Meth and PCP Trigger Same Brain Changes, Leading to Potentially Reversible Cognitive Deficits

[Paracelsus]

A recent study published in Nature Communications has uncovered a novel and shared mechanism underlying cognitive deficits caused by distinct drugs. The research, led by scientists from the University of California San Diego, focused on the effects of methamphetamine (METH) and phencyclidine (PCP) on the brain and found that despite their differing targets, both drugs lead to similar impairments by altering the identity of specific neurons in the prefrontal cortex.

The prefrontal cortex, responsible for executive functions like decision-making and memory, was found to undergo significant changes after drug exposure. Both METH and PCP caused glutamatergic neurons (which normally release the excitatory neurotransmitter glutamate) to acquire a GABAergic identity, releasing the inhibitory neurotransmitter GABA instead. This switch in neurotransmitter type contributed to the observed cognitive deficits, such as impairments in memory and decision-making. The research team demonstrated that this change was reversible by manipulating neural activity, either through chemogenetic methods or by using clozapine, a well-known antipsychotic drug.

One of the key findings of this study is that dopaminergic signaling from the ventral tegmental area (VTA) plays a crucial role in inducing these changes. Both drugs increased dopamine release in the brain, leading to hyperactivity in the prefrontal cortex, which was necessary to drive the switch in neurotransmitter identity. By suppressing this hyperactivity, either genetically or pharmacologically, the researchers were able to reverse the cognitive deficits.

This discovery opens up exciting new possibilities for treating cognitive impairments, not only in the context of drug abuse but also in broader neurological and psychiatric conditions such as schizophrenia and mood disorders, where similar deficits are common. Understanding the shared mechanisms across different drugs can pave the way for more effective treatments targeting these underlying processes.

The full study, titled "Drug-induced change in transmitter identity is a shared mechanism generating cognitive deficits," can be accessed at Nature Communications (clearnet)

 

[PharmacopeiaLabs]

very interesting, i wonder what supplementation of glutamine (glutamate precursor) would do in such cases.

 

[Paracelsus]

Glutamine is indeed a precursor to glutamate, the primary excitatory neurotransmitter in the brain. However, the study indicates that the cognitive deficits arise not from a shortage of glutamate but from a drug-induced change in the identity of certain neurons in the prefrontal cortex.

In the study, methamphetamine (METH) and phencyclidine (PCP) caused glutamatergic neurons—which normally release glutamate—to adopt a GABAergic identity, releasing the inhibitory neurotransmitter GABA instead. This switch contributes to impairments in memory and decision-making. The key issue here is the functional change in the neurons themselves, not merely the levels of glutamate available.

Supplementing with glutamine might increase the overall pool of glutamate precursors, but it is unlikely to reverse the neuron's altered identity or the associated cognitive deficits. The researchers found that reversing these changes required interventions that modulate neural activity, such as chemogenetic techniques or pharmacological agents like clozapine, which influence dopaminergic signaling pathways.

It's also important to note that excessive glutamate can lead to excitotoxicity, potentially causing neuronal damage.