Goldman-Rakic, P.S., Castner, S.A., Svensson, T.H., Siever, L.J. & Williams, G.V. Targeting the dopamine D1 receptor in schizophrenia: insights for cognitive dysfunction. Psychopharmacology (Berl.) 174, 3-16

Department of Neurobiology, Yale University School of Medicine, New Haven, CT 06510, USA.
Psychopharmacology (Impact Factor: 3.88). 07/2004; 174(1):3-16. DOI: 10.1007/s00213-004-1793-y
Source: PubMed


Reinstatement of the function of working memory, the cardinal cognitive process essential for human reasoning and judgment, is potentially the most intractable problem for the treatment of schizophrenia. Since deficits in working memory are associated with dopamine dysregulation and altered D(1) receptor signaling within prefrontal cortex, we present the case for targeting novel drug therapies towards enhancing prefrontal D(1) stimulation for the amelioration of the debilitating cognitive deficits in schizophrenia.
This review examines the role of dopamine in regulating cellular and circuit function within prefrontal cortex in order to understand the significance of the dopamine dysregulation found in schizophrenia and related non-human primate models. By revealing the associations among prefrontal neuronal function, dopamine and D(1) signaling, and cognition, we seek to pinpoint the mechanisms by which dopamine modulates working memory processes and how these mechanisms may be exploited to improve cognitive function.
Dopamine deficiency within dorsolateral prefrontal cortex leads to abnormal recruitment of this region by cognitive tasks. Both preclinical and clinical studies have demonstrated a direct relationship between prefrontal dopamine function and the integrity of working memory, suggesting that insufficient D(1) receptor signaling in this region results in cognitive deficits. Moreover, working memory deficits can be ameliorated by treatments that augment D(1) receptor stimulation, indicating that this target presents a unique opportunity for the restoration of cognitive function in schizophrenia.

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    • "The mesolimbic pathway is involved in reward processing (Koob and Bloom, 1988), effort related functions (Salamone et al., 2007), translation of emotions into actions (Mogenson et al., 1980), and direction of behavior where stimuli and rewards are less predictable (Nicola, 2007). The mesocortical pathway is involved with cognitive functions such as working memory (Moal, 1980; Goldman-Rakic et al., 2004). "
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    ABSTRACT: Chronic methamphetamine abuse commonly leads to psychosis, with positive and cognitive symptoms that are similar to those of schizophrenia. Methamphetamine induced psychosis (MAP) can persist and diagnoses of MAP often change to a diagnosis of schizophrenia over time. Studies in schizophrenia have found much evidence of cortical GABAergic dysfunction. Methamphetamine psychosis is a well studied model for schizophrenia, however there is little research on the effects of methamphetamine on cortical GABAergic function in the model, and the neurobiology of MAP is unknown. This paper reviews the effects of methamphetamine on dopaminergic pathways, with focus on its ability to increase glutamate release in the cortex. Excess cortical glutamate would likely damage GABAergic interneurons, and evidence of this disturbance as a result of methamphetamine treatment will be discussed. We propose that cortical GABAergic interneurons are particularly vulnerable to glutamate overflow as a result of subcellular location of NMDA receptors on interneurons in the cortex. Damage to cortical GABAergic function would lead to dysregulation of cortical signals, resulting in psychosis, and further support MAP as a model for schizophrenia.
    Full-text · Article · Jul 2014 · Frontiers in Human Neuroscience
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    • "Disordered frontal–striatal and frontal–limbic brain network interactions, a defining characteristic of schizophrenia (90, 91), are increasingly established in the adolescent genetic risk state. These interactions are well-understood for working memory and sustained attention, both domains particularly associated with these regions (92), with risk for schizophrenia (70), and with DA (93, 94). During working memory, adolescents at genetic risk for schizophrenia show inefficient regional responses as well as network interactions in frontal and striatal regions. "
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    ABSTRACT: The recent sociodevelopmental cognitive model of schizophrenia/psychosis is a highly influential and compelling compendium of research findings. Here, we present logical extensions to this model incorporating ideas drawn from epigenetic mediation of psychiatric disease, and the plausible effects of epigenetics on the emergence of brain network function and dysfunction in adolescence. We discuss how gene-environment interactions, effected by epigenetic mechanisms, might in particular mediate the stress response (itself heavily implicated in the emergence of schizophrenia). Next, we discuss the plausible relevance of this framework for adolescent genetic risk populations, a risk group characterized by vexing and difficult-to-explain heterogeneity. We then discuss how exploring relationships between epigenetics and brain network dysfunction (a strongly validated finding in risk populations) can enhance understanding of the relationship between stress, epigenetics, and functional neurobiology, and the relevance of this relationship for the eventual emergence of schizophrenia/psychosis. We suggest that these considerations can expand the impact of models such as the sociodevelopmental cognitive model, increasing their explanatory reach. Ultimately, integration of these lines of research may enhance efforts of early identification, intervention, and treatment in adolescents at-risk for schizophrenia.
    Full-text · Article · Jun 2014 · Frontiers in Psychiatry
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    • "The conclusion from this work is that the VTA is comprised of neurochemically similar but anatomically and functionally distinct neurons that mediate discrete aspects of motivated behaviors (Lammel et al., 2012). It is interesting to note that activation of dopaminergic neurons with projections to mPFC results in conditioned place aversion, whereas a much greater body of literature suggests that DA in the PFC plays an important role in electrophysiological and behavioral indices of working memory (Goldman-Rakic, 1994; Stevens et al., 1998; Goldman-Rakic et al., 2004; Arnsten and Li, 2005; Arnsten, 2007; Driesen et al., 2008). "
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    ABSTRACT: Cognitive functions associated with prefrontal cortex (PFC), such as working memory and attention, are strongly influenced by catecholamine [dopamine (DA) and norepinephrine (NE)] release. Midbrain dopaminergic neurons in the ventral tegmental area and noradrenergic neurons in the locus coeruleus are major sources of DA and NE to the PFC. It is traditionally believed that DA and NE neurons are homogeneous with highly divergent axons innervating multiple terminal fields and once released, DA and NE individually or complementarily modulate the prefrontal functions and other brain regions. However, recent studies indicate that both DA and NE neurons in the mammalian brain are heterogeneous with a great degree of diversity, including their developmental lineages, molecular phenotypes, projection targets, afferent inputs, synaptic connectivity, physiological properties, and behavioral functions. These diverse characteristics could potentially endow DA and NE neurons with distinct roles in executive function, and alterations in their responses to genetic and epigenetic risk factors during development may contribute to distinct phenotypic and functional changes in disease states. In this review of recent literature, we discuss how these advances in DA and NE neurons change our thinking of catecholamine influences in cognitive functions in the brain, especially functions related to PFC. We review how the projection-target specific populations of neurons in these two systems execute their functions in both normal and abnormal conditions. Additionally, we explore what open questions remain and suggest where future research needs to move in order to provide a novel insight into the cause of neuropsychiatric disorders related to DA and NE systems.
    Full-text · Article · May 2014 · Frontiers in Neural Circuits
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