In vivo potency and efficacy of the novel cathinone α-pyrrolidinopentiophenone and 3,4-methylenedioxypyrovalerone: self-administration and locomotor stimulation in male rats

Abstract

Rationale: Numerous substituted cathinone drugs have appeared in recreational use. This variety is often a response to legal actions; the scheduling of 3,4-methylenedioxypyrovalerone (MDPV; "bath salts") in the USA was followed by the appearance of the closely related drug α-pyrrolidinopentiophenone (alpha-PVP; "flakka").

Objectives: This study aimed to directly compare the efficacy and potency of alpha-PVP with that of MDPV.

Methods: Groups of male Wistar rats were trained in the intravenous self-administration (IVSA) alpha-PVP or MDPV under a fixed-ratio 1 schedule of reinforcement. An additional group was examined for locomotor and body temperature responses to noncontingent administration of MDVP or alpha-PVP (1.0, 5.6, and 10.0 mg/kg, i.p.).

Results: Acquisition of alpha-PVP (0.1 mg/kg/infusion) IVSA resulted in low, yet consistent drug intake and excellent discrimination for the drug-paired lever. Dose substitution (0.05-0.25 mg/kg/infusion) under a fixed-ratio 1 schedule confirmed potency was similar to MDPV in prior studies. In direct comparison to MDPV (0.05 mg/kg/infusion), rats trained on alpha-PVP (0.05 mg/kg/infusion) responded for more infusions but demonstrated similar drug-lever discrimination by the end of acquisition. However, the dose-response (0.018-0.56 mg/kg/infusion) functions of these drugs under a progressive-ratio schedule of reinforcement reflected identical efficacy and potency. Peak locomotor responses to MDPV or alpha-PVP were observed after the 1.0 mg/kg, i.p. dose and lasted ∼2 h. Modest body temperature decreases were of similar magnitude (∼0.75 °C) for each compound.

Conclusions: The potency and efficacy of MDPV and alpha-PVP were very similar across multiple assays, predicting that the abuse liability of alpha-PVP will be significant and similar to that of MDPV.

Figure 1

Chemical structures of cathinone stimulants α-pyrrolidinopentiophenone (alpha-PVP) and 3,4-methylenedioxypyrovalerone (MDPV) are compared with the amphetamines methamphetamine and 3,4-methylenedioxymethamphetamine (MDMA).

Figure 2. Acquisition of alpha-PVP (0.1 mg/kg/inf) self-administration

Mean (±SEM) infusions and drug-lever discrimination ratios during acquisition (upper panel; N=9) and infusions obtained during dose-substitution (lower panel; Vehicle, 0.025, 0.05, 0.1, 0.25 mg/kg/inf; N=5) under a fixed-ratio 1 response requirement. Significant differences in lever discrimination from the first and third acquisition session are indicated by * in the upper panel. In the lower panel, significant differences from vehicle, 0.025 and 0.05 are indicated by # and a significant difference from vehicle and 0.05 mg/kg/inf is indicated by %.

Figure 3. Comparing the acquisition of alpha-PVP (0.05 mg/kg/inf) and MDPV (0.05 mg/kg/inf) self-administration

Mean (±SEM) infusions obtained per session (upper panel) and drug-paired lever discrimination ratios (lower panel) across sessions of acquisition of alpha-PVP (N=15) and MDPV (N=9) self-administration for those individuals who met acquisition criteria. Significant differences from the first 6 sessions is indicated by #; from the 1^st, 2^nd and 4^th sessions by ‡; versus the 1^st and 3^rd sessions by *; compared with the 1^st session by & and from the 3^rd session by %. See Results for additional significant differences.

Figure 4. Percent of Subjects Acquiring self-administration

The cumulative percentage of rats that reached acquisition criteria are depicted as a function of session and the drug available (MDPV, N=11; alpha-PVP, N = 15) over the 20-session acquisition period. Rats were defined as having acquired self-administration on the first of three sequential sessions for which >= 6 infusions were acquired.

Figure 5. Progressive Ratio Dose Substitution

Mean (±SEM) drug-associated lever presses during the self-administration of alpha-PVP (N=12) or MDPV (N=8) under a progressive-ratio schedule of reinforcement. Significant differences from the 0.018 mg/kg/inf dose condition are signified by *, from the 0.032 dose by & and differences from the 0.56 dose by #.

Figure 6. Locomotor Activity

Mean (N=8; ±SEM) activity rate after alpha-PVP (upper panel) or MDPV (lower panel) was administered i.p. The vehicle condition is the same in both panels as all drug doses were randomized with a single vehicle condition. Significant differences from vehicle alone are indicated by %; from vehicle and the other two active doses by *; from the other two active doses by #; and from the 10 mg/kg dose is indicated by ‡

Figure 7. Thermoregulation

Mean (N=8; ±SEM) body temperature after alpha-PVP (upper panel) or MDPV (lower panel) was administered i.p. The vehicle condition is the same in both panels as all drug doses were randomized with a single vehicle condition. Shaded figures indicate a significant difference from vehicle at the respective timepoint. Open figures indicate a significant difference from vehicle at the respective timepoint and the baseline within treatment condition (15 min prior to injection). Significant differences from baseline (only) are indicated with * and differences from the 1.0 mg/kg dose (within compound) with #.