Opioid Receptor Polymorphism A118G Associated With Clinical Severity in a Drug Overdose Population.
Opioid Receptor Polymorphism A118G Associated with Clinical Severity in a Drug Overdose Population.
Filed under: Addiction Rehab
J Med Toxicol. 2013 Jan 15;
Manini AF, Jacobs MM, Vlahov D, Hurd YL
Genetic variations in the human mu-opioid receptor gene (OPRM1) mediate individual differences in response to pain and opiate addiction. We studied whether the common A118G (rs1799971) mu-opioid receptor single nucleotide polymorphism (SNP) was associated with overdose severity in humans. In addition, we examined an SNP responsible for alternative splicing of OPRM1 (rs2075572). We assessed allele frequencies of the above SNPs and associations with clinical severity in patients presenting to the emergency department (ED) with acute drug overdose. This work was designed as an observational cohort study over a 12-month period at an urban teaching hospital. Participants consisted of consecutive adult ED patients with suspected acute drug overdose for whom discarded blood samples were available for analysis. Specimens were linked with clinical variables (demographics, urine toxicology screens, clinical outcomes) then deidentified prior to genetic SNP analysis. Blinded genotyping was performed after standard DNA purification and whole genome amplification. In-hospital severe outcomes were defined as either respiratory arrest (RA; defined by mechanical ventilation) or cardiac arrest (CA; defined by loss of pulse). We analyzed 179 patients (61% male, median age 32) who overall suffered 15 RAs and four CAs, of whom three died. The 118G allele conferred 5.3-fold increased odds of CA/RA (p<0.05), while the rs2075572 variant allele was not associated with CA/RA. The 118G variant allele in the OPRM1 gene is associated with worse clinical severity in patients with acute drug overdose. These findings mark the first time that the 118G variant allele is linked with clinical drug overdose vulnerability. HubMed – addiction
Repeated in vivo exposure of cocaine induces long-lasting synaptic plasticity in hypocretin/orexin neurons in the lateral hypothalamus in mice.
Filed under: Addiction Rehab
J Physiol. 2013 Jan 14;
Rao Y, Mineur YS, Gan G, Wang AH, Liu ZW, Wu X, Suyama S, de Lecea L, Horvath TL, Picciotto MR, Gao XB
Hypocretin (orexin), a neuropeptide synthesized exclusively in the perifornical/lateral hypothalamus, is critical for drug seeking and relapse, but it is not clear how the circuitry centered on hypocretin neurons is modified by drugs of abuse and how changes in this circuit might alter behaviors related to drug addiction. In this study, we show that repeated, but not single, in vivo cocaine administration leads to a long-lasting, experience-dependent potentiation of glutamatergic synapses on hypocretin neurons in mice following a cocaine-conditioned place preference (CPP) paradigm. The synaptic potentiation occurs postsynaptically and likely involves up-regulation of AMPA-type glutamate receptors on hypocretin neurons. Phosphorylation of c-AMP response element binding protein (CREB) is also significantly increased in hypocretin neurons in cocaine-treated animals, suggesting that CREB-mediated pathways may contribute to synaptic potentiation in these cells. Furthermore, the potentiation of synaptic efficacy in hypocretin neurons persists during cocaine withdrawal, but reverses to baseline levels after prolonged abstinence. Finally, the induction of long-term potentiation (LTP) triggered by a high-frequency stimulation is facilitated in hypocretin neurons in cocaine-treated mice, suggesting that long-lasting changes in synapses onto hypocretin neurons would likely be further potentiated by other stimuli (such as concurrent environmental cues) paired with the drug. In summary, we show here that hypocretin neurons undergo experience-dependent synaptic potentiation that is distinct from that reported in other reward systems, such as the ventral tegmental area, following exposure to cocaine. These findings support the idea that the hypocretin system is important for behavioral changes associated with cocaine administration in animals and humans.
HubMed – addiction
Comparison of body composition, basal metabolic rate and metabolic outcomes of adults with Prader Willi syndrome or lesional hypothalamic disease, with primary obesity.
Filed under: Addiction Rehab
Int J Obes (Lond). 2013 Jan 15;
Lloret-Linares C, Faucher P, Coupaye M, Alili R, Green A, Basdevant A, Clément K, Poitou C
Context:The care of patients with hypothalamic obesity is challenging.Objective:To compare body composition, basal metabolic rate (BMR) and metabolic outcomes of adults, with lesional or genetic hypothalamic obesity, with obese patients suffering from primary obesity, once matched for body mass index (BMI).Design and patients:Adults with hypothalamic obesity of genetic origin (Prader Willi syndrome (PWS)) or acquired hypothalamic damage (HD), such as craniopharygioma, were compared with obese control candidates awaiting bariatric surgery (C), with a BMI between 35 and 65?kg?m(-)(2), and aged between 18 and 50 years.Main outcome measures:Body composition measured by whole-body dual-energy X-ray absorptiometry scanning, BMR using indirect calorimetry, hormonal and metabolic assessments.Results:A total of 27 adults with a genetic diagnosis of PWS, 15 obese subjects with HD and 206 obese controls with similar BMI were studied. Compared with the control group, PWS patients had an increased percentage of fat mass (FM), and a decreased percentage of android FM. The BMR of PWS patients was significantly lower than controls and highly correlated with lean body mass in PWS and C patients. Body composition of HD was similar with those of obese patients. A trend toward an increased prevalence of diabetes in HD patients and of cytolysis in PWS was observed in comparison with primary obese patients.Conclusion:Genetic and lesional hypothalamic obesities have different consequences for phenotypic features such as body composition or BMR compared with primary obese patients. The mechanisms of adipose tissue development and metabolic complications may be different between genetic and lesional obesities.International Journal of Obesity advance online publication, 15 January 2013; doi:10.1038/ijo.2012.228.
HubMed – addiction
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