Overview of Molecular Neurobiology of Drug Addiction
The objective of this Program Project Grant (PPG) funded by the National Institute on Drug Abuse is to establish a better understanding of the molecular changes that drugs of abuse induce in the brain’s reward pathways to cause addiction. Our research focuses on drug-induced changes in gene expression within these reward pathways and, in particular, the role played by two transcription factors, CREB and ∆FosB, in mediating these effects.
The most important reward pathway in brain is the mesolimbic dopamine system. This circuit is composed of dopaminergic neurons of the ventral tegmental area (VTA) and a major target of these dopamine neurons called the nucleus accumbens (NAc). The VTA-NAc circuit is a key detector of a rewarding stimulus. Under normal conditions, the circuit controls an individual’s responses to natural rewards, such as food, sex, and social interactions, and is therefore an important determinant of motivation and incentive drive. In simplistic terms, activation of the pathway tells the individual to repeat what he or she just did to get that reward. It also tells the memory centers in the brain (e.g., hippocampus, amygdala, cortex) to pay particular attention to all features of that rewarding experience, so it can be repeated in the future. These brain reward pathways are depicted in Figure 1, Figure 2, and Figure 3. Not surprisingly, it is a very old pathway from an evolutionary point of view. The use of dopamine neurons to mediate behavioral responses to natural rewards is seen in worms and flies, which evolved more than 1 billion years ago.
The organizing hypothesis of our NIDA PPG is that drugs of abuse, by regulating CREB and ∆FosB, and other transcription factors, in the VTA-NAc induce stable changes in the expression of target genes within these brain regions, which then mediate important aspects of the addiction phenotype.
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Structure of the PPG
Our NIDA is composed of an Administrative Core, two scientific cores and four projects. The Director of the PPG is Dr. Eric Nestler.
- Administrative Core (PI, Eric Nestler). The Administrative Core is responsible for the oversight of the PPG and for coordinating and integrating the PPG ’s many diverse research activities.
- The Transgenic Core (PI, Eric Nestler) provides PPG investigators with the tools needed to manipulate genes and proteins of interest to the PPG within the brain’s reward pathways. The Core utilizes viral-mediated gene transfer and genetic mutant mice, in particular, inducible, cell-targeted mutations in mice. Other key faculty include Rachael Neve at Harvard.
- The Behavioral Core (PI, David Self) provides an extremely broad array of behavioral tests in mice and rats, which represent behavioral models of drug abuse and addiction. Other key faculty Jane Taylor at Yale.
- Project 1 (PI, Eric Nestler) is focused on the role of the transcription factor CREB in the VTA-NAc in drug addiction. Other key faculty include include Bill Carlezon at Harvard.
- Project 2 (PI, Rob Malenka) is focused on establishing the influence of CREB and ∆FosB on the neurophysiological functioning of NAc neurons.
- Project 3 (PI, Eric Nestler )is focused on drug regulation of gene expression, and in particular drug regulation of chromatin remodeling mechanisms, as mediators of long-lasting changes in the VTA-NAc.
- Project 4 (PI, David Self )is focused on the role played by CREB and ∆FosB, and certain key target genes, in regulation of drug reinforcement and craving in self-administration and relapse assays.
Specialized Experimental Methods Utilized by the PPG
A major strength of our NIDA PPG is the application of an awesome array of state-of-the-art molecular and behavioral methodologies to delineate the important role played by the VTA-NAc reward circuit in behavioral abnormalities in rodent models of drug addiction. Through two scientific cores, the Transgenic Core and Behavioral Core, and chromatin and gene regulation studies in Project 3, the PPG offers an unprecedented exploration of molecular and cellular mechanisms of addiction mediated via the brain’s reward pathways.
