Drug-induced change in transmitter identity is a shared mechanism generating cognitive deficits
Nature Communications volume 15, Article number: 8260 (2024 ) Cite this article
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.
Brain impairments are often characterized by constellations of symptoms and behavioral alterations, some of which are shared across disorders. Cognitive deficits are found in mood and neuropsychiatric disorders such as drug misuse, schizophrenia and depression, raising the possibility that shared mechanisms could produce the same impairments in response to different stimuli. While studies have focused on the actions of single drugs, less attention has been given to investigating the mechanisms of action that different drugs of abuse have in common. We investigated the effect of sub-chronic treatment with phencyclidine (PCP) or methamphetamine (METH), two drugs belonging to different classes of chemicals. PCP affects glutamatergic transmission by acting as an NMDA antagonist1, while METH affects signaling by dopamine and other monoamines2. Although differing in their molecular targets in the brain and in some behavioral effects3,4,5,6, PCP and METH have been extensively studied for their ability to cause long-lasting cognitive deficits and mimic symptoms of schizophrenia7,8,9. However, the process by which they generate similar behavioral impairments has been unknown. Understanding shared neuronal mechanisms underlying drug-induced cognitive deficits could foster development of effective treatments and be beneficial for a spectrum of disorders10,11.
