Effects of synthetic cathinones contained in “bath salts” on motor behavior and a functional observational battery in mice
Highlights
► Bath salts are emerging drugs of abuse that contain both legal and illegal cathinones. ► Effects of synthetic cathinones found in bath salts were compared to cocaine and methamphetamine. ► All cathinones produced typical stimulant-induced increases in locomotor activity. ► Some cathinones produced more behaviorally toxic effects than classic stimulants of abuse. ► Individual synthetic cathinones differ in their profile of effects, and differ from known stimulants of abuse.
Introduction
An emerging substance abuse problem is abuse of synthetic research chemicals for their stimulant properties (DEA, 2011, Psychonaut, 2009). These products, commonly labeled as “bath salts” or “plant food,” are administered through insufflation, oral, smoking, rectal and intravenous methods (Psychonaut, 2009, Winstock et al., 2011) and can be purchased legally in most states on the internet, at head shops, or at gas stations (DEA, 2011, Karila and Reynaud, 2010, Schifano et al., 2011, Winstock et al., 2010, Winstock et al., 2011). The active components contained in bath salts are synthetic cathinone analogs. Within the first 8 months that bath salts were on the U.S. drug market, there were more than 1400 cases of misuse and abuse reported to U.S. poison control centers in 47 of 50 states (Spiller et al., 2011). The number of calls to poison control centers in the U.S. regarding bath salts rose from 303 in 2010 to 6072 in 2011 (American Association of Poison Control Centers, 2012). The growing prevalence of bath salt use makes them a major health concern throughout the U.S. and Europe.
Cathinone is naturally occurring in the leaves of the khat plant (Catha edulis), which grows in eastern Africa and southern Arabia where it is used for its amphetamine-like effects (Griffiths et al., 2010). In rats, cathinone produces locomotor increases similar to those produced by amphetamine (Kalix, 1992), and increases extracellular dopamine (Pehek et al., 1990). The synthetic cathinones that have been found in bath salts include, but are not limited to 3-FMC (3-fluoromethcathinone), 4-FMC (4-fluoromethcathinone), buphedrone (α-methylamino-butyrophenone), butylone (beta-keto-N-methyl-3,4-benzodioxyolybutanamine), MDPV (methylenedioxyphyrovalerone), mephedrone (4-methylmethcathinone), methedrone (4-methoxymethcathinone), methylone (3,4-methylenedioxymethcathinone), and naphyrone (naphthylpyrovalerone) (Karila and Reynaud, 2010). MDPV, mephedrone, and methylone are the most commonly found active components worldwide (ACMD, 2010, EMCDDA, 2010, Spiller et al., 2011), with MDPV being the most commonly found component in the U.S. (Spiller et al., 2011).
To the extent that the in vivo effects of synthetic cathinones have been examined, they have been found to share pharmacological properties with other abused drugs that increase levels of monoamine neurotransmitters (e.g., stimulants such as cocaine and methamphetamine). For example, a low dose of mephedrone (3 mg/kg) produced moderate increases in locomotor activity in rats (Kehr et al., 2011), and higher doses (10 mg/kg and 30 m/kg) produced significant locomotor increases in mice (Angoa-Pérez et al., 2012). Acquisition of mephedrone self-administration also has been demonstrated (Hadlock et al., 2011). Anecdotal and case reports of human use of bath salts suggest these substances produce powerful psychological effects, including psychotic behavior, paranoia, delusions, hallucinations, and self-injury (EMCDDA, 2010, Spiller et al., 2011, Striebel and Pierre, 2011). In addition, since 2010, multiple cases of death while under the influence of bath salts in the U.S. have occurred, including some suicides (CDC, 2011, Spiller et al., 2011). Based on poison control center reports and case studies in the U.S., MDPV in particular tends to produce increased aggression, hallucinations, and paranoia (Antonowicz et al., 2011, Spiller et al., 2011). While these data suggest that the abuse liability and pharmacological effects of synthetic cathinones is likely similar to that of known stimulants of abuse, additional data are needed with a broader range of compounds that have been identified in purchased products.
Although some active components in bath salts have already been made illegal in some states (DEA, 2011, Spiller et al., 2011), and the DEA put an emergency ban on MDPV, mephedrone, and methylone in October 2011, it is likely that manufacturers will continue to make slight alterations in the chemical structure of these compounds in order to avoid detection and allow legal sale (Wohlfarth and Weinmann, 2010). This strategy is not without precedence, as Europe has seen the appearance of new bath salt products containing alternative cathinones following earlier legal restrictions (Camilleri et al., 2010). After legislative bans in Europe on MDPV and mephedrone, naphyrone has become the most commonly used bath salt in Europe. It is expected that once naphyrone becomes a controlled substance, a new compound will be ready for export to replace it (Eastwood, 2010).
The primary purpose of the present study was to evaluate the in vivo effects of synthetic cathinones that have been found in bath salts in the U.S. and to compare these effects to those produced by cocaine and methamphetamine. Cocaine is primarily a monoamine transporter blocker/reuptake inhibitor, and methamphetamine is primarily a monoamine transporter substrate/releaser (Fleckenstein et al., 2000, Rothman et al., 2001). Compounds identified in bath salts have been shown to be either cocaine-like monoamine reuptake inhibitors, methamphetamine-like releasers, or a hybrid of both mechanisms (Baumann et al., 2012, Cozzi et al., 1999, Martinez-Clemente et al., 2012, Meltzer et al., 2006, Nagai et al., 2007, Psychonaut, 2009, Winstock et al., 2010).
Section snippets
Subjects
Male ICR mice (Harlan) (n = 8/group) were individually housed in clear plastic cages in a temperature-controlled environment (20–24 °C) with a 12 h light–dark cycle (lights on at 6 a.m.). Mice had ad libitum access to water and food in their home cages at all times, and were approximately 47–56 days old at the beginning of the study. Research reported in this manuscript was approved by the Institutional Animal Care and Use Committee at RTI International, and followed the principles of laboratory
Locomotor activity
Fig. 1 shows effects of each compound on locomotor activity compared to the saline group. For ease of comparison, the results of the saline group are shown in each panel. Over the course of the 90 min session, habituation occurred in the saline group, resulting in attenuation of activity in later bins (compared to bin 1). Data in each panel of the figure were analyzed with a separate mixed model ANOVA, with use of the same saline group. As a consequence of differences in magnitude of drug effect
Discussion
A defining behavioral characteristic of psychomotor stimulants is their propensity to increase locomotion in rodents, an effect that is strongly associated with their high addiction potential (Calabrese, 2008, Wise and Bozarth, 1987). All synthetic cathinones tested in the present study shared this effect, with different cathinones showing different potencies, magnitudes of stimulation, and durations of action. While cathinones increased locomotor activity, the majority of them did not produce
Conclusion
As bath salt manufacturers attempt to remain one step ahead of the legal system, it is likely that some of the other synthetic cathinones investigated here (3-FMC; 4-FMC; methedrone) are already contained in the bath salt formulations currently being sold. Other potential psychoactive components that are legal and may be found in bath salts in the future include 4-methylmethamphetamine (4-MMA), the β-deketo analog of mephedrone, and methylbenzodioxolylbutanamine (MBDB), an amphetamine analog
Conflict of interest statement
The authors have no conflicts of interest.
Acknowledgments
Research supported by RTI International internal research and development funds, as well as the National Institute on Drug Abuse (DA 12970). The authors thank Antonio Landavazo and Timothy Lefever for technical assistance. Reprints may be obtained from the first author at [email protected] or from any of the authors at RTI International, 3040 Cornwallis Rd, Research Triangle Pk, NC 27709.
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