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Stereoselective Differences between the Reinforcing and Motivational Effects of Mephedrone In Self-Administering RatsACS Chem. Neurosci. - Sept. 8, 2017

Mephedrone 4-MMC

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#1 Phlogiston

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Posted 26 September 2017 - 08:20 AM

Bron: http://pubs.acs.org/...emneuro.7b00212

 

Stereoselective Differences between the Reinforcing and Motivational Effects of Cathinone-Derived 4-Methylmethcathinone (Mephedrone) In Self-Administering Rats

Abstract:
Mephedrone (4-methylmethcathinone (4-MMC)) (MEPH) is a new psychoactive substance (NPS) of the synthetic cathinone class. MEPH has a chiral center and exists as two enantiomers (R-,S-MEPH), yet stereospecific effects of MEPH have not been extensively investigated in preclinical assays. Because significant behavioral and neurochemical differences can exist between enantiomers, probing effects of stereochemistry on biological activity enables separation of adverse and therapeutic effects. Our prior work showed that R-MEPH, relative to S-MEPH, produced greater locomotor activation, place preference, and facilitation of brain reward thresholds in rodents. The present study sought to determine if MEPH enantiomers display stereospecific reward and reinforcement in rat self-administration assays. In Experiment 1, rats were trained to self-administer racemic MEPH (0.50 mg/kg/inf), and dose substitution effects of R-MEPH (0.50 mg/kg/inf) and S-MEPH (0.25, 0.50, 2.00 mg/kg/inf) were examined. In Experiment 2, separate rats were trained to self-administer R-MEPH (0.25, 0.50, 2.00 mg/kg/inf) or S-MEPH (0.25, 0.50, 2.00 mg/kg/inf) and were thereafter evaluated under progressive-ratio access conditions. Within this cohort, 50 kHz ultrasonic vocalizations (USVs) were recorded to measure potential differences in subjective positive affect associated with MEPH enantiomer self-administration. We identified enantiomer- and dose-dependent effects on infusions earned during self-administration following acquisition of racemic MEPH, with greatest infusions under low-effort, fixed-ratio 1 access conditions from low-dose S-MEPH self-administration. When taxed with progressive-ratio access conditions, rats trained to self-administer R-MEPH showed higher break points than those of rats trained to self-administer S-MEPH. Additionally, R-MEPH elicited greatest rates of 50 kHz USVs compared to S-MEPH. Taken together, these data suggest that the R-enantiomer of MEPH is primarily responsible for the rewarding, reinforcing, and motivational properties of racemic MEPH, which increases our understanding of stereospecific preferences pertaining to MEPH abuse.

 

 

Dit is interessant, want voor (meth)amfetamine is juist de (S)-vorm de meest rewarding en de sterkere pyschostimulant.


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#2 Immad

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Posted 23 October 2017 - 09:07 PM

Wat is eigenlijk de meest reinforcing enantiomeer van MDMA?



#3 Phlogiston

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Posted 24 October 2017 - 09:50 AM

Uit deze paper:

This stereochemical signature enables separation of addictive and therapeutic effects as enantiomers of established psychostimulants can produce vastly different pharmacological effects. In one study examining stereoselective effects of METH, the S-enantiomer demonstrated 25fold greater potency than R-enantiomer in rats trained in a drug discrimination task [12]. Similarly, S-methcathinone has a 3fold greater ability to substitute for a discriminative stimulus paired with racemic cocaine relative to R-methcathinone [13]. Using selfadministration in nonhuman primates, Wang and colleagues (2007) [14] demonstrated more consistent reinforcement from S-MDMA and racemic MDMA relative to R-MDMA. For MDPV, crystal structures of enantiomers have been described in prior work, and stereoselective effects include potent DAT uptake inhibition and facilitation of brain reward thresholds following systemic S-MDPV relative to racemate R-MDPV or mixture [1516].


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#4 snaap

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Posted 25 October 2017 - 09:00 AM

Hier over de R-enantiomeer van MDMA:

 

https://www.ncbi.nlm...pubmed/28993129

 

S,R(+/-)-3,4-methylenedioxymethamphetamine (SR-MDMA) is an amphetamine derivative with prosocial and putative therapeutic effects. Ongoing clinical trials are investigating it as a treatment for post-traumatic stress disorder (PTSD) and other conditions. However, its potential for adverse effects such as hyperthermia and neurotoxicity may limit its clinical viability. We investigated the hypothesis that one of the two enantiomers of SR-MDMA, R-MDMA, would retain the prosocial and therapeutic effects but with fewer adverse effects. Using male Swiss Webster and C57BL/6 mice, the prosocial effects of R-MDMA were measured using a social interaction test, and the therapeutic-like effects were assessed using a Pavlovian fear conditioning and extinction paradigm relevant to PTSD. Locomotor activity and body temperature were tracked after administration, and neurotoxicity was evaluated post-mortem. R-MDMA significantly increased murine social interaction and facilitated extinction of conditioned freezing. Yet, unlike racemic MDMA, it did not increase locomotor activity, produce signs of neurotoxicity, or increase body temperature. A key pharmacological difference between R-MDMA and racemic MDMA is that R-MDMA has much lower potency as a dopamine releaser. Pretreatment with a selective dopamine D1 receptor antagonist prevented SR-MDMA-induced hyperthermia, suggesting that differential dopamine signaling may explain some of the observed differences between the treatments. Together, these results indicate that the prosocial and therapeutic effects of SR-MDMA may be separable from the stimulant, thermogenic, and potential neurotoxic effects. To what extent these findings translate to humans will require further investigation, but these data suggest that R-MDMA could be a more viable therapeutic option for the treatment of PTSD and other disorders for which SR-MDMA is currently being investigated.


Important notice: Due to the current financial crisis, we have decided to temporarily turn off the light at the end of the tunnel.

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