Comparison of the behavioral and cardiovascular effects of mephedrone with other drugs of abuse in rats

Abstract

Rationale: Exceedingly little experimental research exists on the popular recreational drug mephedrone (4-methylmethcathinone) despite clinical reports concerning its behavioral and cardiovascular toxicity.

Objectives: To characterize mephedrone preclinically by examining its capacity to (1) serve as a discriminative stimulus, (2) disrupt the acquisition of response sequences, and (3) disrupt mean arterial pressure (MAP) and heart rate (HR).

Methods and results: In one group of subjects that reliably discriminated 3.2 mg/kg of mephedrone from saline (n = 9), substitution tests indicated that stimulants (cocaine, MDMA, and methamphetamine) more closely approximated the mephedrone discriminative stimulus than non-stimulants (fenfluramine, morphine, and phencyclidine), although none fully substituted. In a second group (n = 6), mephedrone (0.56-10 mg/kg, i.p.) dose-dependently decreased response rate and increased errors in both components of a procedure in which subjects either acquired a new response sequence each session (repeated acquisition) or completed the same response sequence each session (performance). Finally, in a third group (n = 12), radio telemetry probes were used to measure the changes in MAP and HR elicited by mephedrone and then compared them to a known stimulant, methamphetamine. In these studies, mephedrone (0.01-9 mg/kg, i.v.) elicited increases in MAP and HR that were very similar to those elicited by methamphetamine (0.01-9 mg/kg, i.v.). The tachycardia and pressor responses to mephedrone (3 mg/kg) were blocked by the β-blocker atenolol (1 mg/kg, i.v.) and the α1, α2-blocker phentolamine (3 mg/kg, i.v.), respectively.

Conclusions: Mephedrone produces behavioral and cardiovascular responses that are similar to other stimulants; however, differences from the classical stimulants were also apparent.

Fig. 1

Effects of cumulative doses of mephedrone, cocaine, MDMA, and methamphetamine on the percentage of mephedrone-lever responding (upper panels) and overall response rate (lower panels) in 6–9 male rats. Doses of each drug were administered i.p. 15 min prior to the start of each 10-min FR component. Data points and vertical lines above “C” in the top and bottom panel represent the grand mean and SEM for 1 to 6 saline or vehicle determinations in each of the 9 rats. The data points and vertical lines in the dose-effect curves for each drug represent a grand mean and SEM, which was obtained from the means of 2–5 determinations of mephedrone, 2–3 determinations of cocaine or MDMA, and 1–5 determinations of methamphetamine. Numerical values in parentheses and adjacent to a data point indicate the number of subjects represented by that point when it differed from the total number of subjects for that drug group due to individual differences in the potency of that drug’s rate-decreasing effects. For example, 3.2 mg/kg of mephedrone (filled circles) eliminated responding in one rat, so only 8 of 9 rats received 10 mg/kg and the percentage of mephedrone-lever responding could only be calculated for 5 of the rats that received this dose.

Fig. 2

Effects of cumulative doses of mephedrone, fenfluramine, morphine, and phencyclidine on the percentage of mephedrone-lever responding (upper panels) and overall response rate (lower panels) in 5–9 male rats. Data points and vertical lines above “C” in the top and bottom panel represent the grand mean and SEM for 1 to 6 saline or vehicle determinations in each of the 9 rats. The data points and vertical lines in the dose-effect curves for each drug also represent a grand mean and SEM, which was obtained from the means of 2–5 determinations of mephedrone, 1–3 determinations of fenfluramine, 2 to 4 determinations of morphine, and 1–3 determinations of phencyclidine. Numerical values in parentheses and adjacent to a data point indicate the number of subjects represented by that point when it differed from the total number of subjects for that group due to individual differences in the potency of that drug’s rate-decreasing effects.

Fig. 3

Effects of haloperidol alone and in combination with cumulative doses of mephedrone on the percentage of mephedrone-lever responding (upper panels) and overall response rate (lower panels) in 7 male rats. A single dose of haloperidol was administered 20 min prior to the first component, whereas cumulative doses of mephedrone were administered i.p. 15 min prior to the start of each 10-min FR component. Data points and vertical lines above “C” in each panel represent the grand mean and SEM for 1 to 2 saline or vehicle determinations in 6 of the 7 rats, as one rat did not receive vehicle and saline under test conditions. Data points and vertical lines above “H” in each panel represent the grand mean and SEM for 1–3 determinations of haloperidol alone in each of the 7 rats, whereas the data points and vertical lines in the dose-effect curves for each drug also represent a grand mean and SEM that was calculated from 1–4 determinations of mephedrone with each dose of haloperidol. Asterisks along with a bracket indicate doses of mephedrone that were significantly different from saline and vehicle administration (control). Asterisks without a bracket indicate doses of haloperidol that were significantly different from saline administration (p<0.05) as determined by a one-way ANOVA. A cross with a bracket indicates the only dependent measure for which there was a significant main effect of haloperidol pretreatment as determined by two-way ANOVA.

Fig. 4

Effects of mephedrone on the overall response rate and percentage of errors in 6 male rats responding under a multiple schedule of repeated acquisition and performance of response sequences. The unfilled circles represent data from the acquisition components, whereas the filled circles depict represent data from the performance components. The data points and vertical lines above “C” (i.e., control) and in the dose-effect curves represent a grand mean and standard error of the mean (SEM), as all of the individual subjects received multiple determinations of both saline and each dose of mephedrone. Any points without vertical lines indicate instances in which the SEM is encompassed by the data point. Asterisks indicate effects of mephedrone that differed significantly from control injections. Pound symbols indicate significant differences between the acquisition and performance data. Numerical values in parentheses and adjacent to a data point indicate the number of subjects represented by that point when it differed from the total number of subjects in the group. The percentage of errors was not analyzed or plotted when response rate fell below 5 responses/min in either component due to the small number of responses emitted.

Fig. 5

Within-session pattern of errors in rats after either vehicle (shaded area) injections or injections with different doses of mephedrone (unfilled symbols). The data are plotted as the cumulative number of errors per bin of 60 consecutive responses.

Fig. 6

MAP and HR responses elicited in conscious rats by the intravenous injection of mephedrone (open circles, n=5–7) or methamphetamine (open squares, n=7). The data points and vertical lines above “S” (i.e., saline control) and in the dose-effect curves represent the mean of the peak changes in MAP and HR and standard error of the mean (SEM). Doses of mephedrone and methamphetamine were delivered once per day in mixed order, except for the 9-mg/kg dose, which was given on the final day. Asterisks indicate doses of mephedrone or methamphetamine that were significantly different from saline administration (p<0.05) as determined by a one-way ANOVA.

Fig. 7

Comparison of the peak changes in MAP and HR elicited in conscious rats by mephedrone (3 mg/kg, i.v) alone and after blockade of β-adrenergic receptors with atenolol (1 mg/kg, i.v.) or α-adrenergic receptors with phentolamine (3 mg/kg, i.v.). Data for mephedrone alone are the same as in Figure 6. Separate groups of rats received atenolol and mephedrone (n=6), or phentolamine and mephedrone (n=5). Asterisks indicate significant difference from the peak response elicited by mephedrone alone (p<0.05) as determined by a one-way ANOVA.