Sensitization to the Motor Stimulant Effects of 3,4-Methylenedioxypyrovalerone (MDPV) and Cross-Sensitization to Methamphetamine in Rats

Abstract

Background In recent years, there has been a dramatic increase in abuse of the synthetic cathinone 3,4-methylenedioxypyrovalerone (MDPV), often in combination with other illicit stimulants. Purpose We sought to determine if repeated exposure to MDPV would produce sensitization to the motor stimulant effects of the drug, and whether cross-sensitization would develop with the stimulant effects of methamphetamine (METH). Study design Male Sprague-Dawley rats were administered MDPV (1 or 5 mg/kg) or saline once daily for 5 days at 24 hour intervals, or were administered MDPV (1 mg/kg) or saline once daily for 5 days at 48 hour intervals. For cross-sensitization experiments, rats were administered METH (1 mg/kg) or MDPV (1 or 5 mg/kg) once daily for 5 days at 48 hour intervals, and following a 5 day incubation period, were given an acute challenge injection of either MDPV (0.5 mg/kg) or METH (0.5 mg/kg), respectively. Results Rats repeatedly administered MDPV (1 mg/kg) every 48 hours, but not every 24 hours, demonstrated increased motor activity when given either a subsequent challenge of MDPV (0.5 mg/kg i.p.) or METH (0.5 mg/kg), indicating the development of behavioral sensitization and cross-sensitization, respectively. Moreover, rats repeatedly administered METH (1 mg/kg) every 48 hours did not exhibit cross-sensitization to the motor stimulating effects of a subsequent challenge with MDPV (0.5 mg/kg). Conclusion These results suggest that specific patterns of MDPV administration may lead to lasting changes in behavioral responses to subsequent METH exposure.

Effects of 3,4-methylenedioxypyrovalerone (MDPV) pre-exposure on the aversive effects of MDPV, cocaine and lithium chloride: Implications for abuse vulnerability

“…Further, given that the effects of drug history have been reported to be asymmetrical for some compounds, i.e., Drug A affects Drug B, but not vice versa (for a discussion, see Grakalic and Riley, 2002; for a review, see Riley and Simpson, 2001), the impact of cocaine on MDPV needs further assessment as well. It is interesting to note that several studies assessing the serial interactions between cathinones and psychostimulants (see Gregg, 2013; Watterson et al, 2016), the interaction was asymmetrical. For example, mephedrone exposure sensitizes cocaine’s motoric effects, but cocaine has no effect on motor activity induced by mephedrone (Gregg, 2013).…”

“…For example, mephedrone exposure sensitizes cocaine’s motoric effects, but cocaine has no effect on motor activity induced by mephedrone (Gregg, 2013). Similarly, exposure to MDPV sensitizes methamphetamine-induced motor activity, but not vice versa (Watterson et al, 2016). Finally, it will be important to determine how general the effects of a history with bath salts are, i.e., whether the work reported here with MDPV will generalize to other bath salts which have been reported to have different effects in other behavioral designs (e.g., see Bonano et al, 2014; Creehan et al, 2015; Gregg and Rawls, 2014; Karlsson et al, 2014; Schindler et al, 2015; Watterson et al, 2012a, 2014a; for a discussion of differences between enantiomers of MDPV, see Gannon et al, 2016).…”

“…Although the cathinones have not been examined in this context, Gregg and his colleagues (2013) have recently reported that pre-exposure to mephedrone sensitized mephedrone- and cocaine-, but not methamphetamine-, induced locomotor activity in rats. Further, prior exposure to MDPV sensitizes motor activity to itself and methamphetamine (Watterson et al, 2016) and prior exposure to MDPV and 4-methylmethcathinone (4-MMC) (alone and in combination) sensitizes motor activity to itself as well as to cocaine (Berquist et al, 2016). Interestingly, these interactions are not necessarily symmetrical in that at the specific doses tested exposure to cocaine does not impact mephedrone-induced locomotor activity (Gregg et al, 2013) and exposure to methamphetamine does not sensitize MDPV-induced locomotion (Watterson et al, 2016).…”

The pharmacokinetics of racemic MDPV and its (R) and (S) enantiomers in female and male rats

“…Saline, 0.3, 1, 3, and 5.6 mg/kg ( R,S )-MDPV were administered in the same group of animals with 3–4 days between treatments. Since sensitization is known to occur with some daily MDPV multiple dosing schedules (Berquist et al, 2016; Buenrostro-Jáuregui et al, 2016; Watterson et al, 2016), it is possible that subsequent doses in our studies could have produced greater responses due to a previous exposure to the drug. However, we did not conduct studies of sensitization.…”

Methamphetamine and Ovarian Steroid Responsive Cells in the Posteriodorsal Medial Amygdala are Required for Methamphetamine-enhanced Proceptive Behaviors

“…Nervertheless, the marked reduction in cFos-ir cells suggests that DAUN02 was effective in removing a signicant portion of the targeted cells. Alternatively, as repeated Meth exposure results in sensitization of the neural substrate282930, MePD neurons that might have been low-responders to the Meth/hormone treatment during the lesion phase and thus not targeted may have become sensitized over the two subsequent rounds of exposure resulting in detectable levels of cFos following the third exposure.…”