Role of dopamine-glutamate receptor heteromers and downstream nuclear calcium signaling in addiction
Final Report Abstract
Drug addiction is defined as a compulsive pattern of drug-seeking and -taking behavior, with recurrent episodes of abstinence and relapse, and a loss of control despite negative consequences. This psychiatric disorder is linked to an imbalance of dopamine (DA) and excitatory glutamate (Glu) transmission in discrete brain regions, including the striatum. Most pharmacological treatments to alleviate addiction symptoms target DA or Glu receptors, but the progressive decay of efficacy and severe side effects call for alternative strategies. Prior to the funding period, consortium members identified the oligomerization of DA and Glu receptors as a central node for the development of responses to cocaine. Results obtained by the GLAD coordinator additionally showed that blocking DA and Glu receptor heteromers altered nuclear calcium signals in neurons, which we have previously identified to be instrumental in mediating adaptive responses to synaptic activation. On this background, our research group set out in this consortium to (1) better understand how DA and Glu control the transcriptional program engaged in striatal neurons during the development of long-term adaptations induced by drugs of abuse, and (2) decipher the role of nuclear calcium signaling in responses to drugs of abuse. We employed diverse approaches in vivo and in vitro to achieve these aims, including: analysis of animals’ behavioral responses to cocaine administration, gene expression analyses, virus-mediated expression of calcium indicators and inhibitors of nuclear calcium signaling or DA/Glu receptor oligomerization, virus-mediated manipulation of the expression of the transcription factor Npas4, calcium imaging, neuronal morphological analyses, and electrophysiology. In collaboration with partner P1, we found that synaptic activity of striatal neurons, which compute behavioral effects in response to drugs and in addiction, drives expression of the transcription factor Npas4 via a signaling cascade involving nuclear calcium signaling. Npas4 in turn determines the density of synaptic contacts onto these neurons and their firing rate, and controls behavioral responses to drugs of abuse. Our data additionally indicate that nuclear calcium signals evoked by the activation of DA/Glu receptor heteromers play a key role in molecular, cellular, and behavior adaptations to cocaine (manuscript in preparation). Together, these findings represent a significant breakthrough in our understanding of the cellular and molecular processes underlying addiction, and as such may contribute to the development of innovative strategies with therapeutic potentials to alleviate addiction symptoms.
Publications
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Npas4 regulates medium spiny neuron physiology and gates cocaine‐induced hyperlocomotion. EMBO reports, 22(12).
Lissek, Thomas; Andrianarivelo, Andry; Saint‐Jour, Estefani; Allichon, Marie‐Charlotte; Bauersachs, Hanke Gwendolyn; Nassar, Merie; Piette, Charlotte; Pruunsild, Priit; Tan, Yan‐Wei; Forget, Benoit; Heck, Nicolas; Caboche, Jocelyne; Venance, Laurent; Vanhoutte, Peter & Bading, Hilmar
