Repeated drug use often leads to the accumulation of harmful consequences on health. For most cocaine users, intense negative events eventually make them quit drug. However, for a subset of them, adverse consequences fail to impact subsequent cocaine use. Because harmful events are often delayed, it is hypothesized that impairments in associating drug intake to its long-term adverse effects contribute to continued drug use despite the negative consequences, a key hallmark of addiction.
The ventral pallidum (VP) plays an important role in processing reward-related information. My recent work highlighted the crucial role of an understudied VP neuron subpopulation projecting to the mediodorsal thalamus (MDT) in cocaine reward. Interestingly, the MDT is associated with drug addiction as well as behavioral flexibility and processing the causal consequences of an action. The VP-MDT projection thus seems an excellent candidate for processing the consequences of drug use.
My project will assess how repeated cocaine intake alters VP-MDT functioning to make some individuals unable to process the negative consequences of their actions. Rats with prior drug intake experience will be asked to choose between cocaine with and without delayed negative consequences. While most rats prefer the safe option, a subset fails to distinguish the two choices.
Following extensive behavioral characterization of my model, I will use chemogenetic inhibition of VP-MDT neurons to test the contribution of this circuit in processing delayed negative consequences of cocaine intake for optimal choice. Next, neuronal imaging of calcium transients in VP-MDT neurons will further clarify circuit activation during learning of the negative consequences. Comparing the subset of rats that fail to learn the safe choice to the rest of the population will inform on impaired neuronal activation. I will then identify the molecular substrate of impaired delayed consequences processing, with translatome sequencing of VP-MDT neurons and compare rats with and without acquisition deficits. Finally, viral manipulations targeting alterations specific to rats with impaired consequence detection will confirm their causal role.
Monsieur Michel Engeln (INSTITUT DE NEUROSCIENCES COGNITIVES ET INTEGRATIVES D'AQUITAINE)
The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.
INCIA INSTITUT DE NEUROSCIENCES COGNITIVES ET INTEGRATIVES D'AQUITAINE
Help of the ANR 302,941 euros
Beginning and duration of the scientific project: April 2023 - 48 Months