Drug-induced change in transmitter identity is a shared mechanism generating cognitive deficits

Abstract

Cognitive deficits are a long-lasting consequence 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, impair memory by causing the same glutamatergic neurons in the medial prefrontal cortex to gain a GABAergic phenotype and decrease their expression of the vesicular glutamate transporter. Suppressing drug-induced gain of GABA with RNA-interference prevents the appearance of memory deficits. Drug-induced prefrontal hyperactivity drives this change in transmitter identity. Normalizing the activity of prefrontal glutamatergic neurons after drug-exposure reverses the gain of GABAergic phenotype and rescues the associated memory deficits. Increased activity of dopaminergic neurons in the ventral tegmental area is necessary and sufficient to produce the change in transmitter identity. The results reveal a shared and reversible mechanism by which exposure to different drugs causes cognitive deficits.