrenia will probably provide clues for a better understanding of the disease and for the development of new treatment and prevention strategies.

Adult mice with reduced Nurr1 expression: an animal model for schizophrenia

“…This regulatory adaptation would mean that prefrontal glutamate transmission is deficient, while subcortical DA transmission is overactive. 10 This model provides a possible explanation for our observation that the augmented locomotor response to PCP in Nurr1 heterozygous ( þ /À) mice is mediated by changes in subcortical and cortical DA and NMDA transmission, respectively. Taken together, the Nurr1 ( þ /À) mice display an exaggerated locomotor responses to the psychostimulants/hallucinogens AMPH and PCP, consistent with animal models of schizophrenia.…”

“…DAergic hyperactivity has been the major hypothesis explaining the pathophysiology of schizophrenia involving disturbed DA transmission in mesolimbic and mesocortical pathways. 10 However, the neurochemical correlates to schizophrenia related to the DA hypothesis have remained elusive. Measurements of DA levels and DA receptor densities in postmortem schizophrenic brains have not provided any clear evidences for increases for DA transmission or DA D 2 receptors in schizophrenia.…”

“…9 Glutamate and DA, which share common postsynaptic targets, are believed to interact in a reciprocal manner at both cortical and subcortical structures. 10 Thus, a reduction in DA transmission may act to balance a glutamatergic insufficiency in schizophrenia. 10 Some of the symptoms in schizophrenia appear to involve disturbances in NMDA receptor function in the pFCx, probably mediated via alterations in DA receptor activity.…”

“…10 Thus, a reduction in DA transmission may act to balance a glutamatergic insufficiency in schizophrenia. 10 Some of the symptoms in schizophrenia appear to involve disturbances in NMDA receptor function in the pFCx, probably mediated via alterations in DA receptor activity. 8,11 Interestingly the noncompetitive NMDA antagonist phencyclidine (PCP) has been shown to induce both positive and negative schizophrenic symptoms as well as cognitive deficits.…”

Withdrawal from Chronic Phencyclidine Treatment Induces Long-Lasting Depression in Brain Reward Function

“…Withdrawal from PCP treatment induces in humans and rodents some longlasting behavioral and neurochemical perturbations that have been hypothesized to have relevance to schizophrenia symptomatology and neuropathologies, respectively (Jentsch and Roth, 1999). These observations have led to the hypothesis of hypofunctioning of the glutamatergic system as one of the pathophysiologies mediating schizophrenia (Javitt and Zukin, 1991;Carlsson et al, 2001). The purpose of the present study was to test the hypothesis that withdrawal from PCP administration results in elevations in brain reward thresholds.…”