Psychopharmacology
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Studies employing the Iowa Gambling Task (IGT) demonstrated that areas of the frontal cortex, including the ventromedial prefrontal cortex, orbitofrontal cortex (OFC), dorsolateral prefrontal cortex, and anterior cingulate cortex (ACC), are involved in the decision-making process. However, the precise role of these regions in maintaining optimal choice is not clear. ⋯ Online activity of the IL or PrL cortex is important for maintaining an optimal decision-making strategy, but optimal performance on the rGT does not require frontal cortex dopamine D2 receptor activation. Additionally, these results demonstrate that the roles of different cortical regions in cost-benefit decision-making may be dissociated using the rGT.
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Pain-related anxiety and depression are well known to be comorbid with chronic pain and adversely affect patient quality of life. Recent studies have shown that anxiety-like behaviors also develop with acute surgical pain, but the effects of general anesthetics on acute pain-related anxiety are unknown. ⋯ This study suggests that sevoflurane, but not intravenous anesthetics, inhibits pain-related anxiety, along with ERK activation in the ACC, probably through inhibition of spinal nociceptive transmission. Intraoperative application of inhaled anesthetics may be a better choice to reduce postoperative anxiety.
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Neuroimaging has been identified as a potentially powerful probe for the in vivo study of drug effects on the brain with utility across several phases of drug development spanning preclinical and clinical investigations. Specifically, neuroimaging can provide insight into drug penetration and distribution, target engagement, pharmacodynamics, mechanistic action and potential indicators of clinical efficacy. ⋯ In this review, we present examples and suggestions for how machine learning could help answer fundamental questions spanning the drug discovery pipeline: (1) Who should I recruit for this study? (2) What should I measure and when should I measure it? (3) How does the pharmacological agent behave using an experimental medicine model?, and (4) How does a compound differ from and/or resemble existing compounds? Specifically, we present studies from the literature and we suggest areas for the focus of future development. Further refinement and tailoring of machine learning techniques may help realise their tremendous potential for drug discovery and drug validation.
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Aberrant prefrontal-hippocampal (PFC-HC) connectivity is disrupted in several psychiatric and at-risk conditions. Advances in rodent functional imaging have opened the possibility that this phenotype could serve as a translational imaging marker for psychiatric research. Recent evidence from functional magnetic resonance imaging (fMRI) studies has indicated an increase in PFC-HC coupling during working-memory tasks in both schizophrenic patients and at-risk populations, in contrast to a decrease in resting-state PFC-HC connectivity. Acute ketamine challenge is widely used in both humans and rats as a pharmacological model to study the mechanisms of N-methyl-D-aspartate (NMDA) receptor hypofunction in the context of psychiatric disorders. ⋯ This translational comparison demonstrates a cross-species consistency in pharmacological effect and elucidates ketamine-induced alterations in PFC-HC coupling, a phenotype often disrupted in pathological conditions, which may give clue to understanding of psychiatric disorders and their onset, and help in the development of new treatments.
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Acute low-dose administration of the N-methyl-D-aspartate (NMDA) receptor antagonist, ketamine, produces rapid and sustained antidepressant-like effects in humans and rodents. Recently, we found that the long-lasting effect of ketamine on the forced swim test requires ventral hippocampal (vHipp) activity at the time of drug administration. The medial prefrontal cortex (mPFC), a target of the vHipp dysregulated in depression, is important for cognitive flexibility and response strategy selection. Deficits in cognitive flexibility, the ability to modify thoughts and behaviors in response to changes in the environment, are associated with depression. We have shown that chronic stress impairs cognitive flexibility on the attentional set-shifting test (AST) and induces a shift from active to passive response strategies on the shock-probe defensive burying test (SPDB). ⋯ These results show that ketamine restores cognitive flexibility and coping response strategy compromised by stress. Activity in the vHipp-mPFC pathway may represent a neural substrate for some of the antidepressant-like behavioral effects of ketamine, including cognitive flexibility, but other circuits may mediate the effects of ketamine on coping response strategy.