Cardiovascular effects of 3,4-methylenedioxypyrovalerone (MDPV) in male and female Sprague-Dawley rats

Abstract

Background: 3,4-methylenedioxypyrovalerone (MDPV) toxicity includes intense neurological and cardiovascular events. We examined MDPV-induced cardiovascular, temperature, and locomotor effects following escalating and repeated MDPV administration in adult male and female Sprague-Dawley rats and compared these effects to cocaine in male rats. Methods: Telemetry devices were surgically implanted to allow continuous measurement of cardiovascular, temperature, and locomotor activity over a 22 h period after dosing. Rats were administered increasing intraperitoneal (IP) MDPV doses (1-5.6 mg/kg) every other day, followed two days later by a binge regimen of four injections of 3 mg/kg MDPV at 2 h intervals. MDPV serum concentrations were measured by LC-MS/MS. Cocaine (3-30 mg/kg) and four injections of 30 mg/kg IP were administered to male rats for comparison with male MDPV data. Results: The duration of MDPV cardiovascular effects was significantly greater (p<0.05) in male rats than female rats at 3-5.6 mg/kg. The ED50 for MDPV-induced locomotor was significantly lower in males (2.4 ± 0.3) than females (3.4 ± 0.2). Males showed significantly greater variability in MDPV serum concentrations than females after binge dosing. MDPV produced five-fold more potent cardiovascular effects than cocaine in male rats. MDPV did not alter thermoregulation in either sex, but cocaine binge administration decreased temperature. Conclusion: Effects of MDPV on temperature were not significantly different between sexes. MDPV-induced cardiovascular and locomotor effects in males lasted significantly longer and were more potent than in females. These differences appeared to be related to pharmacokinetic factors leading to greater variance in MDPV serum concentrations in males.

Sex and Gender Differences in the Effects of Novel Psychoactive Substances

“…Similar to (+)-amphetamine- and (+)-methamphetamine [ 125 ], cathinone also induced significantly higher increases in motor activity in females than in males, and when administered in combination with caffeine, it significantly elevated body temperature acutely in male but not female rats [ 126 ]. Moreover, the duration and intensity of MDPV-induced cardiovascular effects differ among the sexes, lasting significantly longer and being more potent in male than female rats [ 127 ]. Moreover, MDPV produced comparable conditioned place preferences in male and female rats, but weaker conditioned taste avoidance in females compared to males [ 128 ].…”

Detrimental effects of the ‘bath salt’ methylenedioxypyrovalerone on social play behavior in male rats

“…These results suggest that the acute effects of MDPV on social play behavior are comparable to the effects of other psychostimulants, which are also abused in social settings, such as amphetamine, methylphenidate, or cocaine, that also exert play-suppressant effects in male rats [14,24,40]. Importantly, sex-dependent differences in the effects of MDPV [54][55][56] and in the structure and intensity of social play behavior [23] have been documented. Therefore, investigating the effects of MDPV on social play behavior in female rats, and the neural mechanisms involved, is an intriguing issue which deserves further investigation.…”

Newly Developed Dopamine D3Receptor Antagonists,R-VK4-40 andR-VK4-116, Do Not Potentiate Cardiovascular Effects of Cocaine or Oxycodone in Rats

“…On this basis, we elected to focus on the cardiovascular effects of these compounds in male rats, although additional studies on opioid reward and analgesia are now underway in female rats. Prior studies in both humans and rodents have shown that females are more resilient to the cardiovascular effects of stimulants than males (Mendelson et al, 1999;Lynch et al, 2008;McClenahan et al, 2019) and neither cardiovascular responses to cocaine nor cocaine pharmacokinetics vary across phases of the menstrual cycle (Mendelson et al, 1999). Although relatively few studies exist on sex differences in the cardiovascular effects of opioids, no sex differences in heart rate responses to acutely administered morphine have been identified (Cruz and Rodríguez-Manzo, 2000).…”