Researchers at Cairo University have reported that subchronic administration of high doses of gabapentin in rats is associated with significant histopathological changes in the hippocampus and alterations in dopamine receptor gene expression. The study, published in the Future Journal of Pharmaceutical Sciences, aims to evaluate the neurotoxic and potential addictive mechanisms of gabapentin misuse, a concern that has grown in Egypt following the scheduling of the related drug pregabalin. While gabapentin is widely prescribed for epilepsy and neuropathic pain, its misuse as a drug of abuse has escalated over the past decade, prompting investigations into its long-term effects on brain tissue and reward pathways.
The investigation utilized thirty adult healthy male albino rats, which were randomly divided into three groups of ten animals each. The first group served as a negative control, receiving a normal diet for fifty days. The second group, designated as the gabapentin misuse group, was subjected to a progressive dosing regimen. The third group, the gabapentin withdrawal group, followed the same dosing protocol as the misuse group but was then maintained for an additional ten days without the drug to assess the effects of abrupt cessation. All rats were housed in a conventional laboratory setting with a steady temperature of 25 degrees Celsius and a 12-hour light-dark cycle.
The dosing strategy was designed to mimic the escalating patterns observed in human substance use disorders. The misuse and withdrawal groups received an initial oral dose of 32.4 mg/kg/day of gabapentin diluted in distilled water for three days. This dose was then increased by 32.4 mg/kg/day every three days until a dependent dose of 324 mg/kg/day was reached at the end of a 30-day period. This dependent dose was maintained for the subsequent 20 days. The researchers calculated this dose to be equivalent to 3600 mg/day in humans, a level associated with dissociative effects and euphoria in addicts, using the Paget equation for species conversion.
At the conclusion of the experimental period, the researchers conducted a series of neurobehavioral tests using an ANY-box apparatus, which automates the assessment of locomotor activity, anxiety, and cognitive function. The tests included an open field test to evaluate anxiety and irritability, a dark and light test to measure anxiety through time spent in dark zones, and a new object recognition test to assess cognitive performance. The results indicated that the control group exhibited better performance and locomotor indices compared to the treated groups. Rats in the misuse group appeared more sedated and lethargic, spending less time in the peripheral zone and exhibiting more immobile episodes. Conversely, rats in the withdrawal group displayed signs of anxiety and agitation, spending more time in dark zones and showing reduced exploration of new objects.
Histopathological analysis of hippocampal tissue revealed distinct differences between the groups. The control group displayed normal architecture, with well-organized pyramidal cells in the hippocampus proprius and granule cells in the dentate gyrus. In contrast, the gabapentin misuse group showed disorganized hippocampal structures, with numerous degenerated pyramidal cells and shrunken neuroglia cells encircled by empty haloes, giving the molecular layer a vacuolated appearance. The dentate gyrus in this group also exhibited many shrunken, darkly stained granule cells. The withdrawal group showed a relative improvement, with most pyramidal cells appearing normal, although some degenerated cells with darkly pigmented nuclei were still present.
Specialized staining techniques further highlighted the neurodegenerative effects of gabapentin misuse. Congo red staining, which marks amyloid beta-pleated-sheet structures, was negative in the control group but showed many positive deposits in the misuse group. The withdrawal group displayed only few positive deposits. Similarly, Periodic acid Schiff (PAS) staining, used to evaluate glycogenosis and neurodegeneration, was significantly elevated in the misuse group compared to the control. The percentage area of both PAS and Congo red-positive stains was statistically significantly higher in the abuse and withdrawal groups than in the control group, with the abuse group showing the most extensive changes.
Immunohistochemical analysis for P53, a marker for apoptosis and DNA integrity, revealed that the control group had a negative immunological response in the cytoplasm of granule and pyramidal cells. The gabapentin misuse group displayed a large number of P53-positive cells in both the dentate gyrus and the hippocampus proprius, indicating increased DNA disintegration and apoptosis. The withdrawal group had fewer P53-positive cells, suggesting a reduction in apoptotic activity after the cessation of the drug. These findings align with previous research indicating that gabapentin can trigger apoptosis through the mitochondrial route and the activation of caspase-3.
