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pubmed: 0006-3223



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

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

Biol Psychiatry. 2016 Oct 13;:

Authors: Szumlinski KK, Lominac KD, Campbell RR, Cohen M, Fultz EK, Brown CN, Miller BW, Quadir SG, Martin D, Thompson AB, von Jonquieres G, Klugmann M, Phillips TJ, Kippin TE

Abstract
BACKGROUND: The high prevalence and severity of methamphetamine (MA) abuse demands greater neurobiological understanding of its etiology.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: Our data point to an idiopathic, genetic, or drug-induced hyperglutamatergic state within the NAC as a mediator of MA addiction vulnerability.

PMID: 27890469 [PubMed - as supplied by publisher]




Genetic Overlap Between Attention-Deficit/Hyperactivity Disorder and Bipolar Disorder: Evidence From Genome-wide Association Study Meta-analysis.

Genetic Overlap Between Attention-Deficit/Hyperactivity Disorder and Bipolar Disorder: Evidence From Genome-wide Association Study Meta-analysis.

Biol Psychiatry. 2016 Oct 18;:

Authors: van Hulzen KJ, Scholz CJ, Franke B, Ripke S, Klein M, McQuillin A, Sonuga-Barke EJ, PGC ADHD Working Group, Kelsoe JR, Landén M, Andreassen OA, PGC Bipolar Disorder Working Group, Lesch KP, Weber H, Faraone SV, Arias-Vasquez A, Reif A

Abstract
BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) and bipolar disorder (BPD) are frequently co-occurring and highly heritable mental health conditions. We hypothesized that BPD cases with an early age of onset (≤21 years old) would be particularly likely to show genetic covariation with ADHD.
METHODS: Genome-wide association study data were available for 4609 individuals with ADHD, 9650 individuals with BPD (5167 thereof with early-onset BPD), and 21,363 typically developing controls. We conducted a cross-disorder genome-wide association study meta-analysis to identify whether the observed comorbidity between ADHD and BPD could be due to shared genetic risks.
RESULTS: We found a significant single nucleotide polymorphism-based genetic correlation between ADHD and BPD in the full and age-restricted samples (rGfull = .64, p = 3.13 × 10(-14); rGrestricted = .71, p = 4.09 × 10(-16)). The meta-analysis between the full BPD sample identified two genome-wide significant (prs7089973 = 2.47 × 10(-8); prs11756438 = 4.36 × 10(-8)) regions located on chromosomes 6 (CEP85L) and 10 (TAF9BP2). Restricting the analyses to BPD cases with an early onset yielded one genome-wide significant association (prs58502974 = 2.11 × 10(-8)) on chromosome 5 in the ADCY2 gene. Additional nominally significant regions identified contained known expression quantitative trait loci with putative functional consequences for NT5DC1, NT5DC2, and CACNB3 expression, whereas functional predictions implicated ABLIM1 as an allele-specific expressed gene in neuronal tissue.
CONCLUSIONS: The single nucleotide polymorphism-based genetic correlation between ADHD and BPD is substantial, significant, and consistent with the existence of genetic overlap between ADHD and BPD, with potential differential genetic mechanisms involved in early and later BPD onset.

PMID: 27890468 [PubMed - as supplied by publisher]