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

ArticleinPsychopharmacology 174(1):3-16 · July 2004with20 Reads
DOI: 10.1007/s00213-004-1793-y · Source: PubMed
Abstract
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.
    • "Thus, a further suggestion driven by our results is a link between working memory processing, habit of cannabis use, and genetic modulation of CB1/COX-2 signaling. This suggestion is also supported by knowledge indicating that activation of CB1 by D9-THC increases COX-2 expression and activity (Chen et al., 2013 ), which in turn stimulates presynaptic glutamate release via a mechanism mediated by charyya, 2016; Goldman-Rakic, Castner, Svensson, Siever, & Williams, 2004). Our results did not indicate an interaction between CNR1 rs1406977 and PTGS2 rs20417 on behavioral efficiency during working memory. "
    [Show abstract] [Hide abstract] ABSTRACT: The CB1 cannabinoid receptor is targeted in the brain by endocannabinoids under physiological conditions as well as by delta9-tetrahydrocannabinol under cannabis use. Furthermore, its signaling appears to affect brain cognitive processing. Recent findings highlight a crucial role of cyclooxygenase-2 (COX-2) in the mechanism of intraneuronal CB1 signaling transduction, while others indicate that two single nucleotide polymorphisms (rs1406977 and rs20417) modulate expression of CB1 (CNR1) and COX-2 (PTGS2) coding genes, respectively. Here, our aim was to use fMRI to investigate in healthy humans whether these SNPs interact in modulating prefrontal activity during working memory processing and if this modulation is linked with cannabis use. We recruited 242 healthy subjects genotyped for CNR1 rs1406977 and PTGS2 rs20417 that performed the N-back working memory task during fMRI and were interviewed using the Cannabis Experience Questionnaire (CEQ). We found that the interaction between CNR1 rs1406977 and PTGS2 rs20417 is associated with dorsolateral prefrontal cortex (DLPFC) activity such that specific genotype configurations (CNR1 C carriers/PTGS2 C carriers and CNR1 TT/PTGS2 GG) predict lower cortical response versus others in spite of similar behavioral accuracy. Furthermore, DLPFC activity in the cluster associated with the CNR1 by PTGS2 interaction was negatively correlated with behavioral efficiency and positively correlated with frequency of cannabis use in cannabis users. These results suggest that a genetically modulated balancing of signaling within the CB1-COX-2 pathway may reflect on more or less efficient patterns of prefrontal activity during working memory. Frequency of cannabis use may be a factor for further modulation of CNR1/PTGS2-mediated cortical processing associated with this cognitive process.
    Full-text · Article · May 2016
    • "In rats CPE, a paralog of CPXM1 (which is highly similar to CPXM2 in that it also lacks the catalytic activity found in other carboxypetidases (Lei et al., 1999)), mediates dopamine transporter (DAT) expression such that co-expression of CPE and DAT results in increased dopamine reuptake in brain (Zhang et al., 2009). Also, a variant of CPXM2 is suggestively associated with cognitive decline in schizophrenia (Hashimoto et al., 2013), where cognitive ability, and more specifically cognitive impairment in schizophrenia, is thought to be modulated by dopaminergic signaling (Nieoullon, 2002; Goldman-Rakic et al., 2004; Knowles et al., 2014). Insofar as the role of dopamine is well established in MDD (Nestler and Carlezon, 2006; Dunlop and Nemeroff, 2007; Tye et al., 2013) and that the gene CPXM2, or at least very similar genes in the same family, appears to influence dopamine functioning in the brain, the present paper highlights a new candidate gene for MDD in a newly established large multiplex MDD pedigree that warrants further investigation. "
    [Show abstract] [Hide abstract] ABSTRACT: Major depressive disorder (MDD) is a common and potentially life-threatening mood disorder. Identifying genetic markers for depression might provide reliable indicators of depression risk, which would, in turn, substantially improve detection, enabling earlier and more effective treatment. The aim of this study was to identify rare variants for depression, modeled as a continuous trait, using linkage and post-hoc association analysis. The sample comprised 1221 Mexican-American individuals from extended pedigrees. A single dimensional scale of MDD was derived using confirmatory factor analysis applied to all items from the Past Major Depressive Episode section of the Mini-International Neuropsychiatric Interview. Scores on this scale of depression were subjected to linkage analysis followed by QTL region-specific association analysis. Linkage analysis revealed a single genome-wide significant QTL (LOD=3.43) on 10q26.13, QTL-specific association analysis conducted in the entire sample revealed a suggestive variant within an intron of the gene LHPP (rs11245316, p=7.8×10(-04); LD-adjusted Bonferroni-corrected p=8.6×10(-05)). This region of the genome has previously been implicated in the etiology of MDD; the present study extends our understanding of the involvement of this region by highlighting a putative gene of interest (LHPP).
    Full-text · Article · Nov 2015
    • "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). "
    [Show abstract] [Hide abstract] 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
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