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TSPO, a Mitochondrial Outer Membrane Protein, Controls Ethanol-Related Behaviors in Drosophila.

Lin R, Rittenhouse D, Sweeney K, Potluri P, Wallace DC - PLoS Genet. (2015)

Bottom Line: Knockdown of dTSPO in adult male neurons results in increased sensitivity to ethanol sedation, and this effect requires the dTSPO depletion-mediated increase in reactive oxygen species (ROS) production and inhibition of caspase activity in fly heads.Hence, mitochondrial TSPO function plays an important role in ethanol sensitivity and tolerance.Since a large array of benzodiazepine analogues have been developed that interact with the peripheral benzodiazepine receptor, the mitochondrial TSPO might provide an important new target for treating AUDs.

View Article: PubMed Central - PubMed

Affiliation: Center for Mitochondrial and Epigenomic Medicine, Children's Hospital of Philadelphia Research Institute, Philadelphia, Pennsylvania, United States of America.

ABSTRACT
The heavy consumption of ethanol can lead to alcohol use disorders (AUDs) which impact patients, their families, and societies. Yet the genetic and physiological factors that predispose humans to AUDs remain unclear. One hypothesis is that alterations in mitochondrial function modulate neuronal sensitivity to ethanol exposure. Using Drosophila genetics we report that inactivation of the mitochondrial outer membrane translocator protein 18kDa (TSPO), also known as the peripheral benzodiazepine receptor, affects ethanol sedation and tolerance in male flies. Knockdown of dTSPO in adult male neurons results in increased sensitivity to ethanol sedation, and this effect requires the dTSPO depletion-mediated increase in reactive oxygen species (ROS) production and inhibition of caspase activity in fly heads. Systemic loss of dTSPO in male flies blocks the development of tolerance to repeated ethanol exposures, an effect that is not seen when dTSPO is only inactivated in neurons. Female flies are naturally more sensitive to ethanol than males, and female fly heads have strikingly lower levels of dTSPO mRNA than males. Hence, mitochondrial TSPO function plays an important role in ethanol sensitivity and tolerance. Since a large array of benzodiazepine analogues have been developed that interact with the peripheral benzodiazepine receptor, the mitochondrial TSPO might provide an important new target for treating AUDs.

No MeSH data available.


Related in: MedlinePlus

Comparable ethanol sensitivity in female tspo-/- and tspo +/+ flies.(A) With 34% ethanol vapor, half sedation time for tspo+/+ was 23.0±2.5 min and for tspo-/- was 20.0±1.7 min, p > 0.05, n = 14 vials tested. (B) With 44% ethanol vapor half sedation time for tspo+/+ was 11.0±0.5 min and for tspo-/- was 11.0±0.5 min, p > 0.05, n = 10. (C) Recovery after withdraw from exposure to 44% ethanol vapor, half recovery rate for tspo+/+ was 16.0±1.2 min and for tspo-/- was 18.0±1.2 min, p > 0.05, n = 8. Data presented as mean ± SEM.
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pgen.1005366.g003: Comparable ethanol sensitivity in female tspo-/- and tspo +/+ flies.(A) With 34% ethanol vapor, half sedation time for tspo+/+ was 23.0±2.5 min and for tspo-/- was 20.0±1.7 min, p > 0.05, n = 14 vials tested. (B) With 44% ethanol vapor half sedation time for tspo+/+ was 11.0±0.5 min and for tspo-/- was 11.0±0.5 min, p > 0.05, n = 10. (C) Recovery after withdraw from exposure to 44% ethanol vapor, half recovery rate for tspo+/+ was 16.0±1.2 min and for tspo-/- was 18.0±1.2 min, p > 0.05, n = 8. Data presented as mean ± SEM.

Mentions: Male and female flies exhibit sexual dimorphic response to ethanol exposure [4] and this sexual dimorphism was also observed in the brains of the TSPO knockout and knockdown flies. Male tspo-/- flies showed an increased sensitivity to ethanol sedation relative to tspo +/+ flies with 34% ethanol exposure and delayed recovery from 54% sedation (Fig 1A and 1D) while female tspo-/- and tspo +/+ flies showed no difference in their response to 34% ethanol exposure (Fig 3A–3C).


