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Computational Design And Molecular Modeling Of Morphine Derivatives For Preferential Binding In Inflamed Tissue, Makena Augenstein, Nayiri Alexander, Matthew Gartner

Biology, Chemistry, and Environmental Sciences Faculty Articles and Research

The opioid epidemic has impacted over 10 million Americans in 2019. Opioids, like morphine, bind non-selectively in both peripheral tissue, leading to effective pain relief, and central tissue, resulting in dangerous side effects and addiction. The inflamed conditions of injured tissues have a lower pH (pH = 6–6.5) environment than healthy tissue (pH = 7.4). We aim to design a morphine derivative that binds selectively within inflamed tissue using molecular extension and dissection techniques. Morphine binds to the μ-opioid receptor (MOR) when the biochemically active amine group is protonated. Fluorination of a β-carbon from the tertiary amine group led to …

Single-Cell Glia And Neuron Gene Expression In The Central Amygdala In Opioid Withdrawal Suggests Inflammation With Correlated Gut Dysbiosis, Sean J. O'Sullivan, Evangelia Malahias, James Park, Ankita Srivastava, Beverly A.S. Reyes, Jonathan Gorky, Rajanikanth Vadigepalli, Elisabeth J. Van Bockstaele, James S. Schwaber

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Drug-seeking in opioid dependence is due in part to the severe negative emotion associated with the withdrawal syndrome. It is well-established that negative emotional states emerge from activity in the amygdala. More recently, gut microflora have been shown to contribute substantially to such emotions. We measured gene expression in single glia and neurons gathered from the amygdala using laser capture microdissection and simultaneously measured gut microflora in morphine-dependent and withdrawn rats to investigate drivers of negative emotion in opioid withdrawal. We found that neuroinflammatory genes, notably Tnf, were upregulated in the withdrawal condition and that astrocytes, in particular, were highly …

Cb1 Receptor Antagonism Blocks Stress-Potentiated Reinstatement Of Cocaine Seeking In Rats, Jayme R. Mcreynolds, Elizabeth M. Doncheck, Oliver Vranjkovic, Geoffrey S. Ganzman, David A. Baker, Cecilia J. Hillard, John R. Mantsch

Biomedical Sciences Faculty Research and Publications

Rationale

Under some conditions, stress, rather than directly triggering cocaine seeking, potentiates reinstatement to other stimuli, including a subthreshold cocaine dose. The mechanisms responsible for stress-potentiated reinstatement are not well defined. Endocannabinoid signaling is increased by stress and regulates synaptic transmission in brain regions implicated in motivated behavior.

Objectives

The objective of this study was to test the hypothesis that cannabinoid type 1 receptor (CB1R) signaling is required for stress-potentiated reinstatement of cocaine seeking in rats.

Methods

Following i.v. cocaine self-administration (2 h access/day) and extinction in male rats, footshock stress alone does not reinstate cocaine seeking but reinstatement is …

Drug Predictive Cues Activate Aversion-Sensitive Striatal Neurons That Encode Drug Seeking, Daniel S. Wheeler, Mykel A. Robble, Emily M. Hebron, Matthew J. Dupont, Amanda L. Ebben, Robert A. Wheeler

Biomedical Sciences Faculty Research and Publications

Drug-associated cues have profound effects on an addict’s emotional state and drug-seeking behavior. Although this influence must involve the motivational neural system that initiates and encodes the drug-seeking act, surprisingly little is known about the nature of such physiological events and their motivational consequences. Three experiments investigated the effect of a cocaine-predictive stimulus on dopamine signaling, neuronal activity, and reinstatement of cocaine seeking. In all experiments, rats were divided into two groups (paired and unpaired), and trained to self-administer cocaine in the presence of a tone that signaled the immediate availability of the drug. For rats in the paired group, …

Exposure To Kynurenic Acid During Adolescence Increases Sign-Tracking And Impairs Long-Term Potentiation In Adulthood, Nicole E. Deangeli, Travis P. Todd, Stephen E. Chang, Hermes H. Yeh, Pamela W. Yeh, David J. Bucci

Dartmouth Scholarship

Changes in brain reward systems are thought to contribute significantly to the cognitive and behavioral impairments of schizophrenia, as well as the propensity to develop co-occurring substance abuse disorders. Presently, there are few treatments for persons with a dual diagnosis and little is known about the neural substrates that underlie co-occurring schizophrenia and substance abuse. One goal of the present study was to determine if a change in the concentration of kynurenic acid (KYNA), a tryptophan metabolite that is increased in the brains of people with schizophrenia, affects reward-related behavior. KYNA is an endogenous antagonist of NMDA glutamate receptors and …

Interactions Among Positions In The Third And Fourth Membrane-Associated Domains At The Intersubunit Interface Of The N-Methyl-D-Aspartate Receptor Forming Sites Of Alcohol Action, Hong Ren, Yulin Zhao, Donard S. Dwyer, Robert W. Peoples

Biomedical Sciences Faculty Research and Publications

The N-methyl-d-aspartate (NMDA) glutamate receptor is a major target of ethanol in the brain. Previous studies have identified positions in the third and fourth membrane-associated (M) domains of the NMDA receptor GluN1 and GluN2A subunits that influence alcohol sensitivity. The predicted structure of the NMDA receptor, based on that of the related GluA2 subunit, indicates a close apposition of the alcohol-sensitive positions in M3 and M4 between the two subunit types. We tested the hypothesis that these positions interact to regulate receptor kinetics and ethanol sensitivity by using dual substitution mutants. In single-substitution mutants, we found that a position …