Corticosterone Potentiation of Cocaine-Induced Reinstatement of Conditioned Place Preference in Mice is Mediated by Blockade of the Organic Cation Transporter 3

The mechanisms by which stressful life events increase the risk of relapse in recovering cocaine addicts are not well understood. We previously reported that stress, via elevated corticosterone, potentiates cocaine-primed reinstatement of cocaine seeking following self-administration in rats and that this potentiation appears to involve corticosterone-induced blockade of dopamine clearance via the organic cation transporter 3 (OCT3). In the present study, we use a conditioned place preference/reinstatement paradigm in mice to directly test the hypothesis that corticosterone potentiates cocaine-primed reinstatement by blockade of OCT3. Consistent with our findings following self-administration in rats, pretreatment of male C57/BL6 mice with corticosterone (using a dose that reproduced stress-level plasma concentrations) potentiated cocaine-primed reinstatement of extinguished cocaine-induced conditioned place preference. Corticosterone failed to re-establish extinguished preference alone but produced a leftward shift in the dose–response curve for cocaine-primed reinstatement. A similar potentiating effect was observed upon pretreatment of mice with the non-glucocorticoid OCT3 blocker, normetanephrine. To determine the role of OCT3 blockade in these effects, we examined the abilities of corticosterone and normetanephrine to potentiate cocaine-primed reinstatement in OCT3-deficient and wild-type mice. Conditioned place preference, extinction and reinstatement of extinguished preference in response to low-dose cocaine administration did not differ between genotypes. However, corticosterone and normetanephrine failed to potentiate cocaine-primed reinstatement in OCT3-deficient mice. Together, these data provide the first direct evidence that the interaction of corticosterone with OCT3 mediates corticosterone effects on drug-seeking behavior and establish OCT3 function as an important determinant of susceptibility to cocaine use

A Glial Variant of the Vesicular Monoamine Transporter Is Required To Store Histamine in the Drosophila Visual System

Unlike other monoamine neurotransmitters, the mechanism by which the brain's histamine content is regulated remains unclear. In mammals, vesicular monoamine transporters (VMATs) are expressed exclusively in neurons and mediate the storage of histamine and other monoamines. We have studied the visual system of Drosophila melanogaster in which histamine is the primary neurotransmitter released from photoreceptor cells. We report here that a novel mRNA splice variant of Drosophila VMAT (DVMAT-B) is expressed not in neurons but rather in a small subset of glia in the lamina of the fly's optic lobe. Histamine contents are reduced by mutation of dVMAT, but can be partially restored by specifically expressing DVMAT-B in glia. Our results suggest a novel role for a monoamine transporter in glia that may be relevant to histamine homeostasis in other systems

FEMOROPLASTY USING AN INJECTABLE AND RESORBABLE CALCIUM PHOSPHATE BISPHOSPHONATE LOADED BONE SUBSTITUTE TO PREVENT CONTRA-LATERAL HIP FRACTURE IN THE ELDERLY: A CADAVERIC BIOMECHANICAL STUDY

IOF World Congress on Osteoporosis/10th European Congress on Clinical and Economic Aspects of Osteoporosis and Osteoarthritis, Florence, ITALY, MAY 05-08, 201

FEMOROPLASTY USING AN INJECTABLE AND RESORBABLE CALCIUM PHOSPHATE BISPHOSPHONATE LOADED BONE SUBSTITUTE TO PREVENT CONTRA-LATERAL HIP FRACTURE IN THE ELDERLY: A CADAVERIC BIOMECHANICAL STUDY

IOF World Congress on Osteoporosis/10th European Congress on Clinical and Economic Aspects of Osteoporosis and Osteoarthritis, Florence, ITALY, MAY 05-08, 201

Bone texture analysis of human femurs using a new device (BMA (TM)) improves failure load prediction

We measured bone texture parameters of excised human femurs with a new device (BMA (TM)). We also measured bone mineral density by DXA and investigated the performance of these parameters in the prediction of failure load. Our results suggest that bone texture parameters improve failure load prediction when added to bone mineral density. Bone mineral density (BMD) is a strong determinant of bone strength. However, nearly half of the fractures occur in patients with BMD which does not reach the osteoporotic threshold. In order to assess fracture risk properly, other factors are important to be taken into account such as clinical risk factors as well as macro- and microarchitecture of bone. Bone microarchitecture is usually assessed by high-resolution QCT, but this cannot be applied in routine clinical settings due to irradiation, cost and availability concerns. Texture analysis of bone has shown to be correlated to bone strength. We used a new device to get digitized X-rays of 12 excised human femurs in order to measure bone texture parameters in three different regions of interest (ROIs). We investigated the performance of these parameters in the prediction of the failure load using biomechanical tests. Texture parameters measured were the fractal dimension (Hmean), the co-occurrence matrix, and the run length matrix. We also measured bone mineral density by DXA in the same ROIs as well as in standard DXA hip regions. The Spearman correlation coefficient between BMD and texture parameters measured in the same ROIs ranged from -0.05 (nonsignificant (NS)) to 0.57 (p = 0.003). There was no correlation between Hmean and co-occurrence matrix nor Hmean and run length matrix in the same ROI (r = -0.04 to 0.52, NS). Co-occurrence matrix and run length matrix in the same ROI were highly correlated (r = 0.90 to 0.99, p < 0.0001). Univariate analysis with the failure load revealed significant correlation only with BMD results, not texture parameters. Multiple regression analysis showed that the best predictors of failure load were BMD, Hmean, and run length matrix at the femoral neck, as well as age and sex, with an adjusted r (2) = 0.88. Added to femoral neck BMD, Hmean and run length matrix at the femoral neck (without the effect of age and sex) improved failure load prediction (compared to femoral neck BMD alone) from adjusted r (2) = 0.67 to adjusted r (2) = 0.84. Our results suggest that bone texture measurement improves failure load prediction when added to BMD

Organic cation transporter 3: Keeping the brake on extracellular serotonin in serotonin-transporter-deficient mice

Mood disorders cause much suffering and are the single greatest cause of lost productivity worldwide. Although multiple medications, along with behavioral therapies, have proven effective for some individuals, millions of people lack an effective therapeutic option. A common serotonin (5-HT) transporter (5-HTT/SERT, SLC6A4) polymorphism is believed to confer lower 5-HTT expression in vivo and elevates risk for multiple mood disorders including anxiety, alcoholism, and major depression. Importantly, this variant is also associated with reduced responsiveness to selective 5-HT reuptake inhibitor antidepressants. We hypothesized that a reduced antidepressant response in individuals with a constitutive reduction in 5-HTT expression could arise because of the compensatory expression of other genes that inactivate 5-HT in the brain. A functionally upregulated alternate transporter for 5-HT may prevent extracellular 5-HT from rising to levels sufficiently high enough to trigger the adaptive neurochemical events necessary for therapeutic benefit. Here we demonstrate that expression of the organic cation transporter type 3 (OCT3, SLC22A3), which also transports 5-HT, is upregulated in the brains of mice with constitutively reduced 5-HTT expression. Moreover, the OCT blocker decynium-22 diminishes 5-HT clearance and exerts antidepressant-like effects in these mice but not in WT animals. OCT3 may be an important transporter mediating serotonergic signaling when 5-HTT expression or function is compromised.Nicole L. Baganz, Rebecca E. Horton, Alfredo S. Calderon, W. Anthony Owens, Jaclyn L. Munn, Lora T. Watts, Nina Koldzic-Zivanovic, Nathaniel A. Jeske, Wouter Koek, Glenn M. Toney, and Lynette C. Daw