Sodium channel activation mechanisms : insights from deuterium oxide and delta-9-tetrahydrocannabinol substitution

Thesis (Ph. D.)--University of Hawaii at Manoa, 1990.Includes bibliographical references (leaves 135-153)Microfiche.xi, 153 leaves, bound ill. 29 cmSchauf and Bullock (1979, 1982) demonstrated that solvent substitution with deuterium oxide (D2O) significantly affects both sodium channel activation and inactivation kinetics without corresponding changes in gating current or tail current rates. They concluded, (a) no significant component of gating current derives from the final channel opening step and, (b) channels must deactivate (during tail currents) by a different pathway from that used in channel opening. By contrast, Oxford (1981) found in squid axons that, when a depolarizing pulse is interrupted by a brief return to holding potential, subsequent reactivation is very rapid and shows almost monoexponential kinetics. Increasing the interpulse interval resulted in secondary activation rate returning towards control, sigmoid kinetics. He concluded that channels open and close via the same pathway. I have repeated both sets of observations, confirming the results obtained in both previous studies, despite the apparently contradictory conclusions reached by these authors. However, I find that secondary activation following a brief interpulse interval is insensitive to D20, although reactivation following longer interpulse intervals returns towards a D20-sensitivity similar to that of primary activation. I conclude that D20sensitive primary activation and D20-insensitive tail current deactivation involve separate pathways. However, D20-insensitive secondary activation involves reversal of the D20-insensitive deactivation step. Strichartz et al. (1978) were the first to investigate the effects of delta-9tetrahydrocannabinol (THC) on sodium channel conductance mechanisms under voltage-clamp conditions. The authors reported that THC modified channel conductance by slowing the activation kinetics of INa and suppressing ionic conductance (gNa) in a voltage-dependent manner. They also noted that channel inactivation processes were not affected by THC action. The authors concluded that the lengthening of !p and the shift in the voltage-dependence of peak gNa are both related to the relative kinetics of sodium activation and inactivation, and since inactivation was unaffected by THC, alterations of activation alone account for these observed changes. I have repeated the above observations, but I can confirm only one of the three results obtained in the previous studies. I find that THC affects both activation and inactivation kinetics. However, I find that the normalized F(Vm) curves are almost identical indicating no significant shift in surface charge following THC treatment

Delayed early developmental trajectories of white matter tracts of functional pathways in preterm-born infants: Longitudinal diffusion tensor imaging data

Probabilistic maps of white matter pathways related to motor, somatosensory, auditory, visual, and limbic functions, and major white matter tracts (the corpus callosum, the inferior fronto-occipital fasciculus, and the middle cerebellar peduncle) were applied to evaluate the developmental trajectories of these tracts, using longitudinal diffusion tensor imaging (DTI) obtained in term-born and preterm-born healthy infants. Nineteen term-born and 30 preterm-born infants completed MR scans at three time points: Time-point 1, 41.6±2.7 postmenstrual weeks; Time-point 2, 46.0±2.9 postmenstrual weeks; and Time-point 3, 50.8±3.7 postmenstrual weeks. The DTI-derived scalar values (fractional anisotropy, eigenvalues, and radial diffusivity) of the three time points are available in this Data article. Keywords: Term, Preterm, Infant, Diffusion tensor imaging, Atla

Structural growth trajectories and rates of change in the first 3 months of infant brain development.

ImportanceThe very early postnatal period witnesses extraordinary rates of growth, but structural brain development in this period has largely not been explored longitudinally. Such assessment may be key in detecting and treating the earliest signs of neurodevelopmental disorders.ObjectiveTo assess structural growth trajectories and rates of change in the whole brain and regions of interest in infants during the first 3 months after birth.Design, setting, and participantsSerial structural T1-weighted and/or T2-weighted magnetic resonance images were obtained for 211 time points from 87 healthy term-born or term-equivalent preterm-born infants, aged 2 to 90 days, between October 5, 2007, and June 12, 2013.Main outcomes and measuresWe segmented whole-brain and multiple subcortical regions of interest using a novel application of Bayesian-based methods. We modeled growth and rate of growth trajectories nonparametrically and assessed left-right asymmetries and sexual dimorphisms.ResultsWhole-brain volume at birth was approximately one-third of healthy elderly brain volume, and did not differ significantly between male and female infants (347 388 mm3 and 335 509 mm3, respectively, P = .12). The growth rate was approximately 1%/d, slowing to 0.4%/d by the end of the first 3 months, when the brain reached just more than half of elderly adult brain volume. Overall growth in the first 90 days was 64%. There was a significant age-by-sex effect leading to widening separation in brain sizes with age between male and female infants (with male infants growing faster than females by 200.4 mm3/d, SE = 67.2, P = .003). Longer gestation was associated with larger brain size (2215 mm3/d, SE = 284, P = 4×10-13). The expected brain size of an infant born one week earlier than average was 5% smaller than average; at 90 days it will not have caught up, being 2% smaller than average. The cerebellum grew at the highest rate, more than doubling in 90 days, and the hippocampus grew at the slowest rate, increasing by 47% in 90 days. There was left-right asymmetry in multiple regions of interest, particularly the lateral ventricles where the left was larger than the right by 462 mm3 on average (approximately 5% of lateral ventricular volume at 2 months). We calculated volume-by-age percentile plots for assessing individual development.Conclusions and relevanceNormative trajectories for early postnatal brain structural development can be determined from magnetic resonance imaging and could be used to improve the detection of deviant maturational patterns indicative of neurodevelopmental disorders

Methylphenidate for methamphetamine use

Background and aimsNo effective pharmacotherapy for methamphetamine (MA) use disorder has yet been found. This study evaluated sustained-release methylphenidate (MPH-SR) compared with placebo (PLA) for treatment of MA use disorder in people also undergoing behavioral support and motivational incentives.DesignThis was a randomized, double-blind, placebo-controlled design with MPH-SR or PLA provided for 10 weeks (active phase) followed by 4 weeks of single-blind PLA. Twice-weekly clinic visits, weekly group counseling (CBT) and motivational incentives (MI) for MA-negative urine drug screens (UDS) were included.SettingTreatment sites were in Los Angeles, California (LA) and Honolulu, Hawaii (HH), USA.ParticipantsA total of 110 MA-dependent (via DSM-IV) participants (LA = 90; HH = 20).MeasurementsThe primary outcome measure is self-reported days of MA use during the last 30 days of the active phase. Included in the current analyses are drug use (UDS and self-report), retention, craving, compliance (dosing, CBT, MI), adverse events and treatment satisfaction.FindingsNo difference was found between treatment groups in self-reported days of MA use during the last 30 days of the active phase (P = 0.22). In planned secondary outcomes analyses, however, the MPH group had fewer self-reported MA use days from baseline through the active phase compared with the PLA group (P = 0.05). The MPH group also had lower craving scores and fewer marijuana-positive UDS than the PLA group in the last 30 days of the active phase. The two groups had similar retention, other drug use, adverse events and treatment satisfaction.ConclusionsMethylphenidate may lead to a reduction in concurrent methamphetamine use when provided as treatment for patients undergoing behavioral support for moderate to severe methamphetamine use disorder, but this requires confirmation