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Attenuation of methamphetamine-induced striatal neurotoxicity involves both neuronal and glial mechanisms
Abstracts / Drug and Alcohol Dependence 146 (2015) e118–e201
evolving perceptions of POs versus heroin. Interview data were transcribed and content analyzed for key themes. Results: Mean age of PO-use initiation was 16.8 years. Most initiated PO use in a recreational context with high school peers as part of a poly-substance/poly-pharmaceutical use pattern. At the time of initiation, POs were viewed as safer, less stigmatized, and less addictive than illicit street drugs. Initiation was facilitated by ready, cost-free access to POs from household sources. As PO use escalated and, for many, opioid dependence developed, difficulties in accessing and affording enough POs to forestall withdrawal led 73% (32/44) to experiment with or transition to heroin use, typically via injection, within two years of PO initiation (mean age: 18.3 years). Of the 33 subjects who reported on treatment experiences, 76% (25/33) had received some treatment, most commonly methadone maintenance (36%; 12/33) and inpatient rehabilitation (30%; 10/33). Eighteen percent (6/33) report buying methadone or buprenorphine on the street for self-treatment. Conclusions: Results suggest that a subset of young adults who initiate nonmedical PO use as teens develop opioid dependence which can motivate them to seek more cost-effective means of maintaining their habits (i.e., transition to heroin and/or injection drug use). There is a pressing need to develop innovative prevention programs to help younger teens avoid initiating nonmedical PO use and to assist current PO users in preventing escalation to riskier forms of opioid use. Financial support: Supported by NIDA grant R01DA035146. http://dx.doi.org/10.1016/j.drugalcdep.2014.09.450 Associations between gray matter volume, smoker status, and smoking heaviness Amanda R. Mathew 1 , Patrick McConnell 1 , Joseph McClernon 2 , Brett Froeliger 1,2 1 Neurosciences, Medical University of South Carolina, Charleston, SC, United States 2 Department of Psychiatry and Behavioral Medicine, Duke University Medical Center, Durham, NC, United States
Aims: Smokers, as compared to nonsmokers, exhibit less gray matter volume (GMV) in several brain regions. In the current study, we sought to replicate and extend the extant literature by examining within-group differences in smokers that are associated with GMV. Methods: Voxel Based Morphometry (VBM) with DARTEL was conducted on anatomical data from several studies of smokers (n = 110) and nonsmokers (n = 79). A mask of between subjects differences in GMV, controlling for age and gender (p < .05; k ≥ 218), was then used to examine relations between GMV and baseline selfreport measures among smokers. We assessed smoking heaviness through two indicators: years smoking and nicotine dependence, measured by FTND total score. Results: There was a significant positive association between years smoking and FTND score (p = .047). As expected, we found smokers to have significantly less GMV throughout the cortex and thalamus. Next, we examined years smoking and FTND score as predictors of GMV among smokers. Years smoking was negatively correlated with GMV in superior frontal gyrus (SFG). FTND was negatively correlated with GMV in medial prefrontal cortex (mPFC) and dorsal anterior cingulate (dACC). Conclusions: Findings provide cross-validation for lower GMV among smokers vs. nonsmokers. Among smokers, indices of
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smoking heaviness were differentially correlated with GMV in particular brain regions. While years smoking was negatively correlated with GMV in SFG, nicotine dependence was negatively associated with GMV in mPFC and Dacc-critical nodes of the emotional appraisal circuit. Findings provide key information about the relationship between smoking and a subset of brain regions, and will be interpreted in light of associations with smoking motives. Financial support: This research is supported through NIDA grants DA026536 to Dr. Froeliger and DA025876 and DA023516 to Dr. McClernon. Dr. Mathew is supported through NIDA grant T32DA007288. http://dx.doi.org/10.1016/j.drugalcdep.2014.09.451 Attenuation of methamphetamine-induced striatal neurotoxicity involves both neuronal and glial mechanisms Rae Matsumoto 1 , Matthew Robson 1 , Ryan Turner 2 , Zachary Naser 2 , Nidhi Kaushal 1 , Christopher McCurdy 3 , Jason Huber 1 , James O’Callaghan 4 1
