Neurotransmitter switching is a form of neuroplasticity where exposure to external stimuli causes neurons to lose the expression of one transmitter and start expressing a different one. My thesis investigates neurotransmitter switching induced by beneficial and detrimental stimuli.One week of running (a beneficial stimulus associated with cognitive enhancement) decreases the number of neuropeptide Y (NPY)-expressing neurons and increases the number of vesicular glutamate transporter 1 (VGLUT1)-expressing neurons in the hippocampal dentate gyrus (DG). Using genetic mouse lines to permanently label NPY neurons, I tested whether the same neurons lose NPY and gain VGLUT1. Unlike wild-type mice, the genetic lines used displayed no transmitter change, demonstrating that transgenic lines can prevent DG transmitter switching. In contrast, treatment with phencyclidine or methamphetamine (detrimental stimuli associated with cognitive deficits) causes glutamatergic neurons in the prelimbic cortex (PrL) to reduce VGLUT1 and gain GABA expression. I tested whether neurogenesis contributes to this switch. No neurogenesis was detected in the PrL of drug-treated mice, supporting the conclusion that drugs induce PrL glutamatergic neurons to decrease VGLUT1 and gain GABA expression. Suppressing drug-induced hyperactivity of glutamatergic neurons in the PrL or dopaminergic neurons in the ventral tegmental area (VTA) prevents the glutamate-to-GABA switch. I tested whether silencing VTA dopaminergic neurons during drug treatment changes PrL activity and found that it does not. Finally, I tested if phencyclidine treatment altered neuronal transmitter expression in the ventrolateral orbitofrontal cortex (VLOFC), adjacent to the PrL. The VLOFC showed no glutamate-to-GABA switch, suggesting that phencyclidine’s effect may be PrL-specific.