Increased conditioned place preference for cocaine in high anxiety-related behavior (HAB) mice is associated with an increased activation in the accumbens corridor

Anxiety disorders and substance use disorders are strongly associated in humans. Accordingly, a widely held but controversial concept in the addiction field, the so-called self-medication hypothesis, posits that anxious individuals are more vulnerable for drug dependence because they use drugs of abuse to alleviate their anxiety. We tested this hypothesis under controlled experimental conditions by quantifying the conditioned place preference (CPP) to 15 mg/kg i.p. cocaine given contingently (COCAINE) in CD1 mice selectively bred for high anxiety-related behavior (HAB) vs normal anxiety-related behavior (NAB). Cocaine was conditioned to the initially nonpreferred compartment in an alternate day design (cocaine vs saline, 4 pairings each). HAB and NAB mice were also tested for the effects of noncontingent (NONCONT) cocaine administration. HAB mice showed a slightly higher bias for one of the conditioning compartments during the pretest than NAB mice that became statistically significant (p=0.045) only after pooling COCAINE and NONCONT groups. Cocaine CPP was higher (p=0.0035) in HAB compared to NAB mice. The increased cocaine CPP was associated with an increased expression of the immediate early genes c-Fos and Early Growth Related Protein 1 (EGR1) in the accumbens corridor, i.e., a region stretching from the anterior commissure to the interhemispheric border and comprising the medial nucleus accumbens core and shell, the major island of Calleja and intermediate part of the lateral septum, as well as the vertical limb of the diagonal band and medial septum. The cocaine CPP-induced EGR1 expression was only observed in D1- and D2-medium spiny neurons, whereas other types of neurons or glial cells were not involved. With respect to the activation by contingent vs noncontingent cocaine EGR1 seemed to be a more sensitive marker than c-Fos. Our findings suggest that cocaine may be more rewarding in high anxiety individuals, plausibly due to an anxiolytic effect

Differences in social interaction- vs. cocaine reward in mouse vs. rat

We previously developed rat experimental models based on the conditioned place preference (CPP) paradigm in which only four 15-min episodes of dyadic social interaction with a sex- and weight-matched male Sprague Dawley rat (1) reversed CPP from cocaine to social interaction despite continuing cocaine training, and (2) prevented the reacquisition/re-expression of cocaine CPP. In a concurrent conditioning schedule, pairing one compartment with social interaction and the other compartment with 15 mg/kg cocaine injections, rats spent the same amount of time in both compartments and the most rewarding sensory component of the composite stimulus social interaction was touch (taction). In the present study, we validated our experimental paradigm in C57BL/6 mice to investigate if our experimental paradigm may be useful for the considerable number of genetically modified mouse models. Only 71% of the tested mice developed place preference for social interaction, whereas 85% of the rats did. Accordingly, 29% of the mice developed conditioned place aversion to social interaction, whereas this was true for only 15% of the rats. In support of the lesser likelihood of mice to develop a preference for social interaction, the average amount of time spent in direct contact was 17% for mice vs 79% for rats. In animals that were concurrently conditioned for social interaction vs cocaine, the relative reward strength for cocaine was 300-fold higher in mice than in rats.Considering that human addicts regularly prefer drugs of abuse to drug-free social interaction, the present findings suggest that our experimental paradigm of concurrent CPP for cocaine vs social interaction is of even greater translational power if performed in C57BL/6 mice, the genetic background for most transgenic rodent models, than in rats