Dopamine (DA) signaling is involved in a plethora of brain functions, including motor control, learning and
memory, and reward. It is affected by the psychostimulants amphetamine and cocaine, which are thought
to act by increasing the extracellular DA levels. In contrast to the extensive studies in neurons, the
involvement of astrocytes in DA signaling and psychostimulant actions remain largely unexplored.
Astrocytes play supportive roles in brain function, and they can also influence neuronal and synaptic
activity through the bidirectional communication with neurons in tripartite synapses. Astrocytes respond
with calcium elevations to several neurotransmitters (such as glutamate, acetylcholine, or
endocannabinoids), and release gliotransmitters that modulate synaptic transmission. However, whether
astrocytes respond to DA and consequently regulate neurotransmission remain largely unknown.
The present proposal aims to define the involvement of astrocytes in DA signaling in the nucleus
accumbens (NAc), a limbic area implicated in reward and addiction, and to identify the astrocyte
contribution to the actions of the psychostimulant amphetamine. We hypothesize that astrocytes participate
in the cellular mechanisms and functional consequences of DA signaling in the NAc and, as a
consequence, they contribute to the synaptic effects of amphetamine. Our preliminary results indicate that
DA activates astrocytes in the NAc, which stimulates the release of the gliotransmitter adenosine that
regulates excitatory synaptic transmission. The present proposal will: 1) define the cellular mechanisms
underlying DA control of the astrocyte activity in the NAc; 2) determine the consequences of DA-mediated
astrocyte activity on synaptic transmission; 3) determine the actions of amphetamine on both astrocytic
activity and astrocyte-mediated synaptic regulation.
We will use state-of-the-art techniques, including pharmacogenetics (“designer receptors exclusively
activated by designer drugs”, DREADDs), optogenetics to selectively stimulate dopaminergic axons,
simultaneous two-photon Ca2+ imaging and electrophysiological recordings, and transgenic mice.
The expected results will reveal astrocytes as cellular elements involved in DA signaling, thus contributing
to the effects of amphetamine. They will define the astrocyte-neuron interactions in the NAc at the cellular
level, paving the way for future studies recognizing astrocytes as elements involved in behaviors associated
with reward as well as psychostimulant drugs. If astrocytes are involved in DA signaling, and astrocyte-
neuron communication is affected by psychostimulants, this will reveal novel mechanisms that may serve
as therapeutic targets in motivation disorders such as drug addiction.