Independent Heritability of Aversive Learning Influences on Cocaine-Seeking and Punishment Resistance in Rats

Cocaine produces widely recognized rewarding effects but also produces aversive effects that occur several minutes after rewarding effects dissipate. Prior work shows these aversive effects are particularly strong in some animals, in whom they produce conditioned avoidance effects that reduce overall cocaine-seeking. The sources of these individual variations are largely unknown, but we found evidence for contributions from heritable influences. Using outbred male and female Sprague Dawley and heterogeneous stock rats, we found that offspring of individuals expressing higher versus lower levels of conditioned avoidance to cocaine on a runway operant task are themselves higher or lower in this trait. These results did not differ between sexes and are consistent with a heritable influence driving conditioned avoidance of cocaine, which could either be genetic or nongenetic. Runway latency to obtain cocaine also differed markedly between seven inbred rat strains (tested in males only), again consistent with a heritable influence. Several control tasks showed that variations in cocaine avoidance were not explained by differences in exploratory locomotion, overall motivation, or resistance of food-seeking to footshock punishment. Notably, the latter punishment resistance task has been linked to addiction-like behaviors in its own right, and performance on this task also varied considerably between inbred strains but did so independently of cocaine avoidance. Hence, punishment resistance and cocaine avoidance may be influenced by independent heritable factors.