Dataset Information

Methamphetamine Addiction Vulnerability: The Glutamate, the Bad, and the Ugly.

ABSTRACT: The high prevalence and severity of methamphetamine (MA) abuse demands greater neurobiological understanding of its etiology.We conducted immunoblotting and in vivo microdialysis procedures in MA high/low drinking mice, as well as in isogenic C57BL/6J mice that varied in their MA preference/taking, to examine the glutamate underpinnings of MA abuse vulnerability. Neuropharmacological and Homer2 knockdown approaches were also used in C57BL/6J mice to confirm the role for nucleus accumbens (NAC) glutamate/Homer2 expression in MA preference/aversion.We identified a hyperglutamatergic state within the NAC as a biochemical trait corresponding with both genetic and idiopathic vulnerability for high MA preference and taking. We also confirmed that subchronic subtoxic MA experience elicits a hyperglutamatergic state within the NAC during protracted withdrawal, characterized by elevated metabotropic glutamate 1/5 receptor function and Homer2 receptor-scaffolding protein expression. A high MA-preferring phenotype was recapitulated by elevating endogenous glutamate within the NAC shell of mice and we reversed MA preference/taking by lowering endogenous glutamate and/or Homer2 expression within this subregion.Our data point to an idiopathic, genetic, or drug-induced hyperglutamatergic state within the NAC as a mediator of MA addiction vulnerability.

SUBMITTER: Szumlinski KK

PROVIDER: S-EPMC5391296 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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Publications

Methamphetamine Addiction Vulnerability: The Glutamate, the Bad, and the Ugly.

Szumlinski Karen K KK Lominac Kevin D KD Campbell Rianne R RR Cohen Matan M Fultz Elissa K EK Brown Chelsea N CN Miller Bailey W BW Quadir Sema G SG Martin Douglas D Thompson Andrew B AB von Jonquieres Georg G Klugmann Matthias M Phillips Tamara J TJ Kippin Tod E TE

Biological psychiatry 20161013 11

<h4>Background</h4>The high prevalence and severity of methamphetamine (MA) abuse demands greater neurobiological understanding of its etiology.<h4>Methods</h4>We conducted immunoblotting and in vivo microdialysis procedures in MA high/low drinking mice, as well as in isogenic C57BL/6J mice that varied in their MA preference/taking, to examine the glutamate underpinnings of MA abuse vulnerability. Neuropharmacological and Homer2 knockdown approaches were also used in C57BL/6J mice to confirm the ...[more]

PMID: 27890469

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Project description:Significant progress in the manufacturing of biopharmaceuticals has been made by increasing the overall titers in the USP (upstream processing) titers without raising the cost of the USP. In addition, the development of platform processes led to a higher process robustness. Despite or even due to those achievements, novel challenges are in sight. The higher upstream titers created more complex impurity profiles, both in mass and composition, demanding higher separation capacities and selectivity in downstream processing (DSP). This creates a major shift of costs from USP to DSP. In order to solve this issue, USP and DSP integration approaches can be developed and used for overall process optimization. This study focuses on the characterization and classification of host cell proteins (HCPs) in each unit operation of the DSP (i.e., aqueous two-phase extraction, integrated countercurrent chromatography). The results create a data-driven feedback to the USP, which will serve for media and process optimizations in order to reduce, or even eliminate nascent critical HCPs. This will improve separation efficiency and may lead to a quantitative process understanding. Different HCP species were classified by stringent criteria with regard to DSP separation parameters into "The Good, the Bad, and the Ugly" in terms of pI and MW using 2D-PAGE analysis depending on their positions on the gels. Those spots were identified using LC-MS/MS analysis. HCPs, which are especially difficult to remove and persistent throughout the DSP (i.e., "Bad" or "Ugly"), have to be evaluated by their ability to be separated. In this approach, HCPs, considered "Ugly," represent proteins with a MW larger than 15 kDa and a pI between 7.30 and 9.30. "Bad" HCPs can likewise be classified using MW (>15 kDa) and pI (4.75-7.30 and 9.30-10.00). HCPs with a MW smaller than 15 kDa and a pI lower than 4.75 and higher than 10.00 are classified as "Good" since their physicochemical properties differ significantly from the product. In order to evaluate this classification scheme, it is of utmost importance to use orthogonal analytical methods such as IEX, HIC, and SEC.

Dataset Information

Methamphetamine Addiction Vulnerability: The Glutamate, the Bad, and the Ugly.

Publications

Methamphetamine Addiction Vulnerability: The Glutamate, the Bad, and the Ugly.

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