Addiction is commonly identified with habitual nonmedical self-administration of drugs. It is usually defined by characteristics of intoxication or by characteristics of withdrawal symptoms. Early aversive postnatal events are known to increase the risk to develop psychiatric disorders (such as addiction) later in life, although they rarely determine alone the nature and outcome of the psychopathology. It has been suggested that early life experiences could have negative consequences (vulnerability) or also confer adaptive value (resilience) in different individuals. We have recently demonstrated that Repeated Cross Fostered (RCF) pups by C57BL/6J (C57) strain show increased sensitivity to cocaine effects and, unexpectedly, increased resilience to depression-like behavior, two phenotypes related to the dopaminergic mesolimbic system function. This brain circuit includes the ventral tegmental area (VTA) and the Nucleus Accumbens (NAc) areas. In addition, RCF animals also show altered DA release, as well as morphological alterations, in the NAC following cocaine administration.
All together, these data suggest that long-lasting effects induced by our early manipulation within VTA, the area from which this circuit arises, could explain the behavioral and neurochemical effects observed in RCF animals.
Preliminary electrophysiology data indicate a critical involvement of dopaminergic neurons of ventral tegmental area (VTA) in the phenotype observed. The goal of this project is to investigate if and how these neurons contribute to the increased cocaine sensitivity by pharmacologically modulating their activity.
Drug consumption is usually driven by is pharmacological effects, which are experienced trough rewarding effect. This behavior is influenced by genetic variability, early life experience and psychosocial factors that could determinate resilience or vulnerability to drug addiction.
Within this framework, the final goal of this project is to investigate the neurobiological basis of susceptibility to cocaine effects observed in our animal model (RCF). We would like to uncover new molecular targets in order, in the future, to set up a therapeutic strategy to rescue/prevent the propensity of some individuals exposed to early critical conditions, to develop an addiction-like phenotype.
We will test the hypothesis that ih current and firing observed in VTA DAergic neurons of RCF animals is responsible for their addiction-like phenotype. To test this hypothesis, RCF animals will be subjected to chronic (4 days) intra-VTA infusion of LTG to restore ih and firing of VTA DAergic neurons. We expect that this pharmacologic manipulation will be able to rescue the electrophysiological and behavioral phenotype of RCF animals.
Our study is the first one evaluating the long-lasting effects of an early life manipulation of VTA DAergic neurons ih current and firing supposed to be involved in sensitivity to cocaine.