TSPO, a Mitochondrial Outer Membrane Protein, Controls Ethanol-Related Behaviors in Drosophila.

Lin R, Rittenhouse D, Sweeney K, Potluri P, Wallace DC - PLoS Genet. (2015)

Comparable ethanol sensitivity in female tspo-/- and tspo +/+ flies.(A) With 34% ethanol vapor, half sedation time for tspo+/+ was 23.0±2.5 min and for tspo-/- was 20.0±1.7 min, p > 0.05, n = 14 vials tested. (B) With 44% ethanol vapor half sedation time for tspo+/+ was 11.0±0.5 min and for tspo-/- was 11.0±0.5 min, p > 0.05, n = 10. (C) Recovery after withdraw from exposure to 44% ethanol vapor, half recovery rate for tspo+/+ was 16.0±1.2 min and for tspo-/- was 18.0±1.2 min, p > 0.05, n = 8. Data presented as mean ± SEM.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4524697&req=5

pgen.1005366.g003: Comparable ethanol sensitivity in female tspo-/- and tspo +/+ flies.(A) With 34% ethanol vapor, half sedation time for tspo+/+ was 23.0±2.5 min and for tspo-/- was 20.0±1.7 min, p > 0.05, n = 14 vials tested. (B) With 44% ethanol vapor half sedation time for tspo+/+ was 11.0±0.5 min and for tspo-/- was 11.0±0.5 min, p > 0.05, n = 10. (C) Recovery after withdraw from exposure to 44% ethanol vapor, half recovery rate for tspo+/+ was 16.0±1.2 min and for tspo-/- was 18.0±1.2 min, p > 0.05, n = 8. Data presented as mean ± SEM.
Mentions: Male and female flies exhibit sexual dimorphic response to ethanol exposure [4] and this sexual dimorphism was also observed in the brains of the TSPO knockout and knockdown flies. Male tspo-/- flies showed an increased sensitivity to ethanol sedation relative to tspo +/+ flies with 34% ethanol exposure and delayed recovery from 54% sedation (Fig 1A and 1D) while female tspo-/- and tspo +/+ flies showed no difference in their response to 34% ethanol exposure (Fig 3A–3C).

Bottom Line: Knockdown of dTSPO in adult male neurons results in increased sensitivity to ethanol sedation, and this effect requires the dTSPO depletion-mediated increase in reactive oxygen species (ROS) production and inhibition of caspase activity in fly heads.Hence, mitochondrial TSPO function plays an important role in ethanol sensitivity and tolerance.Since a large array of benzodiazepine analogues have been developed that interact with the peripheral benzodiazepine receptor, the mitochondrial TSPO might provide an important new target for treating AUDs.

View Article: PubMed Central - PubMed

Affiliation: Center for Mitochondrial and Epigenomic Medicine, Children's Hospital of Philadelphia Research Institute, Philadelphia, Pennsylvania, United States of America.

ABSTRACT
The heavy consumption of ethanol can lead to alcohol use disorders (AUDs) which impact patients, their families, and societies. Yet the genetic and physiological factors that predispose humans to AUDs remain unclear. One hypothesis is that alterations in mitochondrial function modulate neuronal sensitivity to ethanol exposure. Using Drosophila genetics we report that inactivation of the mitochondrial outer membrane translocator protein 18kDa (TSPO), also known as the peripheral benzodiazepine receptor, affects ethanol sedation and tolerance in male flies. Knockdown of dTSPO in adult male neurons results in increased sensitivity to ethanol sedation, and this effect requires the dTSPO depletion-mediated increase in reactive oxygen species (ROS) production and inhibition of caspase activity in fly heads. Systemic loss of dTSPO in male flies blocks the development of tolerance to repeated ethanol exposures, an effect that is not seen when dTSPO is only inactivated in neurons. Female flies are naturally more sensitive to ethanol than males, and female fly heads have strikingly lower levels of dTSPO mRNA than males. Hence, mitochondrial TSPO function plays an important role in ethanol sensitivity and tolerance. Since a large array of benzodiazepine analogues have been developed that interact with the peripheral benzodiazepine receptor, the mitochondrial TSPO might provide an important new target for treating AUDs.

No MeSH data available.


Related in: MedlinePlus