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Brain Sciences
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Abuse Liability and Toxic Potential of Synthetic Psychoactive Cathinones
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Abuse Liability and Toxic Potential of Synthetic Psychoactive Cathinones

A special issue of Brain Sciences (ISSN 2076-3425). This special issue belongs to the section "Neuropharmacology and Neuropathology".

Deadline for manuscript submissions: closed (30 July 2024) | Viewed by 10017

Special Issue Editor

Dr. F. Scott Hall

E-Mail Website
Guest Editor
Department of Pharmacology and Experimental Therapeutics, Frederic and Mary Wolfe Center 282D, The University of Toledo, Toledo, OH, USA
Interests: drug addiction; animal models; ADHD; monoamine transporters; drug overdose

Special Issue Information

Dear Colleagues,

The purpose of this special issue is to provide an update on our evolving understanding of the abuse liability and toxicity of synthetic psychoactive cathinones (SPCs). SPCs are a major class of novel psychoactive substances (NPS) that have become widely used in place of illicit psychostimulant drugs such as methamphetamine, methylenedioxymethamphetamine, and cocaine. They are β-ketone congeners of amphetamines. Most SPCs have emerged into illicit use only in the last couple of decades, and over 400 related analogues are sold illicitly. Their potential for abuse liability is uncertain, as is their toxic potential, and progress in this field is hampered by the very wide number of related analogues that are used. Although evidence suggests that the abuse potential and toxicity of SPCs are often similar to related amphetamines, there are also some clear differences, and it is uncertain to what extent the relative abuse potential or toxicity of the many SPC analogues are greater or lesser than similar amphetamine analogues. Structure activity relationships are only starting to be determined for this large drug class, and really are relatively poorly understood for the related amphetamines, particularly for toxic mechanisms. The articles in this special issue will address these important issues, which have important regulatory and health implications. Among these is the potential of the emergence of very high potency psychostimulant drugs that pose the same threat of escalated risk of drug overdose compared to classic psychostimulant drugs as fentanyl did for opioids. Indeed, it is likely that the next phase of the US drug overdose epidemic will include psychostimulant drugs, including novel psychostimulants.

Dr. F. Scott Hall
Guest Editor

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Keywords

  • addiction
  • overdose
  • drug dependence
  • drug abuse
  • drug use disorder
  • psychostimulant drugs
  • synthetic psychoactive cathinone
  • novel psychoactive substance
  • drug toxicity
  • drug lethality

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Published Papers (5 papers)

