Down-regulation of hippocampal genes regulating dopaminergic, GABAergic and glutamatergic function following combined neonatal phencyclidine and post-weaning social isolation of rats as a neurodevelopmental model for schizophrenia
Background: Dysfunction of dopaminergic, GABAergic and glutamatergic function underlies many core symptoms of schizophrenia. Combined neonatal injection of the N-methyl-D-aspartate (NMDA) receptor antagonist, phencyclidine (PCP) and post-weaning social isolation of rats produces a behavioral syndrom...
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Cambridge University Press
2016
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| Online Access: | https://eprints.nottingham.ac.uk/37102/ |
| _version_ | 1848795392521535488 |
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| author | Gaskin, Philip L.R. Toledo-Rodriguez, Maria Alexander, Stephen P.H. Fone, Kevin C.F. |
| author_facet | Gaskin, Philip L.R. Toledo-Rodriguez, Maria Alexander, Stephen P.H. Fone, Kevin C.F. |
| author_sort | Gaskin, Philip L.R. |
| building | Nottingham Research Data Repository |
| collection | Online Access |
| description | Background: Dysfunction of dopaminergic, GABAergic and glutamatergic function underlies many core symptoms of schizophrenia. Combined neonatal injection of the N-methyl-D-aspartate (NMDA) receptor antagonist, phencyclidine (PCP) and post-weaning social isolation of rats produces a behavioral syndrome with translational relevance to several core symptoms of schizophrenia. This study uses DNA microarray to characterise alterations in hippocampal neurotransmitter-related gene expression and examines the ability of the sodium channel blocker, lamotrigine, to reverse behavioral changes in this model.
Methods: Fifty-four male Lister-hooded rat pups either received phencyclidine (PCP, 10 mg/kg, s.c.), on post-natal day (PND) 7, 9 and 11 before being weaned on PND 23 into separate cages (isolation, PCP-SI, n=31), or vehicle injection and group-housing (2-4 per cage, V-GH, n=23) from weaning. The effect of lamotrigine on locomotor activity, novel object recognition, and prepulse inhibition of acoustic startle was examined (PND60-75) and drug-free hippocampal gene expression on PND70.
Results: Acute lamotrigine (10-15mg/kg i.p.) reversed the hyperactivity and novel object recognition impairment induced by PCP-SI but had no effect on the prepulse inhibition deficit. Microarray revealed small but significant down-regulation of hippocampal genes involved in glutamate metabolism, dopamine neurotransmission and GABA receptor signalling, and in specific schizophrenia-linked genes, including PVALB and GAD67, in PCP-SI rats which resemble changes reported in schizophrenia.
Conclusions: Findings indicate that alterations in dopamine neurotransmission, glutamate metabolism and GABA signalling may contribute to some of the behavioral deficits observed following PCP-SI, and that lamotrigine may have some utility as an adjunctive therapy to improve certain cognitive deficits symptoms in schizophrenia. |
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| id | nottingham-37102 |
| institution | University of Nottingham Malaysia Campus |
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| last_indexed | 2025-11-14T19:31:22Z |
| publishDate | 2016 |
| publisher | Cambridge University Press |
| recordtype | eprints |
| repository_type | Digital Repository |
| spelling | nottingham-371022020-05-04T18:01:15Z https://eprints.nottingham.ac.uk/37102/ Down-regulation of hippocampal genes regulating dopaminergic, GABAergic and glutamatergic function following combined neonatal phencyclidine and post-weaning social isolation of rats as a neurodevelopmental model for schizophrenia Gaskin, Philip L.R. Toledo-Rodriguez, Maria Alexander, Stephen P.H. Fone, Kevin C.F. Background: Dysfunction of dopaminergic, GABAergic and glutamatergic function underlies many core symptoms of schizophrenia. Combined neonatal injection of the N-methyl-D-aspartate (NMDA) receptor antagonist, phencyclidine (PCP) and post-weaning social isolation of rats produces a behavioral syndrome with translational relevance to several core symptoms of schizophrenia. This study uses DNA microarray to characterise