4-Methylamphetamine (4-MA) is an emerging drug of abuse that acts as a substrate at plasma membrane transporters for dopamine (DAT), norepinephrine (NET), and serotonin (SERT), thereby causing non-exocytotic release of monoamine transmitters via reverse transport. Prior studies by us showed that increasing the N-alkyl chain length of N-substituted 4-MA analogs converts 4-MA from a transportable substrate (i.e., releaser) at DAT and NET to a non-transported blocker at these sites. Here we studied the effects of the individual optical isomers of N-methyl-, N-ethyl-, and N-n-propyl 4-MA on monoamine transporters and abuse-related behavior in rats because action/function might be related to stereochemistry. Uptake inhibition and release assays were conducted in rat brain synaptosomes whereas electrophysiological assessments of drug-transporter interactions were examined using cell-based biosensors. Intracranial-self stimulation (ICSS) in rats was employed to assess abuse potential in vivo. The experimental evidence demonstrates that S(+)N-methyl 4-MA is a potent and efficacious releaser at DAT, NET, and SERT with the highest abuse potential among the test drugs whereas R(−)N-methyl 4-MA, is a less potent releaser with reduced abuse potential. The S(+)ethyl analog displays decreased efficacy as a releaser at DAT but retains full release activity at NET and SERT with a reduction in abuse-related effects; the R(−)ethyl analog has a similar profile but is less potent. S(+)N-Propyl 4-MA is a non-transported blocker at DAT and NET, but an efficacious releaser at SERT, whereas the R enantiomer is almost inactive. In conclusion, the S enantiomers of the N-alkyl 4-MA analogs are most potent. Lengthening the N-alkyl chain converts compounds from potent non-selective releasers showing abuse-related effects, to more selective SERT releasers with no apparent abuse potential.
Hepatic artery intimal dissection is a rare complication that has potentially catastrophic results that may result in the inability to utilize the graft. The literature has demonstrated that post-operative hepatic artery dissections have been identified in one study in up to 2.5% of liver transplants post-operatively (Agrawal et al). Hepatic artery dissection can result in intraluminal thrombus formation, thus occluding the vessel and rendering the transplanted organ nonfunctional. Sometimes the graft may be salvaged utilizing deceased donor vessels but the vessel caliber mismatch or complexity of the reconstruction could result in graft loss.Recent studies have published the results of improved outcomes when transplant surgeons and plastic microvascular surgeons collaborate in challenging reconstructive situations. Fewer early biliary complications were observed when a microsurgeon
Post‐traumatic stress disorder (PTSD) is an anxiety disorder that can arise due to exposure to a potentially traumatic event (PTE). Using “cage‐within‐cage resident‐intruder” protocol, subject C57BL/6J mice were exposed to aggressor mice for 10 days with 24 hours rest prior to harvesting. The symbiotic influence of microbiota on the nervous system and behavior has been receiving profound interest. In this longitudinal study, we are focusing on the effect of social stress on the microbiome by sequencing for 16S ribosomal RNA (16S rRNA) amplicon on the Illumina MiSeq platform. Fecal samples were collected at 2 day intervals during the 10 day protocol from control as well as subject mice. DNA was isolated using a kit from MO BIO followed by amplification of variable V3 and V4 region of the 16S rRNA amplicon using the Illumina 16S Metagenomics Library Preparation Protocol. The samples were barcoded using Nextera index primers and pooled in preparation for MiSeq sequencing. We will be able to characterize the fecal microbiota in the presence and absence of social stress and also will be able to correlate changes in bacterial communities in our mouse model of PTSD.DISCLAIMERS: Research was conducted in compliance with the Animal Welfare Act and all other Federal Requirements. The views expressed are those of the authors and do not constitute endorsement by the U.S. Army.
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