PMC:2938983 / 19065-22866 JSONTXT

{"project":"TEST0","denotations":[{"id":"20859447-110-118-266820","span":{"begin":177,"end":181},"obj":"[\"16773445\"]"},{"id":"20859447-231-239-266821","span":{"begin":435,"end":439},"obj":"[\"18230672\"]"},{"id":"20859447-234-242-266822","span":{"begin":458,"end":462},"obj":"[\"18550032\"]"},{"id":"20859447-235-243-266823","span":{"begin":481,"end":485},"obj":"[\"17684498\"]"},{"id":"20859447-235-243-266824","span":{"begin":504,"end":508},"obj":"[\"19078949\"]"},{"id":"20859447-60-68-266825","span":{"begin":571,"end":575},"obj":"[\"19255630\"]"},{"id":"20859447-155-163-266826","span":{"begin":843,"end":847},"obj":"[\"1654746\"]"},{"id":"20859447-177-185-266827","span":{"begin":865,"end":869},"obj":"[\"8122957\"]"},{"id":"20859447-215-223-266828","span":{"begin":1087,"end":1091},"obj":"[\"10063482\"]"},{"id":"20859447-90-98-266829","span":{"begin":1309,"end":1313},"obj":"[\"19255630\"]"},{"id":"20859447-22-30-266831","span":{"begin":2040,"end":2044},"obj":"[\"19255630\"]"},{"id":"20859447-201-209-266832","span":{"begin":2495,"end":2499},"obj":"[\"15787711\"]"},{"id":"20859447-207-215-266833","span":{"begin":2501,"end":2505},"obj":"[\"18094666\"]"},{"id":"20859447-229-237-266834","span":{"begin":2523,"end":2527},"obj":"[\"18427784\"]"},{"id":"20859447-172-180-266835","span":{"begin":2702,"end":2706},"obj":"[\"16500717\"]"},{"id":"20859447-178-186-266836","span":{"begin":2708,"end":2712},"obj":"[\"17329300\"]"},{"id":"20859447-151-159-266838","span":{"begin":3263,"end":3267},"obj":"[\"10978725\"]"},{"id":"20859447-177-185-266839","span":{"begin":3289,"end":3293},"obj":"[\"11106877\"]"}],"text":"Effects of Subchronic PCP Treatment on Discrimination and Reversal\nThere is compelling evidence implicating the glutamate system in the pathophysiology of schizophrenia (Coyle, 2006). As part of a larger research program to elucidate the role of glutamate in cognitive and executive functions, we have studied the effects of null mutations in various components of the glutamate system on the touchscreen-based method (Brigman et al., 2008; Karlsson et al., 2008; Wiedholz et al., 2008; Karlsson et al., 2009). To compliment and extend these studies, we (Brigman et al., 2009) investigated a pharmacological model of glutamatergic dysfunction in schizophrenia – subchronic PCP treatment.\nPCP and other NMDAR antagonists (e.g., ketamine) mimic positive and negative symptoms of schizophrenia in otherwise healthy individuals (Javitt and Zukin, 1991; Krystal et al., 1994). Based upon this observation, Jentsch and colleagues subchronically treated monkeys and rats with PCP and found cognitive deficits and associated prefrontal neurochemical abnormalities (reviewed in Jentsch and Roth, 1999). The subchronic PCP model has since been quite widely employed as a rodent model for executive dysfunctions in schizophrenia.\nIn order to test the subchronic PCP model in the touchscreen-based assay, Brigman et al. (2009) treated C57BL/6J mice with 5 mg/kg PCP twice daily for 7 days and, after a 7-day withdrawal period, tested for discrimination and (in a separate group of mice) reversal in the touchscreen-based task. This treatment and withdrawal duration was based on previous work by Jentsch et al. (1997a). Results showed no significant impairments in drug-treated mice in comparison to vehicle treated controls on either discrimination or reversal, as measured using a range of dependent variables. By contrast, the same treatment regimen that failed to affect discrimination or reversal was sufficient to reduce social behavior – demonstrating that treatment was sufficient to mimic some symptoms of schizophrenia.