Basic Pharmaceutical Sciences, West Virginia University, Morgantown, WV, United States 2 Neurosurgery, West Virginia University, Morgantown, WV, United States 3 Medicinal Chemistry, University of Mississippi, University, MS, United States 4 Health Effects Laboratory Division, CDC/NIOSH, Morgantown, WV, United States Aims: Neurotoxic exposure to methamphetamine (METH) activates a variety of neuronal and glial mechanisms. Sigma receptors are found in both neurons and glia, and have been targeted to reduce cytotoxicity and inflammation in select disease states. Therefore, the purpose of this study was to determine whether the sigma receptor putative antagonist SN79 could mitigate changes in select striatal neuronal and glial processes resulting from neurotoxic exposure to METH. Methods: Male, Swiss Webster mice were treated with a neurotoxic regimen of METH in the absence or presence of pretreatment with SN79. The brains were collected at various time points and striatal samples evaluated for drug-induced changes using immunohistochemistry or fluorescence, real time PCR, and Western blots. Results: SN79 pretreatment significantly attenuated the following METH-induced deficits in striatal neurons: dopamine and serotonin transporter expression, apoptosis. SN79 pretreatment also attenuated METH-induced M1 microglial activation and increases in proinflammatory cytokine mRNA expression (il-6, lif, osm) in the striatum. METH also induced astrogliosis through the activation of JAK2/STAT3 signaling, with SN79 pretreatment preventing the following METH-induced increases in the striatum: GFAP mRNA and protein expression, OSMR expression, phosphorylation of STAT3 (Tyr-705). Conclusions: Together, the data indicate that sigma ligands such as SN79 can convey protective effects against METH by targeting both neuronal and glial processes. Financial support: National Institutes of Health (R01 DA013978, R01 DA023205, R01 NS061954, T32 GM081741). http://dx.doi.org/10.1016/j.drugalcdep.2014.09.452
evolving perceptions of POs versus heroin. Interview data were transcribed and content analyzed for key themes. Results: Mean age of PO-use initiation was 16.8 years. Most initiated PO use in a recreational context with high school peers as part of a poly-substance/poly-pharmaceutical use pattern. At the time of initiation, POs were viewed as safer, less stigmatized, and less addictive than illicit street drugs. Initiation was facilitated by ready, cost-free access to POs from household sources. As PO use escalated and, for many, opioid dependence developed, difficulties in accessing and affording enough POs to forestall withdrawal led 73% (32/44) to experiment with or transition to heroin use, typically via injection, within two years of PO initiation (mean age: 18.3 years). Of the 33 subjects who reported on treatment experiences, 76% (25/33) had received some treatment, most commonly methadone maintenance (36%; 12/33) and inpatient rehabilitation (30%; 10/33). Eighteen percent (6/33) report buying methadone or buprenorphine on the street for self-treatment. Conclusions: Results suggest that a subset of young adults who initiate nonmedical PO use as teens develop opioid dependence which can motivate them to seek more cost-effective means of maintaining their habits (i.e., transition to heroin and/or injection drug use). There is a pressing need to develop innovative prevention programs to help younger teens avoid initiating nonmedical PO use and to assist current PO users in preventing escalation to riskier forms of opioid use. Financial support: Supported by NIDA grant R01DA035146. http://dx.doi.org/10.1016/j.drugalcdep.2014.09.450 Associations between gray matter volume, smoker status, and smoking heaviness Amanda R. Mathew 1 , Patrick McConnell 1 , Joseph McClernon 2 , Brett Froeliger 1,2 1 Neurosciences, Medical University of South Carolina, Charleston, SC, United States 2 Department of Psychiatry and Behavioral Medicine, Duke University Medical Center, Durham, NC, United States
