Repeated administration of N-ethyl-pentedrone induces increased aggression and impairs social exploration after withdrawal in mice

Espinosa-Velasco, María; Reguilón, Marina D.; Bellot, Marina; Nadal-Gratacós, Núria; Berzosa, Xavier; Gómez‐Canela, Cristian; Rodrı́guez-Arias, Marta; Camarasa, Jorge; Escubedo, Elena; Piccoli, David A.; López-Arnau, Raúl

doi:10.1016/j.pnpbp.2022.110562

Cited by 6 publications

(6 citation statements)

References 69 publications

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“…Whole brain c-Fos mapping of present study showed that ACC, VTA, and NAc were significantly activated after chronic use of 3-MMC, which was consistent with its amphetamine-like stimulant properties (Ferreira et al, 2019;Espinosa-Velasco et al, 2022). Dopamine-releasing neurons of the VTA have central roles in reward-related and goal-directed behaviors (Morales and Margolis, 2017), and a major reward-related 10.3389/fnmol.2022.975820 post hoc test, *P < 0.05, **P < 0.01 significant differences for 3-MMC vs saline or METH vs saline, # P < 0.05 significant differences for 3-MMC vs METH.…”

Section: Discussionsupporting

confidence: 82%

Effects of 3-methylmethcathinone on conditioned place preference and anxiety-like behavior: Comparison with methamphetamine

Chen

Zhang²,

Ding³

et al. 2022

Front. Mol. Neurosci.

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3-Methylmethcathinone (3-MMC), a drug belonging to synthetic cathinones family, raised public attention due to its harmful health effects and abuse potential. Although it has similar properties to other cathinone derivatives, the behavioral effects of 3-MMC remain largely unknown. In the present research, we evaluated the rewarding effect of 3-MMC using conditioned place preference (CPP) paradigm and its effect on anxiety-like behavior using elevated plus maze (EPM) and compared with methamphetamine (METH). Then, we performed a whole-brain c-Fos mapping to identify the specific brain regions in response to 3-MMC exposure and explored the changes of synaptic transmission in nucleus accumbens (NAc) using patch-clamp recording after chronic 3-MMC and METH exposure. 3-MMC induced CPP at higher doses of 3 or 10 mg/kg in rats and acute exposure of 3 mg/kg 3-MMC to rats produced anxiolytic-like effect, while anxiety-like behavior was increased after 7 days of injection with 3-MMC. Whole-brain immunostaining revealed increased c-Fos expression in anterior cingulate cortex (ACC), NAc and ventral tegmental area (VTA) after chronic 3-MMC injection compared with saline, which was similar to METH. Especially, 3-MMC induced more neural activation of VTA compared with METH. Finally, we found that amplitude of spontaneous inhibitory postsynaptic currents (sIPSCs) in NAc was decreased after chronic 3-MMC injection, while frequency of sIPSCs and spontaneous excitatory postsynaptic currents (sEPSCs) were not affected. Taken together, our results revealed the addictive potential of 3-MMC and its effect on anxiety-like behavior, which warn the risks of 3-MMC abuse and justify the control of synthetic cathinones. And 3-MMC selectively inhibit inhibitory but not excitatory transmission onto neurons in NAc, which may contribute to its effects.

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Section: Discussionsupporting

confidence: 82%

Effects of 3-methylmethcathinone on conditioned place preference and anxiety-like behavior: Comparison with methamphetamine

Chen

Zhang²,

Ding³

et al. 2022

Front. Mol. Neurosci.

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“…In the same way, i.p. injections of N-ethyl-pentedrone in mice caused an increase in spontaneous horizontal activity [ 40 ]. Ray et al studied α-pyrrolidinopropiophenone (α-PPP) effects on male mice, by administering 4 unit doses of 80 mg/kg of α-PPP every 2 h, for an 8 h period.…”

