ABSTRACT
Cognitive deficits in schizophrenia are a major source of dysfunction for which more effective treatments are needed. The vasopressin-deficient Brattleboro (BRAT) rat has been shown to have several natural schizophrenia-like deficits, including impairments in prepulse inhibition and memory. We investigated BRAT rats and their parental strain, Long-Evans (LE) rats, in a social discrimination paradigm, which is an ethologically relevant animal test of cognitive deficits of schizophrenia based upon the natural preference of animals to investigate conspecifics. We also investigated the effects of the atypical antipsychotic, clozapine, and the putative antipsychotic, PD149163, a brain-penetrating neurotensin-1 agonist, on social discrimination in these rats. Adult rats were administered saline or one of the three doses of clozapine (0.1, 1.0, or 10 mg/kg) or PD149163 (0.1, 0.3, or 1.0 mg/kg), subcutaneously. Following drug administration, adult rats were exposed to a juvenile rat for a 4-min learning period. Animals were then housed individually for 30 min and then simultaneously exposed to the juvenile presented previously and a new juvenile for 4 min. Saline-treated LE rats, but not BRAT rats, exhibited intact social discrimination as evidenced by greater time spent exploring the new juvenile. The highest dose of clozapine and the two highest doses of PD149163 restored social discrimination in BRAT rats. These results provide further support for the utility of the BRAT rat as a genetic animal model relevant to schizophrenia and drug discovery. The potential of neurotensin agonists as putative treatments for cognitive deficits of schizophrenia was also supported.
Subject(s)
Clozapine/pharmacology , Cognition Disorders/drug therapy , Mental Disorders/drug therapy , Neurotensin/agonists , Schizophrenia/drug therapy , Social Behavior , Animals , Antipsychotic Agents/pharmacology , Brain/drug effects , Brain/metabolism , Brain/physiopathology , Cognition Disorders/etiology , Cognition Disorders/physiopathology , Disease Models, Animal , Dose-Response Relationship, Drug , Exploratory Behavior/drug effects , Exploratory Behavior/physiology , Male , Mental Disorders/etiology , Mental Disorders/physiopathology , Neurotensin/analogs & derivatives , Neurotensin/metabolism , Neurotensin/pharmacology , Rats , Rats, Brattleboro , Rats, Long-Evans , Receptors, Neurotensin/agonists , Receptors, Neurotensin/metabolism , Schizophrenia/complications , Schizophrenia/physiopathology , Schizophrenic PsychologyABSTRACT
Studies of neurobiological disorders in the brain, including schizophrenia, rely on the use of postmortem brain tissues, in which an understanding of the effects of various pre- and postmortem variables on gene expression is critical. In several different brain regions, pH has been shown to have a large effect on postmortem brain gene expression patterns. One region that has not yet been evaluated in such studies is the hippocampus, a region often implicated in schizophrenia research. In the present study, we show that postmortem brain pH is similar across different brain regions. Brain pH accounted for greater variation in hippocampal gene expression profiles than any other parameter evaluated, including gender and schizophrenia. The predictive value of brain pH in an independent sample set was also greater than the disease, demonstrating that pH represents one of the most important control parameters in human postmortem gene expression studies in schizophrenia.
Subject(s)
Gene Expression/physiology , Hippocampus/chemistry , Hippocampus/metabolism , Nerve Tissue Proteins/genetics , RNA, Messenger/metabolism , Adult , Age Factors , Aged , Female , Gene Expression Profiling/methods , Humans , Hydrogen-Ion Concentration , Hypoxia-Ischemia, Brain/metabolism , Hypoxia-Ischemia, Brain/physiopathology , Male , Middle Aged , Postmortem Changes , Predictive Value of Tests , RNA, Messenger/analysis , Schizophrenia/genetics , Schizophrenia/metabolism , Schizophrenia/physiopathology , Sex Factors , Smoking/adverse effectsABSTRACT
Nicotine is known to induce the release of multiple neurotransmitters, including glutamate and dopamine, through activation of nicotinic receptors. Gene expression in the N-methyl-d-aspartate postsynaptic density (NMDA-PSD), as well as other functional groups, was compared in postmortem hippocampus of schizophrenic and nonmentally ill smokers and nonsmokers utilizing a microarray and quantitative RT-PCR approach. The expression of 277 genes was significantly changed between all smokers and nonsmokers. Specific gene groups, most notably genes expressed in the NMDA-PSD, were prevalent among these transcripts. Analysis of the interaction between smoking and schizophrenia identified several genes in the NMDA-PSD that were differentially affected by smoking in patients. The present findings suggest that smoking may differentially modulate glutamatergic function in schizophrenic patients and control subjects. The biological mechanisms underlying chronic tobacco use are likely to differ substantially between these two groups.