Gene expression analysis using real-time quantitative polymerase chain reaction (RT qPCR) focused on brain-derived neurotrophic factor (BDNF) and dopamine receptors D1 and D2. The results showed a significant up-regulation of dopamine-2 receptors (D2Rs) in the misuse group, with a mean fold change of 7.63. This up-regulation was reversed in the withdrawal group, where the mean fold change dropped to 1.72. In contrast, dopamine-1 receptors (D1Rs) were down-regulated in the misuse group, with a mean fold change of 0.47, a change that was partially reversed in the withdrawal group to 0.89. The BDNF gene expression was up-regulated in both the misuse and withdrawal groups, with mean fold changes of 3.12 and 2.51, respectively, although this change was not statistically significant compared to the control.
The differential regulation of dopamine receptors is particularly notable in the context of addiction. The relatively low expression of D1Rs compared to D2Rs in the misuse group suggests a potential mechanism for gabapentin’s addictive properties. D1 receptors are generally considered essential for mediating reward and converting it into action, while D2 receptors are more involved in regulating movements. The up-regulation of D2Rs and down-regulation of D1Rs may contribute to the behavioral sensitization and reinforcement behavior associated with recurrent drug use. The researchers noted that inhibiting D1Rs activity has been shown to avoid behavioral sensitization in animal models of drug addiction, further supporting the role of these receptors in gabapentin’s potential for abuse.
The study also observed a significant increase in body weight in both the misuse and withdrawal groups compared to the control group. This weight gain was more pronounced in the misuse group, potentially due to increased appetite and water retention. The relative brain weight of the misuse group was lower than that of the control group, although there was no discernible change in absolute brain weight. These physiological changes, combined with the neurobehavioral and histopathological findings, provide a comprehensive picture of the impact of high-dose gabapentin administration on the rat model.
The authors acknowledge that while the study provides valuable insights into the neurotoxic and addictive mechanisms of gabapentin, it is limited to an animal model. The extrapolation of these findings to human clinical settings requires caution, as the dosing regimen was designed to replicate extreme misuse scenarios rather than therapeutic use. The study does not account for the complex interactions between gabapentin and other substances, such as opioids or alcohol, which are commonly involved in real-world abuse patterns. Furthermore, the study did not measure plasma BDNF levels, which could provide additional information about the systemic effects of gabapentin on neurotrophic factors.
Despite these limitations, the study contributes to the growing body of evidence regarding the risks associated with gabapentin misuse. The findings underscore the need for clinicians to monitor patients with a history of substance use disorders or mood disorders when prescribing gabapentin. The potential for gabapentin to induce neurodegenerative changes and alter dopamine receptor expression highlights the importance of careful prescribing practices and the need for further research to fully understand the long-term effects of gabapentin on the human brain.
The research was approved by the Institutional Animal Care and Use Committee of Cairo University’s Faculty of Medicine, and the study adhered to the National Research Council’s Guide for the Care and Use of Laboratory Animals. The data from this study will be available upon request from the corresponding author. This work represents one of the few experimental studies to investigate the potential for gabapentin abuse and the development of withdrawal manifestations after sudden stoppage of the drug, providing a foundation for future investigations into its safety profile.
Subject of Research: Neurotoxic and addictive mechanisms of gabapentin misuse in a rat model
Article Title: Gabapentin: a newly emerging drug of abuse, neurotoxicity, and potential addictive mechanisms
Article References: El-Kattan, M. A.-E.-S., Saeed, E., Khattab, M. A., Abdel Maksoud, F. A. W., Emad Eldein, M., Abdel-Roaf, N. E., Awad, W., & Elshatory, A. (2026). Gabapentin: a newly emerging drug of abuse, neurotoxicity, and potential addictive mechanisms. Future Journal of Pharmaceutical Sciences, 12(1), Article 49. https://doi.org/10.1186/s43094-026-00976-x
Image Credits: AI Generated
DOI: 10.1186/s43094-026-00976-x
Keywords: gabapentin, neurotoxicity, drug abuse, dopamine receptors, hippocampus, rat model, addiction, histopathology, BDNF, Cairo University, newly, emerging
News Source: Cassandra Pierce. (November 10, 2026). Rat Study Links Gabapentin Abuse to Brain Damage and Dopamine Changes. Scienmag.
