[Show abstract][Hide abstract] ABSTRACT: The functional integrity of the dorsolateral prefrontal cortex (DLPFC) is altered in schizophrenia leading to profound deficits in working memory and cognition. Growing evidence indicates that dysregulation of glutamate signaling may be a significant contributor to the pathophysiology mediating these effects; however, the contribution of NMDA and AMPA receptors in the mediation of this deficit remains unclear. The equivocality of data regarding ionotropic glutamate receptor alterations of subunit expression in the DLPFC of schizophrenics is likely reflective of subtle alterations in the cellular and molecular composition of specific neuronal populations within the region. Given previous evidence of Layer II/III and V pyramidal cell alterations in schizophrenia and the significant influence of subunit composition on NMDA and AMPA receptor function, laser capture microdissection combined with quantitative PCR was used to examine the expression of AMPA (GRIA1-4) and NMDA (GRIN1, 2A and 2B) subunit mRNA levels in Layer II/III and Layer V pyramidal cells in the DLPFC. Comparisons were made between individuals diagnosed with schizophrenia, bipolar disorder, major depressive disorder and controls (n=15/group). All subunits were expressed at detectable levels in both cell populations for all diseases as well as for the control group. Interestingly, GRIA1 mRNA was significantly increased in both cell types in the schizophrenia group compare to controls, while similar trends were observed in major depressive disorder (Layers II/III and V) and bipolar disorder (Layer V). These data suggest that increased GRIA1 subunit expression may contribute to schizophrenia pathology.
Full-text · Article · Jan 2008 · Schizophrenia Research
[Show abstract][Hide abstract] ABSTRACT: Disturbances in glutamate neurotransmission are thought to be one of the major contributing factors to the pathophysiology of schizophrenia. In the dorsolateral prefrontal cortex (DLPFC), glutamate neurotransmission is largely mediated by AMPA receptors. Data regarding alterations of subunit expression in the brains of patients with schizophrenia remain equivocal. This may be due to differences in technique sensitivity, endogenous control selection for normalization of data, or effect of antipsychotic drug treatment in different cohorts of schizophrenia. This study attempted to address these issues by examining the expression of AMPA receptor subunits and splice variants in the DLPFC of two schizophrenia cohorts using quantitative PCR (qPCR) with normalization to the geometric mean of multiple endogenous controls. In addition, a non-human primate model of chronic antipsychotic drug administration was used to determine the extent to which the transcript expression may be altered by antipsychotic drug treatment in the primate DLPFC. AMPA receptor subunits and flip and/or flop splice variants were not significantly different in the DLPFC of schizophrenia subjects versus controls in either of the two cohorts. However, in rhesus monkeys chronically treated with antipsychotic drugs, clozapine treatment significantly decreased GRIA1 and increased GRIA3 mRNA expression, while both clozapine and haloperidol increased the expression of GRIA2 subunit mRNA. Expression of AMPA receptor splice variants was not significantly altered by antipsychotic drug administration. This is the first study to show that AMPA receptor subunit mRNAs in the primate DLPFC are altered by antipsychotic drug administration. Antipsychotic drug-induced alterations may help explain differences in human post-mortem studies regarding AMPA receptor subunit expression and provide some insight into the mechanism of action of antipsychotic drugs.
Full-text · Article · Mar 2007 · Schizophrenia Research
[Show abstract][Hide abstract] ABSTRACT: Although the behavioral-stimulant and reinforcing effects of cocaine and related psychomotor stimulants have been attributed to their actions at the dopamine transporter (DAT), the reinforcing effectiveness of these compounds varies. The properties that confer these differences are important considerations when developing agonist pharmacotherapies for the treatment of stimulant abuse. The present studies focused on the time course of action and pharmacological specificity of six 3-phenyltropane analogs of cocaine (RTI-112, RTI-126, RTI-150, RTI-171, RTI-177, and RTI-336) by observing their behavioral-stimulant, neurochemical, and reinforcing effects in squirrel monkeys. The faster-onset analogs (RTI-126, RTI-150, and RTI-336), and one of the slower-onset DAT selective analogs (RTI-177 and RTI-171) produced behavioral-stimulant effects, while the slower-onset nonselective analog RTI-112 did not. The time to the peak behavioral-stimulant effect and the peak caudate dopamine levels was strongly correlated, but the area under the curve of the time course of behavioral-stimulant effect and dopamine levels was not correlated. These results suggest that the rate of onset plays a more important role than duration of action in the stimulant effect of these analogs. In addition, the slower-onset nonselective analog (RTI-112) clearly did not exhibit any reinforcing effects while the faster-onset nonselective (RTI-126) and all the DAT-selective analogs showed robust reinforcing effects (RTI-150, and RTI-177) or showed trends towards reinforcing effects (RTI-336 and RTI-171). Hence, there was a general trend for compounds that had a faster onset and/or DAT selectivity to produce significant behavioral-stimulant and reinforcing effects.
