# Astrocytes in the Ventral Tegmental Area Are Involved in Cotinine Self-Administration in Male Wistar Rats

## TL;DR

This study shows that astrocytes in the ventral tegmental area may contribute to the reinforcing effects of cotinine, a nicotine metabolite, by influencing dopamine and glutamate levels.

## Contribution

The study identifies a novel role for VTA astrocytes in cotinine reinforcement, which was previously unexplored.

## Key findings

- Cotinine self-administration increases GFAP protein levels specifically in the ventral tegmental area.
- Fluorocitrate in the VTA reduces cotinine self-administration and lowers extracellular dopamine and glutamate levels.
- These findings suggest that VTA astrocytes may regulate cotinine reinforcement through extracellular neurotransmitter transmission.

## Abstract

What are the main findings?
Cotinine self-administration elevates GFAP protein levels in the VTA.Fluorocitrate in the VTA attenuates cotinine self-administration and reduces extracellular glutamate and dopamine levels.

Cotinine self-administration elevates GFAP protein levels in the VTA.

Fluorocitrate in the VTA attenuates cotinine self-administration and reduces extracellular glutamate and dopamine levels.

What are the implications of the main findings?
These results suggest astrocytes may play an important role in cotinine self-administration.These findings may enhance our understanding of nicotine reinforcement.

These results suggest astrocytes may play an important role in cotinine self-administration.

These findings may enhance our understanding of nicotine reinforcement.

Background: Our recent studies indicate that astrocytes in a key mesocorticolimbic region play an important role in nicotine reinforcement. Nicotine self-administration elevated the astrocyte marker glial fibrillary acidic protein (GFAP) in the nucleus accumbens (NAc) core. Metabolic inhibition of astrocytes in the NAc core with fluorocitrate attenuated nicotine self-administration and disrupted local extracellular glutamate and dopamine transmission. Cotinine is the major neuroactive metabolite of nicotine, demonstrating its own reinforcing effects and contributing to the development of nicotine reinforcement. Mechanisms underlying cotinine reinforcement remain underexplored. The objective of this study was to investigate the potential involvement of astrocytes in cotinine reinforcement. Methods: GFAP protein expression was measured in key mesocorticolimbic regions with a Western blot following chronic cotinine self-administration. The effects of fluorocitrate on cotinine self-administration and extracellular glutamate and dopamine levels were determined. Results: GFAP protein levels were higher in rats undergoing chronic cotinine self-administration than in those with saline self-administration within the ventral tegmental area (VTA) but not the nucleus accumbens or the medial prefrontal cortex. Intra-VTA microinjection of fluorocitrate inhibited the maintenance of cotinine self-administration. Perfusion of fluorocitrate in the VTA reduced local extracellular levels of glutamate and dopamine. Conclusions: These results indicate that cotinine self-administration augmented GFAP expression in the VTA and that metabolic inhibition of VTA astrocytes attenuated cotinine self-administration and impaired extracellular dopamine and glutamate transmission. Overall, these findings suggest that astrocytes in the VTA may play an important role in cotinine reinforcement, potentially through regulation of local extracellular glutamate and dopamine transmission.