dizocilpine-maleate and AIDS-Related-Complex

Cognitive dysfunctions are common in major depressive disorder, but have been difficult to recapitulate in animal models. This study shows that Flinders sensitive line (FSL) rats, a genetic rat model of depression, display a pronounced impairment of emotional memory function in the passive avoidance (PA) task, accompanied by reduced transcription of Arc in prefrontal cortex and hippocampus. At the cellular level, FSL rats have selective reductions in levels of NMDA receptor subunits, serotonin 5-HT(1A) receptors and MEK activity. Treatment with chronic escitalopram, but not with an antidepressant regimen of nortriptyline, restored memory performance and increased Arc transcription in FSL rats. Multiple pharmacological manipulations demonstrated that procognitive effects could also be achieved by either disinhibition of 5-HT(1A)R/MEK/Arc or stimulation of 5-HT₄R/MEK/Arc signaling cascades. Taken together, studies of FSL rats in the PA task revealed reversible deficits in emotional memory processing, providing a potential model with predictive and construct validity for assessments of procognitive actions of antidepressant drug therapies.

Topics: AIDS-Related Complex; Analysis of Variance; Animals; Avoidance Learning; Benzopyrans; Brain-Derived Neurotrophic Factor; Citalopram; Depression; Disease Models, Animal; Dizocilpine Maleate; Emotions; Enzyme Inhibitors; Excitatory Amino Acid Antagonists; Exploratory Behavior; Gene Expression Regulation; Hippocampus; Immunoprecipitation; MAP Kinase Signaling System; Memory Disorders; Prefrontal Cortex; Rats; Rats, Mutant Strains; Receptors, N-Methyl-D-Aspartate; Receptors, Serotonin; Selective Serotonin Reuptake Inhibitors; Serotonin; Swimming

The effect of coincident stimulation of convergent corticostriatal inputs was analyzed by the induction of immediate early genes in striatal neurons. Cortical motor areas were stimulated through implanted electrodes in awake, behaving rats, and the induction of the mRNAs encoding the immediate early genes (IEGs) c-fos and arc was analyzed in the striatum with in situ hybridization histochemistry. In the first experiment, unilateral stimulation of the medial agranular cortex, orofacial region of the lateral agranular cortex or the forelimb region of the lateral agranular cortex resulted in IEG induction in the striatum, which was restricted to the topographically related area receiving input from the stimulated cortical area. In a second experiment, stimulation parameters were altered, including frequency, number of pulses/train, and number of trains/s. These parameters did not have a significant effect on IEG induction. Notably, in some cases, in which there was IEG induction not only in the stimulated cortical region, but also in the homologous area in the contralateral hemisphere, very robust IEG induction was observed in the striatum. In a third experiment, the orofacial regions of the lateral agranular cortex of both hemispheres were stimulated coincidently. All of these animals showed robust striatal IEG induction. This IEG induction was attenuated by pretreatment with an NMDA antagonist MK-801. In a fourth experiment, we tested whether the coincidence of bilateral cortical stimulation contributed to the efficacy of striatal IEG induction. Either alternating stimulation or coincident stimulation of non-homologous cortical regions produced significantly lower striatal IEG induction than obtained with coincident stimulation of homologous cortical areas. Enhanced striatal IEG induction occurred in indirect striatal neurons, labeled with enkephalin, but was also present in a large number of enkephalin-negative neurons, most of which are likely direct pathway neurons. These results suggest that regional and temporal convergence of cortical inputs enhances striatal IEG induction.

Topics: AIDS-Related Complex; Animals; Corpus Striatum; Dizocilpine Maleate; Dose-Response Relationship, Radiation; Electric Stimulation; Enkephalins; Excitatory Amino Acid Antagonists; Functional Laterality; Gene Expression; Genes, fos; Genes, Immediate-Early; In Situ Hybridization; Male; Motor Cortex; Rats; Rats, Sprague-Dawley; RNA, Messenger

Focal brain infarcts are surrounded by extended perilesional zones that comprise the partially ischemic penumbra but also completely non-ischemic cortex of the remote ipsilateral hemisphere. To delineate the impact of lesion-associated vs. remote processes on transcriptional programming after focal ischemia, we used cDNA array analysis, quantitative real-time polymerase chain reaction and immunohistochemistry in the photothrombosis model of circumscribed cortical ischemia in rats. At an early stage of 4 h after ischemia, gene induction occurred to a similar extent in the ischemic infarct and remote non-ischemic cortex of the ipsilateral hemisphere. Among the genes induced in non-ischemic cortex we found the NGF-inducible genes PC3, VGF and Arc, the transcriptional regulators I kappa B-alpha and Stat3, and the beta-chemokine MIP-1 alpha (CCL3). At 3 days, the spatial pattern of gene expression had changed dramatically with brain fatty acid-binding protein as the only gene significantly induced in non-ischemic ipsilateral cortex. In contrast, numerous genes were exclusively regulated at the lesion site, comprising genes involved in cell cycle regulation, proteolysis, apoptosis, lipid homeostasis and anti-inflammatory counter-regulation. Cortical spreading depression was identified as the main mechanism underlying gene induction in remote non-ischemic cortex. Our data demonstrate a dynamic spatiotemporal pattern of gene induction, which may contribute to delayed progression of damage or, alternatively, mediate neuroprotection, tissue remodeling and functional compensation.

Topics: AIDS-Related Complex; Animals; Brain Ischemia; Carrier Proteins; Cathepsin K; Cathepsins; Cdc20 Proteins; Cell Cycle Proteins; Cerebral Cortex; Cerebral Infarction; Cortical Spreading Depression; Dizocilpine Maleate; DNA-Binding Proteins; Drug Interactions; Excitatory Amino Acid Antagonists; Fatty Acid-Binding Protein 7; Fatty Acid-Binding Proteins; Functional Laterality; Gene Expression Profiling; Gene Expression Regulation; HSP70 Heat-Shock Proteins; Immunohistochemistry; Male; Nerve Tissue Proteins; Nuclear Receptor Subfamily 4, Group A, Member 1; Oligonucleotide Array Sequence Analysis; Phosphoric Monoester Hydrolases; Potassium Chloride; Proprotein Convertase 1; Rats; Rats, Wistar; Receptors, Cytoplasmic and Nuclear; Receptors, Steroid; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; STAT3 Transcription Factor; Time Factors; Trans-Activators; Transcription Factors; Transcription, Genetic; Transcriptional Activation