Drug vs. natural reward intra-cellular pathways

Drug addiction is a compulsive drug disease and represents a serious social and health problem. Helping the drug dependent individual to reorient his behavior toward non-drug natural rewarding activities is a great challenge in drug dependence therapy. Using animal models, we could show that social interaction can have positive effects against drug taking. Also, we have shown that the brain regions activated after cocaine conditioned place preference (CPP) and social interaction CPP are similar. In this project, we hypothesize that intracellular pathways mediating natural reward such as social interaction are different from those involved in drug reward. To test this hypothesis, we will first assess the expression of the cAMP response element binding protein (CREB) in cocaine reward vs social interaction reward and investigate the expression of cyclic AMP-dependent protein kinase (PKA), extracellular signal-regulated kinase (ERK) and calcium/calmodulin-dependent kinases (CamK) in the nucleus accumbens after cocaine CPP and social interaction CPP. We will then study the effects of intra-nucleus accumbens infusion of U0126 (ERK inhibitor), RpcAMPs (PKA inhibitor) and KN93 (CamK inhibitor) on the expression, acquisition and consolidation of drug vs non-drug social interaction CPP, currently under-investigated. In addition, we will assess the effects of the intra nacc infusion of U0126, RpcAMPs and KN93 on the levels of pCREB, pERK, pPKA and pCamK associated to the expression of drug vs non-drug CPP. We also propose to investigate if social interaction rewarding effects are persistent as they are for cocaine. Finally, we will investigate the effects of intra-nucleus accumbens inhibition of ERK and CamK on the persistence of cocaine CPP and social interaction CPP as well as on the associated expression of pCREB, pERK, and pCamK. We hypothesise that ERK activation is necessary for CREB activation in the nacc affected by drug reward whereas CamK activation is necessary for CREB activation in the nacc affected by natural reward. This project will be the first assessing the implication of CREB pathway and its upstream kinases in cocaine (drug) reward and social interaction (natural) reward in a vertical approach ranging from the behavioral to the pharmacological and molecular level. This knowledge may not only be essential for the designing of effective behavioral and social strategies to prevent drug-related disorders but also may lead to the identification of new targets for the development of new medications for the treatment of drug addiction and other psychiatric diseases.

The expression of the reward that results from the drugs of abuse influences the cascade inside our brain cells called "neurons" in a different way than the reward resulting from natural reward does. In this project we focus on the effects of cocaine and compare them to the effects of social interaction. This is of common interest because drug addicted individuals usually show an impairment of social interaction. Therefore, shifting their preference toward beneficial natural reward such as positive social interaction is a challenge in drug dependence therapy. In this project, we tried to manipulate some candidates inside the brain cells in a region that is part of the reward system called "the nucleus accumbens". We found out that manipulating specific molecules inside the brain cells of this region results in preferring more the cocaine over social interaction. That way, we can identify the molecules that play a role in cocaine or social interaction reward. These molecules can be the basis for the development of new medications that can help the addicted to switch their preference away from drugs of abuse. Natural reward when available as an alternative to drugs can help the addicted individuals to shift their preference away from the drugs of abuse. Therefore, we studied how long the positive effects of social interaction will last when provided as an alternative to drugs. We found that social interaction rewarding effects are short term and in order to be effective it should be maintained for a long time in a drug free state. On the contrary, the rewarding effects of cocaine are persistent and long lasting. In other words, social support or dyadic social therapy should be long enough in order to help the addicted individuals to overcome their addiction. The overall project shows that despite activating the same brain regions, the reward resulting from cocaine and the reward resulting from beneficial social interaction uses different molecules inside of the neurons of the region of the nucleus accumbens. When we identify these molecules, we can understand more the harm drugs of abuse can cause to the brain and we can identify better treatment for drug addiction.