Chronic social defeat stress and cocaine sensitization by sex: the role of glutamate‐glutamine cycle
Authors: Shimamoto Akiko , Rappeneau Virginie , Blaker Amanda L. , Reynolds Collin , Yamamoto Bryan K. 
Published: November 2023

BackgroundApproximately 8 millions of Americans are suffering from comorbid substance use disorders (SUD) and mental illnesses, including mood disorders. The risk of drug abuse can be reduced by half if the symptoms of preceding mood disorders are properly managed. Women are twice as many as men to suffer from mood disorders, particularly major depression (MD). Hence, women may be more at risk to suffer from comorbid SUD and MD.AimThis proposal identifies sex‐specific brain mechanisms associated with depression to prevent the risk of secondary drug abuse, using chronic social defeat stress as an animal model of depression for males and females. The overarching hypothesis is that chronic stress induces sex‐specific impairments in the glutamate‐glutamine cycle in the nucleus accumbens (NAc), a brain area associated with both depression and drug abuse, which determines subsequent behaviors to addictive drugs, such as cocaine.MethodsMale and female Long‐Evans rats were exposed to chronic social defeat stress (CSDS) for 21 days, using a modified resident‐intruder paradigm. The depressive‐like phenotype for intruders was determined with the reduction of saccharin intake, attenuation in weight gain, and disruption in estrous cycle. Rats with daily handling were used as controls for each sex. Ten days after the last social defeat, both the intruders and controls were subjected to a no‐net‐flux in vivo microdialysis to assess glutamate accumulation and extracellular glutamine in the NAc. The contralateral hemispheres were used for determining changes in astrocytes and glutamate transporter‐1 (GLT‐1) in prefrontal cortex (PFC), NAc, and dorsal striatum. Separate cohorts of animals were exposed to CSDS or handling, then exposed to 4 intraperitoneal (i.p.) injections of 15 mg/kg of cocaine with each injections separated by 72 hours, followed by a single injection of 10 mg/kg cocaine tested 10 days later. Brains were harvested to measure GLT‐1 and kinesin, an anterograde mitochondrial motor protein.ResultsBoth male and female intruders reduced saccharin intake over the course of CSDS, compared to their pre‐stress period and to their respective controls. Male intruders showed reductions in striatal GLT‐1 and spontaneous glutamine in the NAc, compared to controls. Female intruders showed reductions in prefrontal and accumbal astrocytes, and prefrontal GLT‐1 protein, compared to controls. Their non‐reproductive days were extended. When 10 μM of glutamate was infused, these females showed a significant accumulation of glutamate compared to controls. These intruder females, but not males, showed behavioral sensitization to cocaine compared to their respective controls. They also showed decreases in GLT‐1 in the NAc and kinesin in PFC.ConclusionPreceding chronic stress may induce behavioral sensitization to cocaine in females, possibly due to the impaired glutamate‐GLT‐1 mechanism. In males, CSDS may facilitate glutamine transfer to presynapses that eventually mitigate cocaine sensitization.Support or Funding InformationNIH G12 MD007586, U54 MD007593, U54 CA163069, R24 DA036420 (Meharry Medical College) NIH R01 DA035499, R01 DA 007606 (Bryan K. Yamamoto)