\nWhile Brigman et al. (2009) was the first study of the PCP model in a rodent touchscreen-based procedure, the lack of impairment may appear somewhat surprising, given PCP-induced deficits have been found on other measures of reversal in rats and mice (summarized in Table 1). However, similar to Brigman et al., negative effects on reversal have also been reported (including in studies in which there are clear PCP-induced deficits in the EDS component, e.g., Rodefer et al., 2005, 2008; Egerton et al., 2008). Direct comparisons between studies are further complicated by variations in treatment regimen and methodology. For example, while Neill and colleagues (Abdul-Monim et al., 2006, 2007) have demonstrated reversal impairments in a light-cue based operant task in rats subjected to a PCP treatment and withdrawal procedure comparable to Brigman et al., their task required subjects to completely inhibit responses on some trials to obtain reward, which likely placed greater demands on inhibitory control than the task used by Brigman et al. (in which a response was always available). This is likely a salient difference because subchronic PCP treatment impairs inhibitory control in rats and non-human primates (Jentsch et al., 1997b, 2000; Jentsch and Taylor, 2001). Clearly, further work is needed to parse the most critical features of reversal assays that render them sensitive to subchronic PCP treatment.\nTable 1 Studies on the effects of acute and chronic PCP treatment on measures of cognitive flexibility. IDS/EDS, intra-dimensional/extra-dimensional set shifting; w/d, withdrawal period prior to testing.\nTable 2 Examples of studies of cognitive flexibility in mutant mice. IDS/EDS, intra-dimensional/extra-dimensional shifting task; MWM, Morris water maze.\n\n"}

{"project":"0_colil","denotations":[{"id":"20859447-16773445-266820","span":{"begin":177,"end":181},"obj":"16773445"},{"id":"20859447-18230672-266821","span":{"begin":435,"end":439},"obj":"18230672"},{"id":"20859447-18550032-266822","span":{"begin":458,"end":462},"obj":"18550032"},{"id":"20859447-17684498-266823","span":{"begin":481,"end":485},"obj":"17684498"},{"id":"20859447-19078949-266824","span":{"begin":504,"end":508},"obj":"19078949"},{"id":"20859447-19255630-266825","span":{"begin":571,"end":575},"obj":"19255630"},{"id":"20859447-1654746-266826","span":{"begin":843,"end":847},"obj":"1654746"},{"id":"20859447-8122957-266827","span":{"begin":865,"end":869},"obj":"8122957"},{"id":"20859447-10063482-266828","span":{"begin":1087,"end":1091},"obj":"10063482"},{"id":"20859447-19255630-266829","span":{"begin":1309,"end":1313},"obj":"19255630"},{"id":"20859447-19255630-266831","span":{"begin":2040,"end":2044},"obj":"19255630"},{"id":"20859447-15787711-266832","span":{"begin":2495,"end":2499},"obj":"15787711"},{"id":"20859447-18094666-266833","span":{"begin":2501,"end":2505},"obj":"18094666"},{"id":"20859447-18427784-266834","span":{"begin":2523,"end":2527},"obj":"18427784"},{"id":"20859447-16500717-266835","span":{"begin":2702,"end":2706},"obj":"16500717"},{"id":"20859447-17329300-266836","span":{"begin":2708,"end":2712},"obj":"17329300"},{"id":"20859447-10978725-266838","span":{"begin":3263,"end":3267},"obj":"10978725"},{"id":"20859447-11106877-266839","span":{"begin":3289,"end":3293},"obj":"11106877"}],"text":"Effects of Subchronic PCP Treatment on Discrimination and Reversal\nThere is compelling evidence implicating the glutamate system in the pathophysiology of schizophrenia (Coyle, 2006). As part of a larger research program to elucidate the role of glutamate in cognitive and executive functions, we have studied the effects of null mutations in various components of the glutamate system on the touchscreen-based method (Brigman et al., 2008; Karlsson et al., 2008; Wiedholz et al., 2008; Karlsson et al., 2009). To compliment and extend these studies, we (Brigman et al., 2009) investigated a pharmacological model of glutamatergic dysfunction in schizophrenia – subchronic PCP treatment.\nPCP and other NMDAR antagonists (e.g., ketamine) mimic positive and negative symptoms of schizophrenia in otherwise healthy individuals (Javitt and Zukin, 1991; Krystal et al., 1994). Based upon this observation, Jentsch and colleagues subchronically treated monkeys and rats with PCP and found cognitive deficits and associated prefrontal neurochemical abnormalities (reviewed in Jentsch and Roth, 1999). The subchronic PCP model has since been quite widely employed as a rodent model for executive dysfunctions in schizophrenia.