Aims: Smokers, as compared to nonsmokers, exhibit less gray matter volume (GMV) in several brain regions. In the current study, we sought to replicate and extend the extant literature by examining within-group differences in smokers that are associated with GMV. Methods: Voxel Based Morphometry (VBM) with DARTEL was conducted on anatomical data from several studies of smokers (n = 110) and nonsmokers (n = 79). A mask of between subjects differences in GMV, controlling for age and gender (p < .05; k ≥ 218), was then used to examine relations between GMV and baseline selfreport measures among smokers. We assessed smoking heaviness through two indicators: years smoking and nicotine dependence, measured by FTND total score. Results: There was a significant positive association between years smoking and FTND score (p = .047). As expected, we found smokers to have significantly less GMV throughout the cortex and thalamus. Next, we examined years smoking and FTND score as predictors of GMV among smokers. Years smoking was negatively correlated with GMV in superior frontal gyrus (SFG). FTND was negatively correlated with GMV in medial prefrontal cortex (mPFC) and dorsal anterior cingulate (dACC). Conclusions: Findings provide cross-validation for lower GMV among smokers vs. nonsmokers. Among smokers, indices of
e197
smoking heaviness were differentially correlated with GMV in particular brain regions. While years smoking was negatively correlated with GMV in SFG, nicotine dependence was negatively associated with GMV in mPFC and Dacc-critical nodes of the emotional appraisal circuit. Findings provide key information about the relationship between smoking and a subset of brain regions, and will be interpreted in light of associations with smoking motives. Financial support: This research is supported through NIDA grants DA026536 to Dr. Froeliger and DA025876 and DA023516 to Dr. McClernon. Dr. Mathew is supported through NIDA grant T32DA007288. http://dx.doi.org/10.1016/j.drugalcdep.2014.09.451 Attenuation of methamphetamine-induced striatal neurotoxicity involves both neuronal and glial mechanisms Rae Matsumoto 1 , Matthew Robson 1 , Ryan Turner 2 , Zachary Naser 2 , Nidhi Kaushal 1 , Christopher McCurdy 3 , Jason Huber 1 , James O’Callaghan 4 1
Basic Pharmaceutical Sciences, West Virginia University, Morgantown, WV, United States 2 Neurosurgery, West Virginia University, Morgantown, WV, United States 3 Medicinal Chemistry, University of Mississippi, University, MS, United States 4 Health Effects Laboratory Division, CDC/NIOSH, Morgantown, WV, United States Aims: Neurotoxic exposure to methamphetamine (METH) activates a variety of neuronal and glial mechanisms. Sigma receptors are found in both neurons and glia, and have been targeted to reduce cytotoxicity and inflammation in select disease states. Therefore, the purpose of this study was to determine whether the sigma receptor putative antagonist SN79 could mitigate changes in select striatal neuronal and glial processes resulting from neurotoxic exposure to METH. Methods: Male, Swiss Webster mice were treated with a neurotoxic regimen of METH in the absence or presence of pretreatment with SN79. The brains were collected at various time points and striatal samples evaluated for drug-induced changes using immunohistochemistry or fluorescence, real time PCR, and Western blots. Results: SN79 pretreatment significantly attenuated the following METH-induced deficits in striatal neurons: dopamine and serotonin transporter expression, apoptosis. SN79 pretreatment also attenuated METH-induced M1 microglial activation and increases in proinflammatory cytokine mRNA expression (il-6, lif, osm) in the striatum. METH also induced astrogliosis through the activation of JAK2/STAT3 signaling, with SN79 pretreatment preventing the following METH-induced increases in the striatum: GFAP mRNA and protein expression, OSMR expression, phosphorylation of STAT3 (Tyr-705). Conclusions: Together, the data indicate that sigma ligands such as SN79 can convey protective effects against METH by targeting both neuronal and glial processes. Financial support: National Institutes of Health (R01 DA013978, R01 DA023205, R01 NS061954, T32 GM081741). http://dx.doi.org/10.1016/j.drugalcdep.2014.09.452