Utility of the Recombinase Driver CX3CR1-ERT2 Rat Strain in Nicotine Self-Administration

Smoking remains a leading preventable cause of death, and nicotine is the primary substance responsible for maintaining use of tobacco products. Preclinical rodent models have shown that neuroimmune signaling is dysregulated by nicotine self-administration (SA) within the nucleus accumbens core (NAcore). Microglia are the resident brain immune cell and prior studies have shown that they play an important role in nicotine-related behaviors. However, while transgenic mouse lines allow for specific evaluations of microglia to determine their role in neurobiology and behavior, there are fewer tools available for rats as a model species, thus limiting our ability to evaluate specific contributions of microglia to nicotine SA. A transgenic rat expressing Cre under the control of the CX3CR1 promoter bred on a Long-Evans (LE) background was recently developed, and here we show that NAcore microglia can be virally transduced with designer receptors exclusively activated by designer drugs (DREADDs) without neuronal expression. We further show that CX3CR1::ERT2 rats readily self-administer nicotine and display a characteristic extinction curve. Together, these validation studies lay the foundation for future use of this transgenic rat line to evaluate the specific contributions of microglia within the brain reward pathway to the neurobehavioral underpinnings of nicotine addiction.