The Effect of Dehydroepiandrosterone Treatment on Neurogenesis, Astrogliosis and Long-Term Cocaine-Seeking Behavior in a Cocaine Self-Administration Model in Rats

Abstract

Cocaine addiction is an acquired behavioral state developed in vulnerable individuals after cocaine exposure. It is characterized by compulsive drug-seeking and high vulnerability to relapse even after prolonged abstinence, associated with decreased neurogenesis in the hippocampus. This addictive state is hypothesized to be a form of “memory disease” in which the drug exploits the physiological neuroplasticity mechanisms that mediate regular learning and memory processes. Therefore, a major focus of the field has been to identify the cocaine-induced neuroadaptations occurring in the usurped brain’s reward circuit. The neurosteroid dehydroepiandrosterone (DHEA) affects brain cell morphology, differentiation, neurotransmission, and memory. It also reduces drug-seeking behavior in an animal model of cocaine self-administration. Here, we examined the long-lasting effects of DHEA treatment on the attenuation of cocaine-seeking behavior. We also examined its short- and long-term influence on hippocampal cells architecture (neurons and astrocytes). Using a behavioral examination, immunohistochemical staining, and diffusion tensor imaging, we found an immediate effect on tissue density and activation of astrocytes, which has a continuous beneficial effect on neurogenesis and tissue organization. This research emphasizes the requites concert between astrocytes and neurons in the rehabilitation from addiction behavior. Thus, DHEA may serve as a treatment that corrects brain damage following exposure to and abstinence from cocaine.

The Effect of Dehydroepiandrosterone Administration during Rehabilitation on White Matter Integrity Among Individuals With Polysubstance Use Disorder

“…One potential mechanism may relate to a recent finding in rodents that DHEA administration led to an increase in white matter (WM) integrity, which in turn was associated with long-term reduction in craving behavior. 4 These findings are in line with the vast neuroimaging literature in humans that links pSUD with WM microstructural abnormalities. [11][12][13][14][15] A recently published meta-analysis of structural neuroimaging studies revealed that pSUD is associated with widespread WM alterations, with reduction in WM integrity in the major fiber pathway of corpus callosum (CC) emerging as the most consistent impairment.…”

“…This finding is in line with a recent rodent study suggesting that DHEA may induce its therapeutic efficacy by contributing to WM integrity. 4 Interestingly, the study in rodents focused on hippocampal cells, demonstrating increased WM tissue density in the dorsal dentate gyrus, which was suggested to contribute to learning and memory processes. 4 Considering the major communicational role of the CC pathway, its restoration may also positively impact decision-making processes that are commonly reported to be hampered in addiction.…”

“…In rodents, DHEA administration attenuated cocaine self-administration and decreased cocaine-seeking behaviors. [3][4][5] In humans, high levels of circulatory DHEA sulfate (DHEA-S) were associated with lower relapse rates among individuals addicted to cocaine, 6 as well as with reduced craving in women with alcohol use disorder. 7 Initial attempts to harness these putative effects to reduce relapse rates were unsuccessful, as DHEA administration did not reduce relapse rates or craving among cocaine-dependent participants compared with placebo.…”

Placenta-Derived Mesenchymal-like Adherent Stromal Cells as an Effective Cell Therapy for Cocaine Addiction in a Rat Model

“…Surprisingly, more cells were present in the reward-associated brain regions than in the reward-unassociated brain regions. We assumed that increased activation of cells in these regions [ 43 , 44 ] would increase blood flow. This could contribute to cell migration and distribution.…”

“…Immunohistochemistry was performed to confirm that GNPs observed at one week in the Coc-nPAD group in the DG indicated live nPAD cells ( Figure 3 b). The DG region was elected for staining since it is affected by cocaine consumption that damages neurogenesis in this region [ 11 , 44 ], which is a main focus of this study. Representative images of the DG show co-localization of the Ku80.…”