SUMMARY Conditioned place preference (CPP) is a widely used model of addiction-related behavior whose underlying mechanisms are not understood. In this study, we used dual site silicon probe recordings in freely moving mice to examine interactions between the hippocampus and nucleus accumbens in cocaine CPP. We found that CPP was associated with recruitment of D2-positive nucleus accumbens medium spiny neurons to fire in the cocaine-paired location, and this recruitment was driven predominantly by selective strengthening of coupling with hippocampal place cells that encode the cocaine-paired location. These findings provide in vivo evidence suggesting that the synaptic potentiation in the accumbens caused by repeated cocaine administration preferentially affects inputs that were active at the time of drug exposure. This provides a potential physiological mechanism by which drug use becomes associated with specific environmental contexts.

Conditioned place preference (CPP) is a widely used model of addiction-related behavior whose underlying mechanism is not understood. In this study, we used dual site silicon probe recordings in freely moving mice to examine interactions between the hippocampus and nucleus accumbens in cocaine CPP. We found that CPP was associated with recruitment of nucleus accumbens medium spiny neurons to fire in the cocaine-paired location, and this recruitment was driven predominantly by selective strengthening of hippocampal inputs arising from place cells that encode the cocaine-paired location. These findings provide in vivo evidence that the synaptic potentiation in the accumbens caused by repeated cocaine administration preferentially affects inputs that were active at the time of drug exposure. This provides a potential physiological mechanism by which drug use becomes associated with specific environmental contexts. INTRODUCTIONDrug addiction is a debilitating condition for which few effective treatments exist, in large part because the underlying mechanisms are not well understood. A key insight into the nature of addiction is that drug use becomes associated with the environmental context in which the drug was administered. Subsequent re-exposure to the associated context then leads to cravings or drug-seeking behavior. One of the simplest animal models of this association is cocaine conditioned place preference (CPP), in which cocaine is repeatedly paired with a specific spatial location causing the animal to spend more time in that location during subsequent exploration. However, despite its simplicity and relevance, the underlying mechanistic basis of cocaine CPP is still not understood.The nucleus accumbens (NAc) is a part of the ventral striatum believed to play a central role in reward-and addiction-related behaviors including CPP. Medium spiny neurons (MSNs) in the NAc are known to fire preferentially near sites where overtrained animals collect water or food rewards (Lansink et al., 2008;Lavoie and Mizumori, 1994;Miyazaki et al., 1998; van der Meer et al., 2010), providing a potential substrate for location-reward association. However, German et al. (German and Fields, 2007) found that morphine place conditioning led to less MSN firing in the morphine-paired location, suggesting that the association of drug reward and spatial location may occur through different mechanisms. Nevertheless, focal lesions (Kelsey et al., 1989) or D1 antagonist injections (Baker et al., 1998) in the NAc block CPP acquisition, and focal amphetamine injections into the NAc are sufficient to induce CPP (Carr and White, 1983), suggesting that locationdependent MSN activity may drive CPP behavior.A large glutamatergic input to the NAc arises from the CA1 and subiculum regions of the hippocampus (HPC) (Phillipson and Griffiths, 1985), which contain "place cells" that fire selectively in specific spatial locations (Kim et al., 2012;O'Keefe, 1976) or contexts (Komorowski et al., 2013). Simultaneous HPC-NAc recordings in rats suggest ...