Short communicationMephedrone (4-methylmethcathinone), a principal constituent of psychoactive bath salts, produces behavioral sensitization in rats
Introduction
Mephedrone (4-methylmethcathinone; MEPH) is a constituent of psychoactive bath salts that continues to gain a foothold in the illicit drug market; it was the sixth most frequently used drug of abuse in a survey of drug users in the United Kingdom (Winstock et al., 2011). MEPH is a substrate of plasma membrane monoamine transporters that increases acute locomotor activity in rats, with a weaker locomotor stimulus than methamphetamine (Baumann et al., 2013, Motbey et al., 2012, Huang et al., 2012). It increases extracellular dopamine (DA) and serotonin (5-HT) in the nucleus accumbens, with preferential effects on 5-HT (Baumann et al., 2012, Kehr et al., 2011). MEPH produces inward currents (depolarizing) at the dopamine transporter similar to dopamine-releasing agents (e.g., amphetamine and methamphetamine; Cameron et al., 2013). Consistent with its reported psychoactive properties, MEPH produces conditioned place preference (CPP) in rats and mice and is self-administered by rats maintained on a fixed-ratio schedule of reinforcement (Hadlock et al., 2011, Lisek et al., 2012). The ability of repeated, intermittent MEPH administration to produce sensitization to stimulant effects of acute MEPH challenge has not been extensively investigated (Lisek et al., 2012, Shortall et al., 2012). Behavioral sensitization is produced by psychostimulants and involves repeated administration of the drug, an absence interval in which the drug is not administered, and reintroduction to the drug (Steketee and Kalivas, 2011). Sensitization is present when motor activity produced by repeated drug exposure exceeds that produced by initial exposure (Robinson and Camp, 1987). On the basis of its structural and pharmacological similarities to commonly abused amphetamines, we hypothesized that repeated exposure to MEPH would elicit behavioral sensitization in rats.
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Animals and drugs
Male Sprague-Dawley rats (260–290 g; Harlan Laboratories, Indianapolis, IN) were housed 2 per cage and maintained on a 12-h light–dark cycle. Food and water were provided ad libitum. Animal use procedures were conducted in accordance with the NIH Guide for the Care and Use of Laboratory Animals and institutional Guidelines for the Care of Animals. MEPH was synthesized by Drs. Allen Reitz and Christopher McCurdy and dissolved in physiological saline and injected intraperitoneally (ip).
Dosing schedules and behavioral experiments
Two
Repeated MEPH exposure produces sensitization of repetitive movement
Activities produced by acute (day 1) and repeated (day 7) MEPH exposure are presented in Fig. 1. Repetitive movement is presented in Fig. 1A as the cumulative number of repetitive-beam breaks in the 90 min following MEPH (or saline) injection (time-course data are shown in box). Significant effects on treatment [F(1, 14) = 66.69, p < 0.0001], time [F(1, 14) = 10.19, p < 0.01], and interaction [F(1, 14) = 5.60, p < 0.01] were identified. Post-hoc analysis indicated that 7 days of repeated MEPH produced
Discussion
Repeated MEPH exposure produced sensitization to repetitive movement caused by acute MEPH. The effect was consistent across multiple paradigms (i.e., constant-dosing and variable dosing schedules, 2- and 10-day MEPH absence intervals, and context-independent and context-dependent designs). Commonalities between sensitization produced by MEPH and established psychostimulant drugs (e.g., cocaine, methamphetamine, MDMA) included the presence of sensitization before and after a fixed period of drug
Role of funding source
This study was funded by National Institutes on Drug Abuse Grant DA032718 (SMR). The Center for Substance Abuse Research (CSAR) grant (DA013429) and training grant (DA07237) funded by NIDA also contributed to the present study. NIDA had no further role in study design; in the collection, analysis and interpretation of data; in the writing of the report; or in the decision to submit the paper for publication.
Contributors
Authors Scott M. Rawls, Ryan Gregg, and Chris Tallarida designed the behavioral studies. Authors Allen B. Reitz and Christopher McCurdy supervised the synthesis of mephedrone. Author Christophe Mesangeau carried out the synthesis of mephedrone. Authors Ryan Gregg and Chris Tallarida conducted the behavioral sensitization studies. Authors Ryan Gregg and Scott Rawls conducted statistical analyses and wrote the manuscript. Drafts of the manuscript were subsequently circulated to all authors for
Conflict of interest
All authors declare that they have no conflicts of interest.
Acknowledgements
None.
References (18)
- et al.
Psychoactive “bath salts”: not so soothing
Eur. J. Pharmacol.
(2013) - et al.
Contrasting effects of d-methamphetamine, 3,4-methylenedioxymethamphetamine, 3,4-methylenedioxypyrovalerone, and 4-methylmethcathinone on wheel activity in rats
Drug Alcohol Depend.
(2012) - et al.
Mephedrone (‘bath salt’) elicits conditioned place preference and dopamine-sensitive motor activation
Drug Alcohol Depend.
(2012) - et al.
Glutamate transporter subtype 1 (GLT-1) activator ceftriaxone attenuates amphetamine-induced hyperactivity and behavioral sensitization in rats
Drug Alcohol Depend.
(2011) - et al.
Long-lasting effects of escalating doses of d-amphetamine on brain monoamines, amphetamine-induced stereotyped behavior and spontaneous nocturnal locomotion
Pharmacol. Biochem. Behav.
(1987) - et al.
Context-dependent behavioural and neuronal sensitization in striatum to MDMA (ecstasy) administration in rats
Eur. J. Neurosci.
(2006) - et al.
Behavioral sensitization to 3,4-methylenedioxymethamphetamine is long-lasting and modulated by the context of drug administration
Behav. Pharmacol.
(2011) - et al.
The designer methcathinone analogs, mephedrone and methylone, are substrates for monoamine transporters in brain tissue
Neuropsychopharmacology
(2012) - et al.
Mephedrone and methylenedioxypyrovalerone (MDPV), major constituents of “bath salts,” produce opposite effects at the human dopamine transporter
Psychopharmacology (Berl.)
(2013)
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