Section: Resultsmentioning

confidence: 99%

Synthetic Cathinones and Neurotoxicity Risks: A Systematic Review

Daziani

Faro

Montana

et al. 2023

IJMS

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According to the EU Early Warning System (EWS), synthetic cathinones (SCs) are the second largest new psychoactive substances (NPS) class, with 162 synthetic cathinones monitored by the EU EWS. They have a similar structure to cathinone, principally found in Catha Edulis; they have a phenethylamine related structure but also exhibit amphetamine-like stimulant effects. Illegal laboratories regularly develop new substances and place them on the market. For this reason, during the last decade this class of substances has presented a great challenge for public health and forensic toxicologists. Acting on different systems and with various mechanisms of action, the spectrum of side effects caused by the intake of these drugs of abuse is very broad. To date, most studies have focused on the substances’ cardiac effects, and very few on their associated neurotoxicity. Specifically, synthetic cathinones appear to be involved in different neurological events, including increased alertness, mild agitation, severe psychosis, hyperthermia and death. A systematic literature search in PubMed and Scopus databases according to PRISMA guidelines was performed. A total of 515 studies published from 2005 to 2022 (350 articles from PubMed and 165 from Scopus) were initially screened for eligibility. The papers excluded, according to the criteria described in the Method Section (n = 401) and after full text analyses (n = 82), were 483 in total. The remaining 76 were included in the present review, as they met fully the inclusion criteria. The present work provides a comprehensive review on neurotoxic mechanisms of synthetic cathinones highlighting intoxication cases and fatalities in humans, as well as the toxic effects on animals (in particular rats, mice and zebrafish larvae). The reviewed studies showed brain-related adverse effects, including encephalopathy, coma and convulsions, and sympathomimetic and hallucinogenic toxidromes, together with the risk of developing excited/agitated delirium syndrome and serotonin syndrome.

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“…The lack of sex differences on corticosterone levels following 2-Cl-4,5-MDMA is similar to previous observations in Sprague Dawley rats following repeated MDMA administration, which did not affect anxiety and serotonin content [ 58 ]. More difficult to predict was the effect of 3,4-MDPHP on plasma corticosterone levels due to the lack of clinical studies and the availability of only one preclinical study, which reported increased plasma corticosterone levels in mice after acute exposure to the new synthetic cathinone derivative N-ethyl-pentedrone (NEPD) [ 34 ]. Yet, in our study, chronic exposure to low doses of 3,4-MDPHP increased corticosterone levels selectively in female rats, suggesting that males are less vulnerable to the effect of this synthetic cathinone on the stress hormonal milieu.…”

Section: Discussionmentioning

confidence: 99%

“…In light of the increasing evidence for sex-dependent differences in NPSs-induced effects, this study involved both male and female animals. Moreover, since a link between the reinforcing effects of NPSs and plasma levels of corticosterone has been reported [ 34 ], at the end of the self-administration training, plasma corticosterone levels were also measured in both sexes to assess potential drug-induced, sex-dependent hormonal stress responses.…”

Section: Introductionmentioning

confidence: 99%

Effects of the Phenethylamine 2-Cl-4,5-MDMA and the Synthetic Cathinone 3,4-MDPHP in Adolescent Rats: Focus on Sex Differences

et al. 2022

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The illicit drug market of novel psychoactive substances (NPSs) is expanding, becoming an alarming threat due to increasing intoxication cases and insufficient (if any) knowledge of their effects. Phenethylamine 2-chloro-4,5-methylenedioxymethamphetamine (2-Cl-4,5-MDMA) and synthetic cathinone 3,4-methylenedioxy-α-pyrrolidinohexanophenone (3,4-MDPHP) are new, emerging NPSs suggested to be particularly dangerous. This study verified whether these two new drugs (i) possess abuse liability, (ii) alter plasma corticosterone levels, and (iii) interfere with dopaminergic transmission; male and female adolescent rats were included to evaluate potential sex differences in the drug-induced effects. Findings show that the two NPSs are not able to sustain reliable self-administration behavior in rats, with cumulatively earned injections of drugs being not significantly different from cumulatively earned injections of saline in control groups. Yet, at the end of the self-administration training, females (but not males) exhibited higher plasma corticosterone levels after chronic exposure to low levels of 3,4-MDPHP (but not of 2-Cl-4,5-MDMA). Finally, electrophysiological patch-clamp recordings in the rostral ventral tegmental area (rVTA) showed that both drugs are able to increase the firing rate of rVTA dopaminergic neurons in males but not in females, confirming the sex dimorphic effects of these two NPSs. Altogether, this study demonstrates that 3,4-MDPHP and 2-Cl-4,5-MDMA are unlikely to induce dependence in occasional users but can induce other effects at both central and peripheral levels that may significantly differ between males and females.

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Repeated administration of N-ethyl-pentedrone induces increased aggression and impairs social exploration after withdrawal in mice

Cited by 6 publications

References 69 publications

Effects of 3-methylmethcathinone on conditioned place preference and anxiety-like behavior: Comparison with methamphetamine

Effects of 3-methylmethcathinone on conditioned place preference and anxiety-like behavior: Comparison with methamphetamine

Synthetic Cathinones and Neurotoxicity Risks: A Systematic Review

Effects of the Phenethylamine 2-Cl-4,5-MDMA and the Synthetic Cathinone 3,4-MDPHP in Adolescent Rats: Focus on Sex Differences

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