Drug intake is sufficient, but conditioning is not necessary for the emergence of compulsive cocaine seeking after extended self-administration

Abstract

Compulsive drug seeking, which is characterized by continued instrumental effort despite contingent punishment, has been shown to emerge after extended drug self-administration. Exactly what aspect of drug self-administration drives the appearance of addictive behavior is unclear, but the mechanistic explanations that have been offered differ in one key respect. On one hand, it has been suggested that dysfunctional conditioning during self-administration drives unrealistic reward expectations, ultimately producing resistance to punishment. If this is indeed the pathological process that drives compulsive behavior, then compulsivity should be apparent only in the presence of the pavlovian and instrumental stimuli that underwent frequent pairing with the drug reward. On the other hand, it has also been suggested that extended drug intake produces general changes to reward and decision-making circuits that manifest as compulsive drug seeking. Unfortunately, conditioning history and drug intake are generally intrinsically intertwined. However, here we used an animal model of compulsive cocaine seeking to selectively manipulate drug intake and the degree of conditioning in the test context, to investigate which of the two is more important for the emergence of compulsive cocaine seeking. The results show that extended drug intake alone is sufficient, but extended conditioning in the test context is not necessary for the emergence of compulsive cocaine seeking, resolving a fundamental question in addiction research.

Figure 1

Main differences between cocaine self-administration in context A and B.

Figure 2

Experimental design and instrumental contingencies. The aim of these experiments was to tease apart the relative contribution of conditioning and drug intake in the appearance of compulsive drug seeking after extended self-administration. In the first experiment, rats were trained in the seeking taking task and the compulsivity of drug seeking was subsequently assessed in the same context. In the second experiment, animals went through training in two contexts, long-access cocaine self-administration in an alternative context, and were finally tested for compulsive drug seeking in the training context. In the third experiment, the animals went through training in two contexts, and long-access cocaine self-administration and testing for compulsive drug seeking in the same contexts. These experiments thus allow for investigation of the selective effects of conditioning history and drug intake on the emergence of compulsive responding. Contexts A and B were randomly assigned to context 1 and 2. RI: Random Interval schedule.

Figure 3

Cumulative drug intake and conditioning history in the test context at the time of testing for compulsivity. (a) Cocaine intake was more than sixfold lower in the limited intake group. (b) The number of response, cocaine pairings in the test context was more than fivefold higher in the extended intake many pairings group. ^***P<0.001.

Figure 4

Effect of varying cocaine intake and conditioning on compulsivity of cocaine seeking. (a) At the group level, increased cocaine intake produced more compulsive drug seeking, while conditioning history did not affect drug seeking under punishment. ^*P<0.05 between limited intake few pairings and extended intake few pairings groups. ^#P<0.05 between limited intake few pairings and extended intake many pairings groups. B=baseline session, P=punished session. (b) Distribution of compulsive drug seeking. The extended intake few pairings and extended intake many pairings groups contained three and four animals, respectively, that completed ⩾6 cycles under punishment, whereas the limited intake group contained none.

Figure 5

Effect of prior cocaine intake on compulsivity of sucrose seeking. After the animals in the limited and extended cocaine self-administration experiments were trained on sucrose seeking through chain-pulling in a third context, there was no difference in the response of the groups to punishment of sucrose seeking.