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Daily isoflurane exposure increases barbiturate insensitivity in medullary respiratory and cortical neurons via expression of ε-subunit containing GABA ARs. Hengen Keith B,Nelson Nathan R,Stang Kyle M,Johnson Stephen M,Smith Stephanie M,Watters Jyoti J,Mitchell Gordon S,Behan Mary PloS one The parameters governing GABAA receptor subtype expression patterns are not well understood, although significant shifts in subunit expression may support key physiological events. For example, the respiratory control network in pregnant rats becomes relatively insensitive to barbiturates due to increased expression of ε-subunit-containing GABAARs in the ventral respiratory column. We hypothesized that this plasticity may be a compensatory response to a chronic increase in inhibitory tone caused by increased central neurosteroid levels. Thus, we tested whether increased inhibitory tone was sufficient to induce ε-subunit upregulation on respiratory and cortical neurons in adult rats. Chronic intermittent increases in inhibitory tone in male and female rats was induced via daily 5-min exposures to 3% isoflurane. After 7d of treatment, phrenic burst frequency was less sensitive to barbiturate in isoflurane-treated male and female rats in vivo. Neurons in the ventral respiratory group and cortex were less sensitive to pentobarbital in vitro following 7d and 30d of intermittent isoflurane-exposure in both male and female rats. The pentobarbital insensitivity in 7d isoflurane-treated rats was reversible after another 7d. We hypothesize that increased inhibitory tone in the respiratory control network and cortex causes a compensatory increase in ε-subunit-containing GABAARs. 10.1371/journal.pone.0119351
A comparison of mitochondrial toxicity of mephedrone on three separate parts of brain including hippocampus, cortex and cerebellum. Naserzadeh Parvaneh,Taghizadeh Ghorban,Atabaki Behnaz,Seydi Enayatollah,Pourahmad Jalal Neurotoxicology Mephedrone (4-methylmethcathinone) is a new and popular drug of abuse and also widely available on the internet and still legal in some parts of the world. The central nervous system is the target of mephedrone and recent evidence suggested that mephedrone could affect mitochondria in brain tissue. However, the underlying mechanisms of mephedrone toxicity in brain mitochondria have not yet been well understood. In this study, mitochondria from three separate parts of rat brain hippocampus, cortex, and cerebellum were obtained using differential centrifugation and were incubated with different concentrations of mephedrone (3, 6 and 12 μM). Then, the mitochondrial parameters toxicity were determined. The results showed that mephedrone (3, 6 and 12 μM) induced impairment in the activity of the mitochondrial complex II and IV. Also, mephedrone (3, 6 and 12 μM) increased mitochondrial reactive oxygen species (ROS) level, collapsed mitochondria membrane potential (MMP), induced swelling in the mitochondria and damaged the mitochondrial outer membrane (MOM) in the mitochondria obtained from hippocampus, cortex, and cerebellum, which in all cases is associated with the cytochrome c release. Furthermore, increased disturbance in oxidative phosphorylation was also shown by the decrease in ATP level in mephedrone-treated mitochondria indicating mitochondrial dysfunction in separate parts of the brain. This study suggests that mephedrone via increasing oxidative stress and impairment of the mitochondrial respiratory chain in the hippocampus, cortex, and cerebellum may play a key role in the neurotoxicity. 10.1016/j.neuro.2019.02.014