Biological psychiatry
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Biological psychiatry · Dec 2008
Delta FosB-mediated alterations in dopamine signaling are normalized by a palatable high-fat diet.
Sensitivity to reward has been implicated as a predisposing factor for behaviors related to drug abuse as well as overeating. However, the underlying mechanisms contributing to reward sensitivity are unknown. We hypothesized that a dysregulation in dopamine signaling might be an underlying cause of heightened reward sensitivity whereby rewarding stimuli could act to normalize the system. ⋯ These results establish an underlying sensitivity to changes in reward related to dysregulation of Delta FosB and dopamine signaling that can be normalized with palatable diets and may be a predisposing phenotype in some forms of obesity.
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Biological psychiatry · Dec 2008
Varied access to intravenous methamphetamine self-administration differentially alters adult hippocampal neurogenesis.
Chronic abuse of methamphetamine produces deficits in hippocampal function, perhaps by altering hippocampal neurogenesis and plasticity. We examined how intravenous methamphetamine self-administration modulates active division, proliferation of late progenitors, differentiation, maturation, survival, and mature phenotype of hippocampal subgranular zone (SGZ) progenitors. ⋯ Intermittent (occasional access) and daily (limited and extended access) self-administration of methamphetamine impact different aspects of neurogenesis, the former producing initial pro-proliferative effects and the latter producing downregulating effects. These findings suggest that altered hippocampal integrity by even modest doses of methamphetamine could account for pronounced pathology linked to methamphetamine abuse.
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Biological psychiatry · Nov 2008
ReviewOptimizing the design and analysis of clinical functional magnetic resonance imaging research studies.
With the widespread availability of functional magnetic resonance imaging (fMRI), there has been rapid progress in identifying neural correlates of cognition and emotion in the human brain. In conjunction with basic research studies, fMRI has been increasingly applied in clinical disorders, making it a central research tool in human psychopathology, psychopharmacology, and genetics. In the present article, we discuss a number of conceptual and methodological challenges that confront the implementation of fMRI in clinical and translational research, and we offer a set of recommendations intended to enhance the interpretability and reproducibility of results in clinical fMRI.
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Biological psychiatry · Nov 2008
Acute hippocampal brain-derived neurotrophic factor restores motivational and forced swim performance after corticosterone.
Alterations in cellular survival and plasticity are implicated in the neurobiology of depression, based primarily on the characterization of antidepressant efficacy in naïve rodents rather than on models that capture the debilitating and protracted feelings of anhedonia and loss of motivation that are core features of depression. ⋯ Together these findings link persistent alterations in hippocampal BDNF expression and CREB transcriptional activity with a persistent depressive-like state-as opposed to ADT efficacy. These results identify hippocampal BDNF as an essential molecular substrate that bidirectionally regulates appetitive instrumental behavior. Additionally, we suggest this CORT model might provide a powerful tool for future investigation into the neurobiology of complex stress-associated depressive symptoms that persist long after stress exposure itself.
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Biological psychiatry · Nov 2008
Loss of glial glutamate and aspartate transporter (excitatory amino acid transporter 1) causes locomotor hyperactivity and exaggerated responses to psychotomimetics: rescue by haloperidol and metabotropic glutamate 2/3 agonist.
Recent data suggest that excessive glutamatergic signaling in the prefrontal cortex may contribute to the pathophysiology of schizophrenia and that promoting presynaptic glutamate modulation via group II metabotropic glutamate 2/3 (mGlu2/3) receptor activation can exert antipsychotic efficacy. The glial glutamate and aspartate transporter (GLAST) (excitatory amino acid transporter 1 [EAAT1]) regulates extracellular glutamate levels via uptake into glia, but the consequences of GLAST dysfunction for schizophrenia are largely unknown. ⋯ Schizophrenia-related abnormalities in GLAST KO raise the possibility that loss of GLAST-mediated glutamate clearance could be a pathophysiological risk factor for the disease. Our findings provide novel support for the hypothesis that glutamate dysregulation contributes to the pathophysiology of schizophrenia and for the antipsychotic potential of mGlu2/3 agonists.