Full-text · Article · Feb 2007 · Pharmacology Biochemistry and Behavior
[Show abstract][Hide abstract] ABSTRACT: Recent evidence indicates that functional impairment of the orbital and medial fields of the prefrontal cortex may underlie the deficits in executive control of behavior that characterize addictive disorders, including alcohol addiction. Moreover, previous studies have indicated that alcohol alters GABA neurotransmission and one substrate of these effects may be through the reconfiguration of the subunits constituting the GABA(A) receptor complex. Given that GABAergic transmission has an integral role in cortical processing, influencing local and interregional communication, understanding alcohol-induced alterations in GABA(A) receptors in prefrontal fields of the primate brain may provide insight into the functional impairment of these brain regions in the alcohol-addicted state and extend our understanding of the molecular consequences of long-term use in these critical brain regions.
To address this problem, the effects of chronic ethanol self-administration in male cynomolgus monkeys on GABA(A) receptor subunit mRNA expression was studied in 3 frontal cortical fields: orbitofrontal cortex (OFC; area 13), anterior cingulate cortex (ACC; area 24), and the dorsolateral prefrontal cortex (DLPFC; area 46). Quantitative polymerase chain reaction revealed significant alterations in GABA(A) subunit mRNA expression in the OFC and DLPFC but not in the ACC. Specifically, expression of the alpha2, alpha4, beta1, beta3, and gamma1 to gamma3 subunit mRNAs was significantly less in the OFC, whereas the expression of beta1, beta2, gamma1, and delta subunit mRNAs was less in the DLPFC of alcohol-treated monkeys.
These findings suggest that ethanol-induced alterations in GABA(A) function may be due to alterations in GABA(A) subunit mRNA levels and subunit-specific alterations are selective to particular cortical fields.
Full-text · Article · Jan 2007 · Alcoholism Clinical and Experimental Research
[Show abstract][Hide abstract] ABSTRACT: Psychiatric diseases such as schizophrenia and autism spectrum disorders are generally considered to be neurodevelopmental in origin. Dysregulated gene and/or protein expression in the brain of adult schizophrenic patients must be understood in the context of a developmental model. This chapter discusses the basic mechanisms of transcriptional regulation and current knowledge of altered gene expression in schizophrenia focusing on glutamatergic and synaptic mechanisms. The relevance of these gene expression changes to neurodevelopment and other potential mechanisms of regulation in schizophrenia, and ideas about intervention to readjust dysregulated expression are considered.
[Show abstract][Hide abstract] ABSTRACT: Altered NMDA receptor subunit protein levels have been reported in various regions of the schizophrenic brain; however, chronic antipsychotic administration in schizophrenic subjects may confound interpretation.
The effects of chronic antipsychotic drug administration (haloperidol and clozapine) on protein levels of NR1, NR2A and NR2B proteins were evaluated in the nucleus accumbens (NAc), putamen (PUT), dorsolateral prefrontal cortex (DLPFC), superior temporal gyrus (STG), and entorhinal cortex (EC) of rhesus monkeys using Western blot analysis.
Haloperidol administration significantly decreased NR1 expression in the DLPFC. In contrast, NR2B expression was not affected by antipsychotic administration in any brain region examined. NR2A was not reliably detected in any of the brain regions.
Results indicate that the NR1 subunit in the DLPFC may be a substrate for antipsychotic action and that glutamatergic hypofunction in the DLPFC commonly associated with cognitive dysfunction in schizophrenia may be associated with haloperidol administration.
Full-text · Article · Oct 2006 · Biological Psychiatry
[Show abstract][Hide abstract] ABSTRACT: The striatum of the primate brain can be subdivided into three distinct anatomical subregions: caudate (CAU), putamen (PUT), and ventral striatum (VS). Although these subregions share several anatomical connections, cell morphological, and histochemical features, they differ considerably in their vulnerability to different neurological and psychiatric diseases, and these brain regions have significantly different functions in health and disease. In order to better understand the molecular underpinnings of the different disease and functional vulnerabilities, transcriptional profiles were generated from the CAU, PUT, and VS of five juvenile rhesus macaques (Macaca mulatta) using human cDNA neuromicroarrays containing triplicate spots of 1227 cDNAs. Differences in microarray gene expression were assessed using z score analysis and 1.5-fold change between paired subregions. Clustering of genes based on dissimilarity of expression patterns between regions revealed subregion specific expression profiles encoding G-protein-coupled receptor signaling transcripts, transcription factors, kinases and phosphatases, and cell signaling and signal transduction transcripts. Twelve transcripts were examined using quantitative real-time PCR (qPCR), and 81% demonstrated alterations similar to those seen with microarray analysis, some of which were statistically significant. Subregion specific transcription profiles support the anatomical differentiation and potential disease vulnerabilities of the respective subregions.
Full-text · Article · May 2006 · Experimental Neurology