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

The purpose of this study was to determine whether chronic administration of D 9-tetrahydrocannabinol (THC) during adolescence would (1) modify any sex-specific effects of THC on learning and (2) affect the development of tolerance to THC as an adult. Male and female rats received daily injections of saline or 5.6 mg/kg of THC from postnatal day 35-75, yielding four groups (female/saline, female/THC, male/saline, and male/THC). Rats were then trained on a procedure that assayed both learning and performance behavior and administered 0.32-18 mg/kg of THC acutely as adults (experiment 1). THC produced rate-decreasing and error-increasing effects in both sexes; however, female rats were more sensitive than male rats were to the rate-decreasing effects. Rats were then chronically administered 10 mg/kg of THC (experiment 2). Rats that received THC during adolescence developed tolerance to the rate-decreasing effects more slowly and less completely than did rats that received saline; in addition, females developed tolerance to the error-increasing effects of THC slower than males did. Western blot analysis of brain tissue indicated long-term changes in hippocampal and striatal cannabinoid type-1 receptor (CB1R) levels despite levels that were indistinguishable immediately after chronic treatment during adolescence. Striatal CB1R levels were increased in adult rats that received THC during adolescence; hippocampal CB1R levels varied by sex. In summary, female rats were more sensitive than male rats were to the acute and chronic effects of THC, and chronic administration of THC during adolescence produced long-term changes in CB1R levels that correlated with decreased tolerance development to the rate-decreasing effects of THC.

Pain is a serious health problem that is commonly treated with opioids, although the doses of opioids needed to treat pain are often similar to those that decrease respiration. Combining opioids with drugs that relieve pain through non-opioid mechanisms can decrease the doses of opioids needed for analgesia, resulting in an improved therapeutic window, but only if the doses of opioids that decrease respiration are not similarly decreased. Using small doses of opioids to treat pain has the potential to reduce the number of overdoses and deaths. This study investigated whether the cannabinoid receptor agonists Δ-tetrahydrocannabinol (Δ-THC) and CP 55,940 modify the ventilatory-depressant effects of morphine and fentanyl in three monkeys. Ventilatory parameters, including minute volume (V), were monitored with a head plethysmograph. When given alone, morphine (0.032 - 10 mg/kg) and fentanyl (0.00032 - 0.1 mg/kg) dose dependently decreased V. Doses of Δ-THC (1 mg/kg) and CP 55,940 (0.01 mg/kg) that enhance the potency of opioids to produce antinociception modestly decreased ventilation when given alone but did not significantly change morphine or fentanyl dose-effect curves. A larger dose of CP 55,940 (0.032 mg/kg) shifted the fentanyl dose-effect curve downward in two monkeys, without significantly changing the morphine dose-effect curve. In summary, cannabinoid receptor agonists, which increase the potency of opioids to produce antinociception, did not increase their potency to depress ventilation. Thus, the therapeutic window is greater for opioids when they are combined with cannabinoid receptor agonists, indicating a possible advantage for these drug mixtures in treating pain.

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Increased abuse of opioids is contributing to an escalation in overdose deaths. Benzodiazepines are frequently abused with opioids, possibly because they increase the potency and/or effectiveness of opioids to produce reinforcing effects. This study used a concurrent-choice procedure to determine whether monkeys would choose to self-administer a mixture of the opioid remifentanil and the benzodiazepine midazolam over remifentanil alone. Initially, three monkeys could respond on one lever for saline and on a second lever for either remifentanil alone or midazolam alone. Thereafter, monkeys chose between a dose of remifentanil (0.32 g/kg/infusion) that did not change and a dose of remifentanil that varied across sessions; for some sessions, midazolam was combined with varying doses of remifentanil. All monkeys received more infusions of remifentanil (0.0032-0.32g/kg/infusion) than saline, whereas only two monkeys responded more for midazolam than for saline. When 0.32 g/kg/infusion remifentanil was available on one lever and a dose of remifentanil that varied across sessions (0.1-1g/kg/infusion) was available on the other lever, monkeys chose the larger dose. Combining 3.2 g/kg/infusion midazolam with 0.32g/kg/infusion remifentanil increased responding for the mixture over 0.32 g/kg/infusion remifentanil alone, although monkeys chose remifentanil alone over mixtures containing smaller doses of remifentanil. When 10g/kg/infusion midazolam was combined with 0.1 g/kg/infusion remifentanil, monkeys chose the mixture over 0.32g/kg/infusion remifentanil alone. Thus, monkeys prefer some opioid/benzodiazepine mixtures to larger doses of the opioid alone, suggesting that opioid/benzodiazepine coabuse might be due to increased potency (and possibly effectiveness) of opioids to produce reinforcing effects.