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Research Uncovers Mechanism Behind Drug-Induced Cognitive Impairments

The long-term impacts of drug abuse can lead to a variety of adverse effects, notably the deterioration of memory and cognitive performance that may linger for years. Recent research conducted by neurobiologists at the University of California San Diego has pinpointed a particular brain mechanism responsible for these cognitive impairments triggered by drug use.

Researchers from the Department of Neurobiology within the School of Biological Sciences delved into the cognitive decline associated with methamphetamine and phencyclidine (commonly known as PCP or “angel dust”). Despite the different ways these drugs interact with the brain, both appear to elicit similar declines in cognitive function. This raises a critical question: how can two chemically distinct drugs produce alike memory deficits?

The findings from this study, spearheaded by Assistant Project Scientist Marta Pratelli in Professor Nicholas Spitzer’s lab, have been documented in Nature Communications. The research indicated that both methamphetamine and PCP prompted neurons to alter their communication methods through a phenomenon called neurotransmitter switching.

Neurotransmitter switching signifies a form of brain plasticity, an intriguing territory of research dedicated to understanding how alterations in experience can affect the brain’s structure and functionality. Spitzer and colleagues have previously explored the implications of neurotransmitter switching in various conditions, including autism spectrum disorder, post-traumatic stress disorder, and the benefits of physical exercise.

In their examination of mouse cerebral cortex, the scientists discovered that exposure to meth and PCP resulted in a shift from the excitatory neurotransmitter glutamate to the inhibitory neurotransmitter GABA (gamma-aminobutyric acid) within neurons located in the prelimbic region—an area of the frontal cortex crucial for executive function. This neurotransmitter switch was notably associated with diminished performance in memory tasks; when GABA expression was inhibited, the drug-affected mice regained their capacity to effectively complete these tasks.

Further exploration revealed that the researchers could reverse the neurotransmitter switching even after repeated drug exposure. They utilized molecular techniques to lower electrical activity in the brain and administered clozapine, an antipsychotic medication. Both methods successfully mitigated memory losses and improved cognitive task performance in the drug-exposed mice.

“These results suggest that with precise manipulation of neuronal activity, we may reduce some of the detrimental effects stemming from extensive drug use,” Pratelli remarked.

This study also highlighted that the drugs induced an increase in dopamine release and stimulated heightened electrical activity in the cerebral cortex—factors deemed necessary for the neurotransmitter switch to take place.

“Our research uncovers a common and reversible mechanism that could explain the emergence of cognitive impairments following exposure to various drugs,” Spitzer explained.

The implications of these findings extend beyond just treatment strategies for meth and PCP misuse. A deeper comprehension of the brain’s mechanisms related to drug-induced memory loss could provide pathways for novel therapeutic approaches applicable to a range of conditions. The research team comprised Marta Pratelli, Anna Hakimi, Arth Thaker, Hyeonseok Jang, Hui-quan Li, Swetha Godavarthi, Byung Kook Lim, and Nicholas Spitzer. Financing for this endeavor came from the National Institute on Drug Abuse (grants R21 CEBRA DA048633 and R21 DA050821) and the Overland Foundation.

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