Drug-seeking motivation level in male rats determines offspring susceptibility or resistance to cocaine-seeking behaviour

Qiumin Le,Lan Ma,Haikun Song,Yuqing Zhou,Dingailu Ma,Huiwen Zhu,Weiqing Hou,Xiangchen Yu,Feizhen Wu,Biao Yan,Yanqing Li

doi:10.1038/ncomms15527

Abstract

Liability to develop drug addiction is heritable, but the precise contribution of non-Mendelian factors is not well understood. Here we separate male rats into addiction-like and non-addiction-like groups, based on their incentive motivation to seek cocaine. We find that the high incentive responding of the F0 generation could be transmitted to F1 and F2 generations. Moreover, the inheritance of high incentive response to cocaine is contingent on high motivation, as it is elicited by voluntary cocaine administration, but not high intake of cocaine itself. We also find DNA methylation differences between sperm of addiction-like and non-addiction-like groups that were maintained from F0 to F1, providing an epigenetic link to transcriptomic changes of addiction-related signalling pathways in the nucleus accumbens of offspring. Our data suggest that highly motivated drug seeking experience may increase vulnerability and/or reduce resistance to drug addiction in descendants.

Highlights

Rats were first subjected to self-administration at a fixed ratio (FR) of 1, switched to FR3 and FR5 on days 6 and 8, and tested on a progressive ratio (PR) schedule on day 13 to assess their motivation for drug reinforcement
Extensive studies have been focused on the identification of genetic variations that are associated with risk of developing drug addiction, and genome-wide linkage and association studies have revealed many genes and genetic variants associated with drug response and related behaviour[24,25,26,27]
We used a rat model of cocaine self-administration and showed that high incentive motivation elicited by voluntary cocaine administration could be transmitted to subsequent generations

Summary

Results

Cocaine-IP F1 sired by rats receiving non-contingent cocaine injections showed significantly lower responses than Saline-IP F1 rats (Fig. 4b), while the F2 offspring of Cocaine-IP and Saline-IP exhibited no difference in cocaine self-administration (Fig. 4c). These data suggest that chronic cocaine intake a Saline-SA (n = 23)

Motivation score

Discussion

Methods