The effects of cocaine and heroin polydrug use on drug-related motivation and affective state in Lister-Hooded rats

Cocaine and heroin are commonly abused drugs and are often used together. Such polydrug use increases the risk of psychopathology, overdose, and poorer treatment outcomes compared to single-drug use. Developing effective treatments for polydrug use requires animal models incorporating multiple theories of drug addiction. Therefore, our study investigated the unique motivational and hedonic effects of sequential cocaine and heroin use by recording ultrasonic vocalisations in 32 rats undergoing three self-administration procedures.

Subjects were first trained under a fixed ratio 1 schedule. Self-administration behaviour was acquired after 4 sessions with each drug. Cocaine consumption increased at a higher rate than heroin and total consumption of cocaine was higher than heroin. Significantly more Non-FM calls, associated with locomotion and exploration, were emitted during the final heroin session than the first but no differences in other subtypes were observed.

Subjects then underwent 14 days of behavioural economics, where the dose per infusion decreased across sessions, to obtain metrics of drug demand. Pmax, the maximum price paid for infusion was higher for heroin than cocaine. However, normalization to baseline consumption, Q0, abolished this difference, indicating that demand for cocaine and heroin was similar. Rats emitted fewer 50kHz at lower doses of cocaine but showed no differences across heroin doses suggesting that the hedonic effects of cocaine but not heroin decreased at lower doses.

Lastly, subjects underwent 5 sessions under a progressive ratio schedule with the opioid antagonist naltrexone administered before one of the sessions to assess the involvement of opioidergic signalling in drug motivation. Naltrexone reduced heroin but not cocaine breakpoints. Interestingly, naltrexone reduced both Non-FM and FM calls, associated with pleasurable activities, during heroin sessions but only reduced FM calls during cocaine sessions. This suggests that opioid antagonism influences the hedonic effects of both drugs, but only affects motivation for heroin.