Glutamate Signaling Reduced When Dopamine Neurons Fire Faster

A small cluster of neurons found in the midbrain use dopamine to send signals to neurons involved in many processes including motivation and attention.

Drugs of abuse such as amphetamine co-opt motivation by increasing dopamine signaling. When used excessively, the drugs can engender delusional thinking, as is seen in schizophrenia.

In contrast, the drugs used to treat schizophrenia block excess dopamine signaling. Recently it has been shown that dopamine neurons in the middle part of the midbrain release both dopamine and glutamate. The exact role of this dopamine neuron glutamate signaling has been difficult to find out.

Previous experiments involved genetically modifying dopamine neurons so that they would not release glutamate. However, this affected how the neurons develop, making it difficult to discern the effects of glutamate signaling.

Dopamine Neuron Signalling

Now, in genetically modified mice that have less glutaminase in their dopamine neurons than normal, Columbia University’s Susana Mingote and colleagues find that glutamate signaling is reduced only when dopamine neurons fire more rapidly. This did not change how dopamine neurons develop or how they use dopamine to signal.

ventral midbrain

Confocal mosaic z-projected image of the ventral midbrain showing TH (green, left) and PAG (magenta, right) immunoreactivity. Merged image (center) shows that some TH+ DA neurons co-express PAG (white).
Credit: Mingote et al, eLife

This reduction in dopamine neuron glutamate signaling affects two behaviors that are driven by the activity of dopamine neurons. First, it reduces the effects of a process called amphetamine sensitization, in which repeated doses of amphetamine increase dopamine neuron signaling so that events associated with drug use take up more attention than they normally would.

Second, the modified mice were better able to ignore familiar, irrelevant sounds in their environment; the mice continued to pay less attention to a familiar sound, even when it was paired with a shock and came to predict an unpleasant event – a process known as potentiation of latent inhibition.

Schizophrenia Treatment

The effects on both of these processes suggest that dopamine neuron glutamate signaling helps animals decide which features of their environment are most important.

This result suggests a new way of treating schizophrenia. When humans take amphetamine repeatedly, which produces sensitization, they can develop psychosis, a principal symptom of schizophrenia.

During a period of psychosis, thoughts and perceptions are disturbed, making it difficult to distinguish between relevant or irrelevant things in the environment. By reducing amphetamine sensitization and potentiating latent inhibition, blocking dopamine neuron glutamate signaling might help to treat the symptoms of schizophrenia.

Susana Mingote, Nao Chuhma, Abigail Kalmbach, Gretchen M Thomsen, Yvonne Wang, Andra Mihali, Caroline Sferrazza, Ilana Zucker-Scharff, Anna-Claire Siena, Martha G Welch, José Lizardi-Ortiz, David Sulzer, Holly Moore, Inna Gaisler-Salomon, Stephen Rayport
Dopamine neuron dependent behaviors mediated by glutamate cotransmission
eLife 2017;6:e27566

© 2017 eLife Sciences Publications Ltd. Republished via Creative Commons Attribution license.