alterations in hippocampal neurotransmitter-related gene expression and examines the ability of the sodium channel blocker, lamotrigine, to reverse behavioral changes in this model. Methods: Fifty-four male Lister-hooded rat pups either received phencyclidine (PCP, 10 mg/kg, s.c.), on post-natal day (PND) 7, 9 and 11 before being weaned on PND 23 into separate cages (isolation, PCP-SI, n=31), or vehicle injection and group-housing (2-4 per cage, V-GH, n=23) from weaning. The effect of lamotrigine on locomotor activity, novel object recognition, and prepulse inhibition of acoustic startle was examined (PND60-75) and drug-free hippocampal gene expression on PND70. Results: Acute lamotrigine (10-15mg/kg i.p.) reversed the hyperactivity and novel object recognition impairment induced by PCP-SI but had no effect on the prepulse inhibition deficit. Microarray revealed small but significant down-regulation of hippocampal genes involved in glutamate metabolism, dopamine neurotransmission and GABA receptor signalling, and in specific schizophrenia-linked genes, including PVALB and GAD67, in PCP-SI rats which resemble changes reported in schizophrenia. Conclusions: Findings indicate that alterations in dopamine neurotransmission, glutamate metabolism and GABA signalling may contribute to some of the behavioral deficits observed following PCP-SI, and that lamotrigine may have some utility as an adjunctive therapy to improve certain cognitive deficits symptoms in schizophrenia. Cambridge University Press 2016-07-15 Article PeerReviewed Gaskin, Philip L.R., Toledo-Rodriguez, Maria, Alexander, Stephen P.H. and Fone, Kevin C.F. (2016) Down-regulation of hippocampal genes regulating dopaminergic, GABAergic and glutamatergic function following combined neonatal phencyclidine and post-weaning social isolation of rats as a neurodevelopmental model for schizophrenia. International Journal of Neuropsychopharmacology . ISSN 1469-5111 Isolation Rearing Lamotrigine Microarray Phencyclidine Schizophrenia Glutamate http://ijnp.oxfordjournals.org/content/early/2016/07/15/ijnp.pyw062 doi:10.1093/ijnp/pyw062 doi:10.1093/ijnp/pyw062 |
| spellingShingle | Isolation Rearing Lamotrigine Microarray Phencyclidine Schizophrenia Glutamate Gaskin, Philip L.R. Toledo-Rodriguez, Maria Alexander, Stephen P.H. Fone, Kevin C.F. Down-regulation of hippocampal genes regulating dopaminergic, GABAergic and glutamatergic function following combined neonatal phencyclidine and post-weaning social isolation of rats as a neurodevelopmental model for schizophrenia |
| title | Down-regulation of hippocampal genes regulating dopaminergic, GABAergic and glutamatergic function following combined neonatal phencyclidine and post-weaning social isolation of rats as a neurodevelopmental model for schizophrenia |
| title_full | Down-regulation of hippocampal genes regulating dopaminergic, GABAergic and glutamatergic function following combined neonatal phencyclidine and post-weaning social isolation of rats as a neurodevelopmental model for schizophrenia |
| title_fullStr | Down-regulation of hippocampal genes regulating dopaminergic, GABAergic and glutamatergic function following combined neonatal phencyclidine and post-weaning social isolation of rats as a neurodevelopmental model for schizophrenia |
| title_full_unstemmed | Down-regulation of hippocampal genes regulating dopaminergic, GABAergic and glutamatergic function following combined neonatal phencyclidine and post-weaning social isolation of rats as a neurodevelopmental model for schizophrenia |
| title_short | Down-regulation of hippocampal genes regulating dopaminergic, GABAergic and glutamatergic function following combined neonatal phencyclidine and post-weaning social isolation of rats as a neurodevelopmental model for schizophrenia |
| title_sort | down-regulation of hippocampal genes regulating dopaminergic, gabaergic and glutamatergic function following combined neonatal phencyclidine and post-weaning social isolation of rats as a neurodevelopmental model for schizophrenia |
| topic | Isolation Rearing Lamotrigine Microarray Phencyclidine Schizophrenia Glutamate |
| url | https://eprints.nottingham.ac.uk/37102/ https://eprints.nottingham.ac.uk/37102/ https://eprints.nottingham.ac.uk/37102/ |