Effects of synthetic cathinones contained in “bath salts” on motor behavior and a functional observational battery in mice

Abstract

Synthetic stimulants commonly sold as “bath salts” are an emerging abuse problem in the U.S. Users have shown paranoia, delusions, and self-injury. Previously published in vivo research has been limited to only two components of bath salts (mephedrone and methylone). The purpose of the present study was to evaluate in vivo effects of several synthetic cathinones found in bath salts and to compare them to those of cocaine (COC) and methamphetamine (METH). Acute effects of methylenedioxyphyrovalerone (MDPV), mephedrone, methylone, methedrone, 3-fluoromethcathinone (3-FMC), 4-fluoromethcathinone (4-FMC), COC, and METH were examined in male ICR mice on locomotor activity, rotorod, and a functional observational battery (FOB). All drugs increased locomotor activity, with different compounds showing different potencies and time courses in locomotor activity. 3-FMC and methylone decreased performance on the rotorod. The FOB showed that in addition to typical stimulant induced effects, some synthetic cathinones produced ataxia, convulsions, and increased exploration. These results suggest that individual synthetic cathinones differ in their profile of effects, and differ from known stimulants of abuse. Effects of 3-FMC, 4-FMC, and methedrone indicate these synthetic cathinones share major pharmacological properties with the ones that have been banned (mephedrone, MDPV, methylone), suggesting that they may be just as harmful.

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).