TL neuro

September 21, 2017

Locomotor and Reinforcing Effects Of Pentedrone, Pentylone and Methylone

Filed under: Cathinones, Methylone — mtaffe @ 9:59 am

Pentylone and pentedrone are designer drugs within the cathinone stimulant class of drugs that are often referred to as “bathsalts”. These two entities have appeared in the recreational user populations as confirmed by results from ecstasydata.org, a review of trip reports on bluelight.org and erowid.org, as well as in a few scientific reports.

Second-generation substituted cathinone drugs such as pentylone and pentedrone have received less research attention compared with first generation bathsalts such as mephedrone and, in particular, methylone. This is sufficient motivation to explore the abuse liability and other properties of the more recently emerged drugs. In addition, this growing diversity of cathinone derivatives allows us to further determine the role of various structural substitution elements that may be common to both amphetamine and cathinone drugs of abuse. In this study, we investigated the 3,4-methylenedioxy motif  in the contrast of the effects of pentedrone with pentylone. This motif, when added to methamphetamine to produce MDMA, confers reduced rewarding potency and efficacy, reduced locomotor potency, reduced efficacy to induce stereotyped, repetitive behavior and increased thermoregulatory disruption. In contrast, the presence of the 3,4-methylenedioxy substitution produces no change in vivo in the context of the closely related, restricted transporter inhibitor cathinones α-PVP and MDPV which exhibit similar efficacy and potency on both locomotor and self-administration assays in rats . Pentedrone and pentylone also include the extended alkyl-tail carbon chain that is present on MDPV and α-PVP which may be related to the restriction of those drugs to transporter inhibition. This might predict that the 3,4-methylenedioxy motif has minimal impact on these additional compounds (which lack the pyrrolidine ring of MDPV and α-PVP).

The following has recently been accepted for publication:

Javadi-Paydar, M., Nguyen, J.D., Vandewater, S.A., Dickerson, T.J., and Taffe, M.A. Locomotor and Reinforcing Effects Of Pentedrone, Pentylone and Methylone In Rats. Neuropharmacology, doi: https://doi.org/10.1016/j.neuropharm.2017.09.002. [ Publisher Site ][ PubMed ]

We assessed locomotor activity changes produced by i.p. injection of Pentylone and Pentedrone in contrast with the effects of Methylone. This was conducted in a group of female rats (N=8) prepared with radiotelemetry devices which report both both temperature and an activity rate within a housing chamber. These studies found that 1 mg/kg of any of these drugs was insufficient to significantly increase activity, however increases were observed for 5 or 10 mg/kg of each compound. There were similar dose-effect relationships found in a group of male rats.

There was no sign of the type of reduction in activity that is often seen after high dose methamphetamine in the ~5-10 mg/kg range. Such reductions are produced because the rat is engaged in stereotyped, repetitive behaviors (called “stereotypy”) which resolve over the course of about 90-120 minutes, depending on dose, whereupon a boost in activity is often observed. This pattern we are reporting here is, however, fairly consistent with what would be observed for MDMA in this 5-10 mg/kg dose range. So these results are as would be predicted from the pharmacology and by reference to the better-studied entactogen compound, MDMA.

 

We also assessed drug self-administration by way of conducting dose-substitution under Fixed Ratio 1 (FR1) conditions. (Each lever press results in an infusion of drug.). This was conducted in a group of female rats who had been trained originally with alpha-PVP (N=4) or Pentedrone (N=6), but this training history was essentially irrelevant to the dose-response and is not separated for the analysis.

In this figure we depict the mean infusions of the three drugs that are obtained across a range of doses.  A significant difference from vehicle is indicated with *, from the 0.025 mg/kg dose with &, from the 0.05 mg/kg dose with §, from the 0.30 mg/kg dose by % and a significant difference from methylone and α-PHP, respectively, is indicated with #. The takeaway points are first that the ascending and descending limbs of the typical “inverted-U” dose effect function have been captured. This is important to enhance confidence that you are not missing a dose that would engender peak responding. So the essentially parallel curves for Methylone and Pentylone can be interpreted as nearly identical potency of the drugs. Pentylone is more effective, as can be interpreted by the fact the curve is shifted upwards, relative to the one for Methylone. In contrast, the peak for Pentedrone is at a lower dose, indicating that this compound is more potent. The efficacy is not clearly different from either other drug as the curve falls somewhat in between in terms of the peak number of infusions obtained.

 

Overall this study confirms that differences between Pentylone and Pentedrone are subtle and they exhibit a profile of dose-effect relationships that is as would be predicted for entactogens. Therefore the 3,4-methylenedioxy motif appears to convey little difference in the context of this core structure. There is some evidence for enhanced abuse liability relative to Methylone and this will be of great interest to follow up with additional models. The difference between Pentylone and Methylone lies in the presence of the extended alpha alkyl chain which enhances lipophilicity, potentially letting Pentylone enter the brain more rapidly.

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