TY - JOUR
T1 - Fluorocitrate inhibition of astrocytes reduces nicotine self-administration and alters extracellular levels of glutamate and dopamine within the nucleus accumbens in male wistar rats
AU - Tan, Xiaoying
AU - Neslund, Elizabeth M.
AU - Fentis, Khawla
AU - Ding, Zheng Ming
N1 - Publisher Copyright:
© 2024 Elsevier Ltd
PY - 2024/9/1
Y1 - 2024/9/1
N2 - Emerging evidence suggests an important role of astrocytes in mediating behavioral and molecular effects of commonly misused drugs. Passive exposure to nicotine alters molecular, morphological, and functional properties of astrocytes. However, a potential involvement of astrocytes in nicotine reinforcement remains largely unexplored. The overall hypothesis tested in the current study is that astrocytes play a critical role in nicotine reinforcement. Protein levels of the astrocyte marker glial fibrillary acidic protein (GFAP) were examined in key mesocorticolimbic regions following chronic nicotine intravenous self-administration. Fluorocitrate, a metabolic inhibitor of astrocytes, was tested for its effects on behaviors related to nicotine reinforcement and relapse. Effects of fluorocitrate on extracellular neurotransmitter levels, including glutamate, GABA, and dopamine, were determined with microdialysis. Chronic nicotine intravenous self-administration increased GFAP expression in the nucleus accumbens core (NACcr), but not other key mesocorticolimbic regions, compared to saline intravenous self-administration. Both intra-ventricular and intra-NACcr microinjection of fluorocitrate decreased nicotine self-administration. Intra-NACcr fluorocitrate microinjection also inhibited cue-induced reinstatement of nicotine seeking. Local perfusion of fluorocitrate decreased extracellular glutamate levels, elevated extracellular dopamine levels, but did not alter extracellular GABA levels in the NACcr. Fluorocitrate did not alter basal locomotor activity. These results indicate that nicotine reinforcement upregulates the astrocyte marker GFAP expression in the NACcr, metabolic inhibition of astrocytes attenuates nicotine reinforcement and relapse, and metabolic inhibition of astrocytes disrupts extracellular dopamine and glutamate transmission. Overall, these findings suggest that astrocytes play an important role in nicotine reinforcement and relapse, potentially through regulation of extracellular glutamate and dopamine neurotransmission.
AB - Emerging evidence suggests an important role of astrocytes in mediating behavioral and molecular effects of commonly misused drugs. Passive exposure to nicotine alters molecular, morphological, and functional properties of astrocytes. However, a potential involvement of astrocytes in nicotine reinforcement remains largely unexplored. The overall hypothesis tested in the current study is that astrocytes play a critical role in nicotine reinforcement. Protein levels of the astrocyte marker glial fibrillary acidic protein (GFAP) were examined in key mesocorticolimbic regions following chronic nicotine intravenous self-administration. Fluorocitrate, a metabolic inhibitor of astrocytes, was tested for its effects on behaviors related to nicotine reinforcement and relapse. Effects of fluorocitrate on extracellular neurotransmitter levels, including glutamate, GABA, and dopamine, were determined with microdialysis. Chronic nicotine intravenous self-administration increased GFAP expression in the nucleus accumbens core (NACcr), but not other key mesocorticolimbic regions, compared to saline intravenous self-administration. Both intra-ventricular and intra-NACcr microinjection of fluorocitrate decreased nicotine self-administration. Intra-NACcr fluorocitrate microinjection also inhibited cue-induced reinstatement of nicotine seeking. Local perfusion of fluorocitrate decreased extracellular glutamate levels, elevated extracellular dopamine levels, but did not alter extracellular GABA levels in the NACcr. Fluorocitrate did not alter basal locomotor activity. These results indicate that nicotine reinforcement upregulates the astrocyte marker GFAP expression in the NACcr, metabolic inhibition of astrocytes attenuates nicotine reinforcement and relapse, and metabolic inhibition of astrocytes disrupts extracellular dopamine and glutamate transmission. Overall, these findings suggest that astrocytes play an important role in nicotine reinforcement and relapse, potentially through regulation of extracellular glutamate and dopamine neurotransmission.
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U2 - 10.1016/j.neuropharm.2024.110001
DO - 10.1016/j.neuropharm.2024.110001
M3 - Article
C2 - 38750804
AN - SCOPUS:85193518600
SN - 0028-3908
VL - 255
JO - Neuropharmacology
JF - Neuropharmacology
M1 - 110001
ER -