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Research

Jump to: Review

23 pages, 3193 KiB  
Article
Methamphetamine and the Synthetic Cathinone 3,4-Methylenedioxypyrovalerone (MDPV) Produce Persistent Effects on Prefrontal and Striatal Microglial Morphology and Neuroimmune Signaling Following Repeated Binge-like Intake in Male and Female Rats
by Erin K. Nagy, Paula F. Overby, Jonna M. Leyrer-Jackson, Vincent F. Carfagno, Amanda M. Acuña and M. Foster Olive
Brain Sci. 2024, 14(5), 435; https://doi.org/10.3390/brainsci14050435 - 27 Apr 2024
Viewed by 1288
Abstract
Psychostimulants alter cellular morphology and activate neuroimmune signaling in a number of brain regions, yet few prior studies have investigated their persistence beyond acute abstinence or following high levels of voluntary drug intake. In this study, we examined the effects of the repeated [...] Read more.
Psychostimulants alter cellular morphology and activate neuroimmune signaling in a number of brain regions, yet few prior studies have investigated their persistence beyond acute abstinence or following high levels of voluntary drug intake. In this study, we examined the effects of the repeated binge-like self-administration (96 h/week for 3 weeks) of methamphetamine (METH) and 21 days of abstinence in female and male rats on changes in cell density, morphology, and cytokine levels in two addiction-related brain regions—the prefrontal cortex (PFC) and dorsal striatum (DStr). We also examined the effects of similar patterns of intake of the cocaine-like synthetic cathinone derivative 3,4-methylenedioxypyrovalerone (MDPV) or saline as a control. Robust levels of METH and MDPV intake (~500–1000 infusions per 96 h period) were observed in both sexes. We observed no changes in astrocyte or neuron density in either region, but decreases in dendritic spine densities were observed in PFC pyramidal and DStr medium spiny neurons. The microglial cell density was decreased in the PFC of METH self-administering animals, accompanied by evidence of microglial apoptosis. Changes in microglial morphology (e.g., decreased territorial volume and ramification and increased cell soma volume) were also observed, indicative of an inflammatory-like state. Multiplex analyses of PFC and DStr cytokine content revealed elevated levels of various interleukins and chemokines only in METH self-administering animals, with region- and sex-dependent effects. Our findings suggest that voluntary binge-like METH or MDPV intake induces similar cellular perturbations in the brain, but they are divergent neuroimmune responses that persist beyond the initial abstinence phase. Full article
(This article belongs to the Special Issue Abuse Liability and Toxic Potential of Synthetic Psychoactive Cathinones)
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10 pages, 807 KiB  
Article
Dopamine Concentration Changes Associated with the Retrodialysis of Methylone and 3,4-Methylenedioxypyrovalerone (MDPV) into the Caudate Putamen
by Robert Goldsmith, Amal Aburahma and Jon E. Sprague
Brain Sci. 2024, 14(3), 265; https://doi.org/10.3390/brainsci14030265 - 8 Mar 2024
Viewed by 1290
Abstract
Structural modifications to synthetic psychoactive cathinones (SPCs), a class of drugs that contain a β-keto modification of the phenethylamine pharmacophore of amphetamine, induce differences in dopamine transporter (DAT) activity. Here, in vivo retrodialysis was utilized to deliver the SPCs 3,4-methylenedioxypyrovalerone (MDPV, a DAT [...] Read more.
Structural modifications to synthetic psychoactive cathinones (SPCs), a class of drugs that contain a β-keto modification of the phenethylamine pharmacophore of amphetamine, induce differences in dopamine transporter (DAT) activity. Here, in vivo retrodialysis was utilized to deliver the SPCs 3,4-methylenedioxypyrovalerone (MDPV, a DAT inhibitor) or methylone (a DAT substrate) into the caudate putamen of male Sprague-Dawley rats. Dialysate samples were collected prior to and post drug administration, and temporal changes in dopamine concentration were quantified using HPLC-EC methods. Methylone elicited a 200% increase and MDPV a 470% increase in dopamine levels at the 10 min time point. The findings demonstrate that in vivo retrodialysis can be used to evaluate the effects of SPCs on neurotransmission in the brain. Full article
(This article belongs to the Special Issue Abuse Liability and Toxic Potential of Synthetic Psychoactive Cathinones)
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Graphical abstract