\nIn order to test the subchronic PCP model in the touchscreen-based assay, Brigman et al. (2009) treated C57BL/6J mice with 5 mg/kg PCP twice daily for 7 days and, after a 7-day withdrawal period, tested for discrimination and (in a separate group of mice) reversal in the touchscreen-based task. This treatment and withdrawal duration was based on previous work by Jentsch et al. (1997a). Results showed no significant impairments in drug-treated mice in comparison to vehicle treated controls on either discrimination or reversal, as measured using a range of dependent variables. By contrast, the same treatment regimen that failed to affect discrimination or reversal was sufficient to reduce social behavior – demonstrating that treatment was sufficient to mimic some symptoms of schizophrenia.\nWhile Brigman et al. (2009) was the first study of the PCP model in a rodent touchscreen-based procedure, the lack of impairment may appear somewhat surprising, given PCP-induced deficits have been found on other measures of reversal in rats and mice (summarized in Table 1). However, similar to Brigman et al., negative effects on reversal have also been reported (including in studies in which there are clear PCP-induced deficits in the EDS component, e.g., Rodefer et al., 2005, 2008; Egerton et al., 2008). Direct comparisons between studies are further complicated by variations in treatment regimen and methodology. For example, while Neill and colleagues (Abdul-Monim et al., 2006, 2007) have demonstrated reversal impairments in a light-cue based operant task in rats subjected to a PCP treatment and withdrawal procedure comparable to Brigman et al., their task required subjects to completely inhibit responses on some trials to obtain reward, which likely placed greater demands on inhibitory control than the task used by Brigman et al. (in which a response was always available). This is likely a salient difference because subchronic PCP treatment impairs inhibitory control in rats and non-human primates (Jentsch et al., 1997b, 2000; Jentsch and Taylor, 2001). Clearly, further work is needed to parse the most critical features of reversal assays that render them sensitive to subchronic PCP treatment.\nTable 1 Studies on the effects of acute and chronic PCP treatment on measures of cognitive flexibility. IDS/EDS, intra-dimensional/extra-dimensional set shifting; w/d, withdrawal period prior to testing.\nTable 2 Examples of studies of cognitive flexibility in mutant mice. IDS/EDS, intra-dimensional/extra-dimensional shifting task; MWM, Morris water maze.\n\n"}

{"project":"2_test","denotations":[{"id":"20859447-16773445-38208261","span":{"begin":177,"end":181},"obj":"16773445"},{"id":"20859447-18230672-38208262","span":{"begin":435,"end":439},"obj":"18230672"},{"id":"20859447-18550032-38208263","span":{"begin":458,"end":462},"obj":"18550032"},{"id":"20859447-17684498-38208264","span":{"begin":481,"end":485},"obj":"17684498"},{"id":"20859447-19078949-38208265","span":{"begin":504,"end":508},"obj":"19078949"},{"id":"20859447-19255630-38208266","span":{"begin":571,"end":575},"obj":"19255630"},{"id":"20859447-1654746-38208267","span":{"begin":843,"end":847},"obj":"1654746"},{"id":"20859447-8122957-38208268","span":{"begin":865,"end":869},"obj":"8122957"},{"id":"20859447-10063482-38208269","span":{"begin":1087,"end":1091},"obj":"10063482"},{"id":"20859447-19255630-38208270","span":{"begin":1309,"end":1313},"obj":"19255630"},{"id":"20859447-19255630-38208272","span":{"begin":2040,"end":2044},"obj":"19255630"},{"id":"20859447-15787711-38208273","span":{"begin":2495,"end":2499},"obj":"15787711"},{"id":"20859447-18094666-38208274","span":{"begin":2501,"end":2505},"obj":"18094666"},{"id":"20859447-18427784-38208275","span":{"begin":2523,"end":2527},"obj":"18427784"},{"id":"20859447-16500717-38208276","span":{"begin":2702,"end":2706},"obj":"16500717"},{"id":"20859447-17329300-38208277","span":{"begin":2708,"end":2712},"obj":"17329300"},{"id":"20859447-10978725-38208279","span":{"begin":3263,"end":3267},"obj":"10978725"},{"id":"20859447-11106877-38208280","span":{"begin":3289,"end":3293},"obj":"11106877"}],"text":"Effects