Summary: Scientists have uncovered a mechanism in the brain that explains how drugs like methamphetamine and PCP impair cognitive functions, particularly memory. The study shows that these drugs trigger neurotransmitter switching in the cerebral cortex, where excitatory glutamate neurons switch to inhibitory GABA neurons, leading to memory deficits.
Interestingly, researchers were able to reverse this switch and restore memory performance in mice using molecular tools and the antipsychotic drug clozapine. This discovery could pave the way for developing therapies to counteract drug-induced cognitive impairments and other brain disorders.
Key Facts:
- Meth and PCP cause neurons to switch from glutamate to GABA, impairing memory.
- Reversing this neurotransmitter switch restores cognitive function in mice.
- The findings could lead to new therapies for drug abuse and other brain disorders.
Source: UCSD
The effects of sustained drug abuse can manifest in many ways. Loss of memory and reduced cognitive functions are some of the effects that can persist for years. Neurobiologists at the University of California San Diego have now identified a mechanism in the brain that generates drug-induced cognitive impairments.
Scientists in the Department of Neurobiology, School of Biological Sciences, investigated how methamphetamine and phencyclidine (PCP or “angel dust”), which take effect by activating different targets in the brain, induce a similar reduction in cognitive ability. How could the same difficulties in memory emerge in response to drugs that trigger different actions in the brain?
The results of this investigation, led by Assistant Project Scientist Marta Pratelli in Professor Nicholas Spitzer’s laboratory, are published in Nature Communications. They showed that meth and PCP caused neurons to change the way they communicate through a process known as neurotransmitter switching.
Neurotransmitter switching is a form of brain plasticity, an evolving area of research investigating how the brain changes function and structure in response to experience. In recent years, Spitzer and his colleagues have also identified roles for neurotransmitter switching in autism spectrum disorder, post-traumatic stress disorder and in exercise.
Examining the cerebral cortex of mice, the investigators found that meth and PCP each caused a switch from the excitatory neurotransmitter glutamate to the inhibitory neurotransmitter GABA (gamma-aminobutyric acid) in the same neurons in the prelimbic region, an area of the frontal cortex involved in executive functions.
This switch was linked to a decrease in memory task performance since drug-treated mice performed well in the tasks when the expression of GABA was blocked.
Further experiments showed that even after repeated exposure to the drugs, the researchers were able to reverse this neurotransmitter switch using molecular tools to locally decrease the brain’s electrical activity or using clozapine, an antipsychotic drug. Each of these treatments reversed the memory loss, restoring the performance of mice in the cognitive tasks.
“These results suggest that targeted manipulation of neuronal activity may be used to ameliorate some of the negative effects of repeated drug abuse,” said Pratelli.
In this new study, the researchers found that a drug-induced increase in the release of dopamine, a neurotransmitter involved in reward, and an increase in the electrical activity of neurons in the cerebral cortex, were required to produce the neurotransmitter switch.
“This study reveals a shared and reversible mechanism that regulates the appearance of cognitive deficits upon exposure to different drugs,” said Spitzer.
The researchers note in their paper that a deeper understanding of brain mechanisms tied to loss of memory from drug use could boost prospects for new treatments, not only resulting in therapy for meth and PCP consumption, but for other disorders as well.
The researchers included Marta Pratelli, Anna Hakimi, Arth Thaker, Hyeonseok Jang, Hui-quan Li, Swetha Godavarthi, Byung Kook Lim and Nicholas Spitzer.
Funding: Funding for the study was provided by the National Institute on Drug Abuse (R21 CEBRA grant DA048633; and R21 DA050821) and the Overland Foundation.
About this addiction and cognition research news
Author: Mario Aguilera
Source: UCSD
Contact: Mario Aguilera – UCSD
Image: The image is credited to Neuroscience News
Original Research: Open access.
“Drug-induced change in transmitter identity is a shared mechanism generating cognitive deficits” by Marta Pratelli et al. Nature Communications
Abstract
Drug-induced change in transmitter identity is a shared mechanism generating cognitive deficits
Cognitive deficits are long-lasting consequences of drug use, yet the convergent mechanism by which classes of drugs with different pharmacological properties cause similar deficits is unclear.
We find that both phencyclidine and methamphetamine, despite differing in their targets in the brain, cause the same glutamatergic neurons in the medial prefrontal cortex of male mice to gain a GABAergic phenotype and decrease expression of their glutamatergic phenotype.
Suppressing drug-induced gain of GABA with RNA-interference prevents appearance of memory deficits. Stimulation of dopaminergic neurons in the ventral tegmental area is necessary and sufficient to produce this gain of GABA.
Drug-induced prefrontal hyperactivity drives this change in transmitter identity. Returning prefrontal activity to baseline, chemogenetically or with clozapine, reverses the change in transmitter phenotype and rescues the associated memory deficits.
This work reveals a shared and reversible mechanism that regulates the appearance of cognitive deficits upon exposure to different drugs.
