Reciprocal Substitution Between Methamphetamine and Heroin in Terms of Reinforcement Effects in Rats

Abstract

Heroin and methamphetamine are both popular illicit drugs in China. Previous clinical data showed that habitual users of either heroin or methamphetamine abuse the other drug for substitution in case of unavailability of their preferred drug. The present study aimed to observe whether heroin can substitute the methamphetamine reinforcement effect in rats, and vice versa. Rats were trained to self-administer heroin or methamphetamine (both 50 mg/kg/infusion) under an FR1 reinforcing schedule for 10 days. After having extracted the dose-effect curve of the two drugs, we administered methamphetamine at different doses (12.5-200 mg/kg/infusion) to replace heroin during the period of self-administration, and vice versa. The heroin dose-effect curve showed an inverted U-shaped trend, and the total intake dose of heroin significantly increased when the training dose increased from 50 to 100 or 200 mg/kg/infusion. Following replacement with methamphetamine, the total dose-effect curve shifted leftwards and upwards. By contrast, although the dose-effect curve of methamphetamine also showed an inverted U-shaped trend, the total dose of methamphetamine significantly decreased when the training dose decreased from 50 to 25 mg/kg/infusion; conversely, when the methamphetamine training dose increased, the total dose did not change significantly. The total dose-effect curve shifted rightwards after heroin was substituted with methamphetamine. Although heroin and methamphetamine had their own independent reward effects, low doses of methamphetamine can replace the heroin reward effect, while high doses of heroin can replace the methamphetamine reward effect. These results demonstrated that heroin and methamphetamine can substitute each other in terms of reinforcement effects in rats.

Assessment of abuse potential of carfentanil

“…In the studies, rats steadily acquired significant self‐administration at a range of doses of carfentanil (0.05–0.1 μg/kg), fentanyl (0.1–10.0 μg/kg) and heroin (25–100 μg/kg). Compared with the peak doses of fentanyl (1 μg/kg) and heroin (25 μg/kg), the peak dose of carfentanil maintained the highest response of 0.1 μg/kg, and the results of control drugs were consistent with prior reports 31,32 . The rank order of potency as a reinforcer was measured by the unit dose that maintained the highest response: carfentanil > fentanyl > heroin.…”

“…Compared with the peak doses of fentanyl (1 μg/kg) and heroin (25 μg/kg), the peak dose of carfentanil maintained the highest response of 0.1 μg/kg, and the results of control drugs were consistent with prior reports. 31,32 The rank order of potency as a reinforcer was measured by the unit dose that maintained the highest response: carfentanil > fentanyl > heroin. Intriguingly, in the dose-substitution test, carfentanil caused lower drug-using motivation (lower infusions number) at peak dose than fentanyl but not heroin (Figure 3C).…”

Methamphetamine Use, Methamphetamine Use Disorder, and Associated Overdose Deaths Among US Adults

“…Prevalence of past-year methamphetamine use disorder (MUD) increased 33% from 0.3% (539 000 people) in 2016 to 0.4% (904 000 people) in 2019 . Methamphetamine may serve as an opioid substitute or provide synergistic euphoria for those who co-use opioids . Currently, methamphetamine use is increasing among people who misuse opioids and those who are admitted for heroin treatment, whereas heroin use is increasing among people who are admitted into primary methamphetamine treatment .…”

“…4 Methamphetamine may serve as an opioid substitute or provide synergistic euphoria for those who co-use opioids. 5,6 Currently, methamphetamine use is increasing among people who misuse opioids 7 and those who are admitted for heroin treatment, 8 whereas heroin use is increasing among people who are admitted into primary methamphetamine treatment. 9 Fifty percent of psychostimulant-involved overdose deaths also involved opioids in 2017.…”

Differential expression profiling of tRNA-Derived small RNAs and their potential roles in methamphetamine self-administered rats

“…After 3 days of recovery from surgery, rats were trained for 4 h daily for 14 consecutive days to self-administer METH under a fixed ratio paradigm in the operant chamber, and the procedure was in accordance with our previous reports ( Mei et al, 2020 ; Xu et al, 2021 ). In brief, there exist two nose-poke holes in the operant chamber, an active and inactive one.…”