Train-of-Four and Tetanic Fade Are Not Always a Prejunctional Phenomenon as Evaluated by Toxins Having Highly Specific Pre- and Postjunctional Actions.

Train-of-Four and Tetanic Fade Are Not Always a Prejunctional Phenomenon as Evaluated by Toxins Having Highly Specific Pre- and Postjunctional Actions.

Anesth Analg. 2013 Mar 11;
Nagashima M, Yasuhara S, Martyn JA

BACKGROUND:Nerve-stimulated fade in muscle is generally accepted as a prejunctional phenomenon mediated by block of prejunctional acetylcholine receptors (AChRs) at the nerve terminal, whereas decrease of twitch tension is considered a postjunctional effect due to block of muscle AChRs. Using ligands with specific pre- or postjunctional effects only, we tested the hypothesis that fade is not necessarily a prejunctional phenomenon.METHODS:Neuromuscular function in rats was evaluated after IM (2.5 U) or IV (12.0 U) injection of botulinum toxin (Botx), or IV (250 ?g/kg) ?-bungarotoxin (?-BTX) alone. The acute neuromuscular effects of IV 2 mg/kg dihydro-?-erythroidine (DH?E), alone and in combination with ?-BTX, were also tested. Botx decreases vesicular release of ACh, and ?-BTX binds to postjunctional nicotinic AChRs only, whereas DH?E binds specifically to prejunctional ?3?2 AChRs only. In view of the lack of acute effects of Botx even at 2 hours after IV injection, its neuromuscular effects were also evaluated at 24 hours after IM injection (0.6 U) and compared with IM injection of ?-BTX (25 ?g/kg) or saline also given 24 hours earlier. The sciatic nerve-tibialis muscle preparation, during train-of-four and tetanic stimulation, was used to test neuromuscular effects in vivo.RESULTS:IV and IM Botx had no observable neuromuscular effects at 2 hours. IV ?-BTX caused twitch depression within a few minutes, and significant fade (P = 0.002) at 75% of baseline twitch tension; these effects persisted until the end of the observation period of 2 hours. IV DH?E alone caused no significant change in single twitch (P = 0.899) or train-of-four ratio (P = 0.394), but significantly enhanced the fade of IV ?-BTX (P = 0.001 at 75% of baseline twitch tension). IM Botx or ?-BTX, at 24 hours after their injection, resulted in a significant decrease of single twitch and tetanic tensions (P < 0.0001), but Botx did not cause fade, whereas ?-BTX caused significant (P < 0.0001) fade at 24 hours. The tibialis muscle weights and protein expression of ?1 subunit of AChR (Western blots) did not differ between Botx, ?-BTX and saline-injected groups at 24 hours but increased in denervated muscle (positive control).CONCLUSIONS:Botx-induced decreased ACh release in and of itself does not cause fade but does cause decrease of absolute tensions. Decrease of available (functional) postjunctional AChRs by ?-BTX did induce fade. The prejunctional fade effects of DH?E on ?3?2 AChRs become manifest only when the margin of safety was decreased by concomitant administration of ?-BTX. Thus, fade during repetitive stimulation is not always a prejunctional phenomenon and may also reflect the decreased margin of safety of neurotransmission, which can be due to a pure postjunctional AChRs block or to a combination of both pre- and postjunctional AChRs block. Block of prejunctional ?3?2 AChRs alone is not necessary and sufficient to cause fade. HubMed – depression

Discovery of disubstituted piperidines and homopiperidines as potent dual NK1 receptor antagonists-serotonin reuptake transporter inhibitors for the treatment of depression.

Bioorg Med Chem. 2013 Feb 19;
Wu YJ, He H, Bertekap R, Westphal R, Lelas S, Newton A, Wallace T, Taber M, Davis C, Macor JE, Bronson J

This report describes the synthesis, structure-activity relationships and activity of piperidine, homopiperidine, and azocane derivatives combining NK1 receptor (NK1R) antagonism and serotonin reuptake transporter (SERT) inhibition. Our studies culminated in the discovery of piperidine 2 and homopiperidine 8 as potent dual NK1R antagonists-SERT inhibitors. Compound 2 demonstrated significant activity in the gerbil forced swimming test, suggesting that dual NK1R antagonists-SERT inhibitors may be useful in treating depression disorders. HubMed – depression

Deficits in cue detection underlie event-based prospective memory impairment in major depression: an eye tracking study.

Psychiatry Res. 2013 Mar 7;
Chen S, Zhou R, Cui H, Chen X

This study examined the cue detection in the non-focal event-based prospective memory (PM) of individuals with and without a major depressive disorder using behavioural and eye tracking assessments. The participants were instructed to search on each trial for a different target stimulus that could be present or absent and to make prospective responses to the cue object. PM tasks included cue only and target plus cue, whereas ongoing tasks included target only and distracter only. The results showed that a) participants with depression performed more poorly than those without depression in PM; b) participants with depression showed more fixations and longer total and average fixation durations in both ongoing and PM conditions; c) participants with depression had lower scores on accuracy in target-plus-cue trials than in cue-only trials and had a higher gaze rate of targets on hits and misses in target-plus-cue trials than did those without depression. The results indicate that the state of depression may impair top-down cognitive control function, which in turn results in particular deficits in the engagement of monitoring for PM cues. HubMed – depression

COMM-TC: Depression Treatment in Overweight Youth: Advantageous Approaches – COMMTC Depression Treatment in Overweight Youth Advantageous Approaches. Uploaded by envisionnm on Mar 05 2013. Presented by Dan Rifkin MD at Envision New Mexico UNM School of Medicine Health Sciences Center in Albuquerque NM on February 15 2013. Envision NM.