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Altered cognitive function can occur as a consequence of long-term drug use and is viewed as a key feature of substance use disorders. [1] These cognitive deficits can be caused by drug-induced changes in the transmitter expressed by certain cortical neurons. [2] However, new research has shown methods by which these cognitive deficits could be reversed, providing great hope for the future treatment of those affected by substance use disorders.
How cognitive deficits might be reversed
A study done by University of California researchers looked at the effects certain drugs, namely phencyclidine and methamphetamine, had on the brains of mice. [2] They found not only that the drugs caused the same cognitive changes, including a switch in the neurotransmitter of the prelimbic cortex in the brain, but also that this could be reversed using two different methods. The prelimbic cortex is part of the medial prefrontal cortex of the brain and plays an important role in the modulation of behavior and decision-making. Changes in this area can therefore lead to drug-seeking behavior.
First method
Firstly, clozapine, an antipsychotic medication that acts on serotonin and dopamine receptors, was shown to reverse the drug-induced cognitive changes. [2] In the study, clozapine was administered to the mice three days after phencyclidine was given and was continued for two weeks. Researchers found that this reversed both the transmitter changes and the associated memory deficits. Crucially, the clozapine only affected the neurons that had changed due to drug treatment and didn’t affect the neurons in the control mice.
Second method
Chemogenetics, which refers to the modulation of neuron activity through genetically engineered neurotransmitter receptors, was the second method of reversing the cognitive deficit. [2][3] In this study, specific interneurons were chemogenetically activated after the drug-induced neurotransmitter changes had occurred, suppressing the prelimbic cortex hyperactivity. This intervention reversed the neurotransmitter changes and reduced the memory impairments, providing a similar outcome to the clozapine treatment.
Insights
The key insight from this research is that suppressing the drug-induced prelimbic cortex hyperactivity, either by clozapine treatment or chemogenetics, can reverse the adverse cognitive changes. Subsequently, the associated behavior alterations can be normalized. This suggests that the cognitive change seen in substance use disorders is not permanent; instead, it can be targeted by treatment.
Understanding cognitive deficits caused by drug use
The cognitive deficits caused by substance use and addiction can exacerbate drug-seeking behavior and make achieving abstinence increasingly challenging. [4] Generally speaking, drugs of abuse hyperactivate and dysregulate the reward system in the brain, increasing dopamine release and leading to ongoing drug-seeking behavior to feel the same pleasure again. [4] This dysregulation causes the individual to no longer feel pleasure from things they did before, such as eating or exercising. These effects can be particularly prominent in adolescents and young adults, whose brains are still developing.
This study showed that despite phencyclidine and methamphetamine’s different mechanisms of action, they caused cognitive deficits in the same way. [2] They both caused neurotransmitter switches from glutamate (an excitatory neurotransmitter) to GABA (an inhibitory neurotransmitter) in the prelimbic cortex of the brain. [2][5] This switch is significant, as these neurotransmitters have opposite effects, like switching an accelerator to a brake in the region of the brain that is crucial in decision-making. Over time, this neurotransmitter switch is associated with the cognitive deficits and behavioral changes that are seen in drug addiction.
Understanding this process has identified a shared mechanism by which drugs cause cognitive deficits, making it possible to develop targeted treatments. It’s possible that other drugs seen in substance use disorders, such as opioids, also affect the brain in the same way, but more research is required to better understand this.
Implications in addiction recovery
It was previously thought that cognitive damage from drug use was permanent, but this research has suggested otherwise, which could have huge implications for addiction recovery. While this is only one study looking at two different drugs (and in mice, as animal studies are considered inferior), it still provides a base for future research in this area. If further studies in humans can identify a similar mechanism in which other drugs cause cognitive decline, there is hope that in time medical or chemogenetic treatment for the cognitive deficits from addiction could be available.
Currently, addiction recovery treatment involves multiple areas, such as medical detox, targeted therapies, and support groups. However, there is no specific treatment for drug-induced cognitive deficits.
Related: How Long Does Brain Recovery Take After Addiction?
Having treatment like this available would vastly increase the effectiveness of addiction recovery treatment, offering individuals a lifeline where the non-physical drug-induced damage can be fully reversed. This would give significant hope to those struggling with substance use disorders who might currently feel hopeless due to their longstanding drug-induced cognitive deficits. While more research is needed, this is a very promising first step in creating a more effective treatment for addiction recovery.
Current limitations and future research
Despite the positive results of this research, there are some limitations to consider. First, this study was done on mice and not humans, and while animal responses are often replicated in human trials, the responses are not always the same. Also, the mice were administered the clozapine directly into their abdominal cavity lining. In contrast, humans would likely self-administer the medication as a tablet, and this could impact treatment success and outcomes.
This study looked at two drugs, phencyclidine and methamphetamine, but there are several other drugs, such as opioids, which also affect the prelimbic cortex. With this in mind, further research is required to see if other drugs also cause the same neurotransmitter switch.
This study will act as a base for future research, firstly looking into the effects of other substances on neurotransmitters and then eventually moving into human trials.
Conclusion: A new frontier in brain recovery
This research has highlighted that the cognitive decline from prolonged substance use may not be as permanent as previously thought. Instead, it could be reversed with either specific drugs (like clozapine) or with chemogenetics. While further research is needed, this is a promising development in addiction recovery treatment.
There is hope that in the near future, therapeutic treatments for cognitive deficits could be available to help complement the existing addiction recovery treatments. Close to 50 million Americans struggle with a substance use disorder, so the impact of this new research could be huge. [6]
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