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 The Role of Glutamate and Chronic Stress in Cocaine Sensitization 

In Glutamate inputs from the laterodorsal tegmental nucleus to the ventral tegmental area are essential for the induction of cocaine sensitization in male mice, by Amit Puranik, Nicole Buie, Dena Arizanovska, Paul Vezina, and Stephan Steidl, shows how LDTg, the source for VTA glutamate, is very important for cocaine sensitization. The experiment was done with male mice. The induction of sensitization is contributed significantly by the potentiation, through drug-induction, of the ventral tegmental area (VTA).   

For the experiment, only male mice were used, were tested in open-field boxes, and were kept under standard conditions. They used optogenetic techniques to test how big of a role "LDTg GLU neurons and their afferents in the VTA" play in cocaine sensitization (Puranik, A., Buie, N. et al., 2022). For the first three days all mice were injected with saline. Then, during the subsequent exposure phase, for five days half the eYFP and NpHR groups of mice were injected with cocaine, while the other half were injected with saline. After the injections all the mice “were connected to optical tethers and received light stimulation to the brain target site” (Puranik, A., Buie, N. et al., 2022). Other testing also took place in the experiment. The results of the experiment show the importance of the role of VTA glutamatergic signaling in cocaine sensitization, as the "inhibition of LDTg glutamatergic inputs to the VTA during cocaine exposure prevents the sensitization of locomotor activation” (Puranik, A., Buie, N. et al., 2022).  

In Impairment of Glutamate Homeostasis in the Nucleus Accumbens Core Underpins Cross-Sensitization to Cocaine Following Chronic Restraint Stress, by María P. Avalos, Andrea S. Guzman, Constanza Garcia-Keller, et al. Shows the connection between chronic restraint stress and the sensitization of cocaine. The study examines the effects of chronic restraint stress (CRS) on the sensitization of cocaine with the emphasis on "both the subcompartments of the nucleus accumbens (NA), the core (NAcore) and shell (NAshell)" (Avalos, M. P., Guzman, A. S. et al., 2022). Adult male Wistar rats were used in the experiment. The results of the study show that an increase in CRS in response to cocaine also resulted in an increase in dopamine levels in the NAcore, with the non-stress group. It was also found that the glutamate homeostasis was impaired due to CRS induction. 

For the experiment, adult male Wistar rats were used. They were separated into two groups, the CRS group and the non-CRS group. The CRS group was restrained for two hours every day for seven days. After two weeks, the groups were "randomly assigned to the behavioral, biochemical or neurochemical studies" (Avalos, M. P., Guzman, A. S. et al., 2022). On day seventeen, all the animals were randomly assigned to ceftriaxone or saline solution. Then, on day twenty-one, locomotor activity was tested in the animals, with the objective of detecting behavioral sensitization. On this day, the animals received saline or cocaine injections depending on their group. Basal samples of glutamate and dopamine samples were also collected. The results of the study show that CRS is able to have "stimulating properties of cocaine on motor activity and dopamine release in the NAcore,... but also an impairment of glutamate mechanisms" (Avalos, M. P., Guzman, A. S. et al., 2022).  

Both these studies show two different aspects of cocaine sensitization. The first study shows the role of VTA glutamatergic signaling in cocaine sensitization, while the second study shows the role of chronic restraint stress on the sensitization of cocaine. In the second study, chronic restraint stress has the effect of sensitization of cocaine, it also plays a role in glutamate mechanism through impairment. Both studies highlight the importance of glutamate, through impairment and/or signaling, in cocaine sensitization.  

 

References 

Avalos, M. P., Guzman, A. S., Garcia-Keller, C., Mongi-Bragato, B., Esparza, M. A., Rigoni, D., Sanchez, M. A., Calfa, G. D., Bollati, F. A., & Cancela, L. M. (2022). Impairment of glutamate homeostasis in the nucleus accumbens core underpins cross-sensitization to cocaine following chronic restraint stress. Frontiers in Physiology, 13. https://doi.org/10.3389/fphys.2022.896268 

Puranik, A., Buie, N., Arizanovska, D., Vezina, P., & Steidl, S. (2022). Glutamate inputs from the laterodorsal tegmental nucleus to the ventral tegmental area are essential for the induction of cocaine sensitization in male mice. Psychopharmacology, 239(10), 3263–3276. https://doi.org/10.1007/s00213-022-06209-2