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Department of Neurobiology and Developmental Sciences
Jackson T. Stephens Spine & Neurosciences Institute
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CTN Student Research - Paige Beck

Paige Beck PBBeck@uams.edu

We recorded the effects of administration of the stimulant modafinil on the amplitude of the sleep state-dependent auditory P13 evoked potential in freely moving rats, a measure of arousal that is thought to be generated by the cholinergic arm of the reticular activating system, specifically the pedunculopontine nucleus (PPN).   Groups of rats were implanted for recording auditory evoked responses and the effects on P13 potential amplitude of intracranial injections into the PPN of neuroactive agents determined.  The effects of intracranial injections into the PPN of modafinil showed that P13 potential amplitude increased in a dose-dependent manner at doses of 100, 200 and 300 microM.  The effect was blocked by pretreatment with either of the gap junction antagonists carbenoxolone (300 microM) or mefloquine (25 microM), which by themselves slightly decreased P13 potential amplitude.   These results suggest that modafinil increases arousal levels as determined by the amplitude of the P13 potential, an effect blocked by gap junction antagonists, suggesting that one mechanism by which modafinil increases arousal may be by increasing electrical coupling.

A                                                                     B

Effects of the gap junction antagonists on MOD-induced changes on P13 potential amplitude.  A.  Percent change in average P13 potential amplitude after saline (X), and after MOD at 300 microM, as well as after CBX alone at 300 microM (filled triangles) and CBX at 300 microM followed 20 min later by MOD at 300 microM (open triangles) compared to pre-injection control for each agent.  CBX alone (filled triangles) induced transient decreases compared to saline alone at 10, 25 and 55 min (p<0.01, asterisks not shown for clarity), while pretreatment with CBX blocked the effects of MOD at all time points (open triangles) and was not different from saline (X).  When a three factor, two way analysis between MOD at 300 microM (filled circles), CBX at 300 microM (filled triangles) and CBX+MOD (open triangles) was done (pre- and post injection values at all time points after MOD vs CBX vs CBX+MOD), significant increases were present for MOD vs CBX+MOD at 25, 35 and 55 min (** p<0.01), as well as 45 min (*p<0.05) (upper asterisks in figure 2A), suggesting the presence of CBX suppressed the increases seen with MOD alone.  Comparison between CBX and CBX+MOD showed only significance at 10 min (*p<0.05, asterisk at bottom of figure 2A).  Significant differences between MOD alone and CBX alone were present at 10-55 min (p<0.01, asterisks not shown for clarity).  B.  Percent change in average P13 potential amplitude after saline (X), and after MOD at 300 microM (filled circles), as well as after MEF alone at 25 microM (filled squares) and MEF at 25 microM followed 20 min later by MOD at 300 microM (open squares) compared to pre-injection control for each agent.  One-way ANOVA comparison between MEF alone and saline induced significant decreases at 5, 10, 15, 25, 35 ( p<0.01), and 45 min (p<0.05) (asterisks not shown for clarity), but pretreatment with MEF blocked the effects of MOD at all time points (open squares) and was not different from saline (X).  When a three factor, Two way analysis (pre- and post injection values at all time points after MOD vs MEF vs MEF+MOD between MOD at 300 microM (filled circles) and MEF+MOD (open squares) was done, significant increases were present comparing MOD vs MEF+MOD at 10 and 15 min (*p<0.05) and 25-55 min (** p<0.01) (upper asterisks in figure 2B), suggesting the presence of MEF suppressed the increases seen with MOD alone.  When MEF vs MEF+MOD were compared, significant decreases were present only at 10 and 35 min (**p<0.01) (lower asterisks in figure 2B).  Significant differences between MOD alone and MEF alone were present at 10-55 min (p<0.01, asterisks not shown for clarity).