Chemogenetic Inhibition of Ventral Tegmental Area Dopamine Neurons Does Not Affect Cue-elicited Alcohol Seeking

Abstract

Alcohol use disorder (AUD) is characterized by an impaired ability to control alcohol use despite negative consequences. Individuals with AUD often have significant physiological and subjective reactions to presentations of cues associated with alcohol availability. Alcohol-predictive cues evoke a conditioned motivational state that elicits alcohol-seeking behaviors, which can then drive other aspects of addiction, such as compulsive drinking and relapse. Previous rat studies found that dopamine neurons in the ventral tegmental area (VTA) play a key role in cue-elicited reward seeking (Halbout et al., 2019). A recent study showed that chemogenetic inhibition of VTA dopamine neurons reduces alcohol seeking in a Pavlovian paradigm (Valyear et al., 2020), where alcohol and cues were delivered simultaneously. However, it remains controversial to what extent the activity of VTA dopamine neurons encodes the motivational properties of alcohol-predictive cues. Here, we tested whether cue-elicited alcohol seeking is reduced when VTA dopamine neurons are chemogenetically inhibited. Fifteen TH-Cre-positive rats (females = 8, males = 7) were intermittently exposed to 15% ethanol. They underwent training to associate an auditory cue with alcohol. Cue-elicited alcohol seeking is measured by port entry probability and latency in response to cues. After training, the rats received hM4Di-DREADD or control virus infusion surgery to suppress VTA dopamine neurons bilaterally. They were then given ligand or vehicle injections and tested responses to cues under extinction and test conditions. After the tests, their brain tissues were examined for viral and cFos expressions. Overall, chemogenetic inhibition of VTA dopamine neurons has no effect on cue-elicited alcohol seeking. Such a diverging result may be driven by task differences between Pavlovian and operant conditioning. This suggests that different neural systems may underlie the conditioned motivational state evoked by a cue depending on the time of the cue’s presentation relative to reward delivery.