17 pages, 1685 KiB  
Article
Impacts of Self-Administered 3,4-Methylenedioxypyrovalerone (MDPV) Alone, and in Combination with Caffeine, on Recognition Memory and Striatal Monoamine Neurochemistry in Male Sprague Dawley Rats: Comparisons with Methamphetamine and Cocaine
by Robert W. Seaman, Jr., Kariann Lamon, Nicholas Whitton, Brian Latimer, Agnieszka Sulima, Kenner C. Rice, Kevin S. Murnane and Gregory T. Collins
Brain Sci. 2024, 14(3), 258; https://doi.org/10.3390/brainsci14030258 - 6 Mar 2024
Viewed by 1325
Abstract
Recent data suggest that 3,4-methylenedioxypyrovalerone (MDPV) has neurotoxic effects; however, the cognitive and neurochemical consequences of MDPV self-administration remain largely unexplored. Furthermore, despite the fact that drug preparations that contain MDPV often also contain caffeine, little is known regarding the toxic effects produced [...] Read more.
Recent data suggest that 3,4-methylenedioxypyrovalerone (MDPV) has neurotoxic effects; however, the cognitive and neurochemical consequences of MDPV self-administration remain largely unexplored. Furthermore, despite the fact that drug preparations that contain MDPV often also contain caffeine, little is known regarding the toxic effects produced by the co-use of these two stimulants. The current study investigated the degree to which self-administered MDPV or a mixture of MDPV+caffeine can produce deficits in recognition memory and alter neurochemistry relative to prototypical stimulants. Male Sprague Dawley rats were provided 90 min or 12 h access to MDPV, MDPV+caffeine, methamphetamine, cocaine, or saline for 6 weeks. Novel object recognition (NOR) memory was evaluated prior to any drug self-administration history and 3 weeks after the final self-administration session. Rats that had 12 h access to methamphetamine and those that had 90 min or 12 h access to MDPV+caffeine exhibited significant deficits in NOR, whereas no significant deficits were observed in rats that self-administered cocaine or MDPV. Striatal monoamine levels were not systematically affected. These data demonstrate synergism between MDPV and caffeine with regard to producing recognition memory deficits, highlighting the importance of recapitulating the manner in which drugs are used (e.g., in mixtures containing multiple stimulants, binge-like patterns of intake). Full article
(This article belongs to the Special Issue Abuse Liability and Toxic Potential of Synthetic Psychoactive Cathinones)
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24 pages, 3943 KiB  
Article
Effects of Serial Polydrug Use on the Rewarding and Aversive Effects of the Novel Synthetic Cathinone Eutylone
by Hayley N. Manke, Samuel S. Nunn, Agnieszka Sulima, Kenner C. Rice and Anthony L. Riley
Brain Sci. 2023, 13(9), 1294; https://doi.org/10.3390/brainsci13091294 - 7 Sep 2023
Cited by 2 | Viewed by 1488
Abstract
Background: As individual synthetic cathinones become scheduled and regulated by the Drug Enforcement Administration (DEA), new ones regularly are produced and distributed. One such compound is eutylone, a novel third-generation synthetic cathinone whose affective properties (and abuse potential) are largely unknown. The following [...] Read more.
Background: As individual synthetic cathinones become scheduled and regulated by the Drug Enforcement Administration (DEA), new ones regularly are produced and distributed. One such compound is eutylone, a novel third-generation synthetic cathinone whose affective properties (and abuse potential) are largely unknown. The following experiments begin to characterize these effects and how they may be impacted by drug history (a factor affecting reward/aversion for other drugs of abuse). Methods: Eutylone was assessed for its ability to induce conditioned taste avoidance (CTA; aversive effect) and conditioned place preference (CPP; rewarding effect) and their relationship (Experiment 1). Following this, the effects of exposure to cocaine or 3,4-methylenedioxymethamphetamine [MDMA] on eutylone’s affective properties were investigated (Experiment 2). Results: Eutylone produced dose-dependent CTA and CPP (Experiment 1), and these endpoints were unrelated. Pre-exposure to cocaine and MDMA differentially impacted taste avoidance induced by eutylone (MDMA > cocaine) and did not impact eutylone-induced place preference. Conclusions: These data indicate that eutylone, like other synthetic cathinones, has co-occurring, independent rewarding and aversive effects that may contribute to its abuse potential and that these effects are differentially impacted by drug history. Although these studies begin the characterization of eutylone, future studies should examine the impact of other factors on eutylone’s affective properties and its eventual reinforcing effects (i.e., intravenous self-administration [IVSA]) to predict its use and abuse liability. Full article
(This article belongs to the Special Issue Abuse Liability and Toxic Potential of Synthetic Psychoactive Cathinones)
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Review

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18 pages, 769 KiB  
Review
Synthetic Cathinones: Epidemiology, Toxicity, Potential for Abuse, and Current Public Health Perspective
by Shanshan Chen, Wenhua Zhou and Miaojun Lai
Brain Sci. 2024, 14(4), 334; https://doi.org/10.3390/brainsci14040334 - 29 Mar 2024
Cited by 2 | Viewed by 3989
Abstract
Synthetic cathinones, derived from cathinone found in the plant Catha edulis, represent the second largest and most frequently seized group of new psychoactive substances. They are considered as β-keto analogs of amphetamine, sharing pharmacological effects with amphetamine and cocaine. This review describes the [...] Read more.
Synthetic cathinones, derived from cathinone found in the plant Catha edulis, represent the second largest and most frequently seized group of new psychoactive substances. They are considered as β-keto analogs of amphetamine, sharing pharmacological effects with amphetamine and cocaine. This review describes the neurotoxic properties of synthetic cathinones, encompassing their capacity to induce neuroinflammation, dysregulate neurotransmitter systems, and alter monoamine transporters and receptors. Additionally, it discusses the rewarding and abuse potential of synthetic cathinones drawing from findings obtained through various preclinical animal models, contextualized with other classical psychostimulants. The review also offers an overview of current abuse trends of synthetic cathinones on the illicit drug market, specifying the aspects covered, and underscores the risks they pose to public health. Finally, the review discusses public health initiatives and efforts to reduce the hazards of synthetic cathinones, including harm reduction methods, education, and current clinical management strategies. Full article
(This article belongs to the Special Issue Abuse Liability and Toxic Potential of Synthetic Psychoactive Cathinones)
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