of Subchronic PCP Treatment on Discrimination and Reversal\nThere is compelling evidence implicating the glutamate system in the pathophysiology of schizophrenia (Coyle, 2006). As part of a larger research program to elucidate the role of glutamate in cognitive and executive functions, we have studied the effects of null mutations in various components of the glutamate system on the touchscreen-based method (Brigman et al., 2008; Karlsson et al., 2008; Wiedholz et al., 2008; Karlsson et al., 2009). To compliment and extend these studies, we (Brigman et al., 2009) investigated a pharmacological model of glutamatergic dysfunction in schizophrenia – subchronic PCP treatment.\nPCP and other NMDAR antagonists (e.g., ketamine) mimic positive and negative symptoms of schizophrenia in otherwise healthy individuals (Javitt and Zukin, 1991; Krystal et al., 1994). Based upon this observation, Jentsch and colleagues subchronically treated monkeys and rats with PCP and found cognitive deficits and associated prefrontal neurochemical abnormalities (reviewed in Jentsch and Roth, 1999). The subchronic PCP model has since been quite widely employed as a rodent model for executive dysfunctions in schizophrenia.\nIn order to test the subchronic PCP model in the touchscreen-based assay, Brigman et al. (2009) treated C57BL/6J mice with 5 mg/kg PCP twice daily for 7 days and, after a 7-day withdrawal period, tested for discrimination and (in a separate group of mice) reversal in the touchscreen-based task. This treatment and withdrawal duration was based on previous work by Jentsch et al. (1997a). Results showed no significant impairments in drug-treated mice in comparison to vehicle treated controls on either discrimination or reversal, as measured using a range of dependent variables. By contrast, the same treatment regimen that failed to affect discrimination or reversal was sufficient to reduce social behavior – demonstrating that treatment was sufficient to mimic some symptoms of schizophrenia.\nWhile Brigman et al. (2009) was the first study of the PCP model in a rodent touchscreen-based procedure, the lack of impairment may appear somewhat surprising, given PCP-induced deficits have been found on other measures of reversal in rats and mice (summarized in Table 1). However, similar to Brigman et al., negative effects on reversal have also been reported (including in studies in which there are clear PCP-induced deficits in the EDS component, e.g., Rodefer et al., 2005, 2008; Egerton et al., 2008). Direct comparisons between studies are further complicated by variations in treatment regimen and methodology. For example, while Neill and colleagues (Abdul-Monim et al., 2006, 2007) have demonstrated reversal impairments in a light-cue based operant task in rats subjected to a PCP treatment and withdrawal procedure comparable to Brigman et al., their task required subjects to completely inhibit responses on some trials to obtain reward, which likely placed greater demands on inhibitory control than the task used by Brigman et al. (in which a response was always available). This is likely a salient difference because subchronic PCP treatment impairs inhibitory control in rats and non-human primates (Jentsch et al., 1997b, 2000; Jentsch and Taylor, 2001). Clearly, further work is needed to parse the most critical features of reversal assays that render them sensitive to subchronic PCP treatment.\nTable 1 Studies on the effects of acute and chronic PCP treatment on measures of cognitive flexibility. IDS/EDS, intra-dimensional/extra-dimensional set shifting; w/d, withdrawal period prior to testing.\nTable 2 Examples of studies of cognitive flexibility in mutant mice. IDS/EDS, intra-dimensional/extra-dimensional shifting task; MWM, Morris water maze.\n\n"}