Abstract
Substance abuse disorders are linked to alteration of circadian rhythms, although the molecular and neuronal pathways implicated have not been fully elucidated. Addictive drugs, such as cocaine, induce a rapid increase of dopamine levels in the brain. Here, we show that acute administration of cocaine triggers reprogramming in circadian gene expression in the striatum, an area involved in psychomotor and rewarding effects of drugs. This process involves the activation of peroxisome protein activator receptor gamma (PPARγ), a nuclear receptor involved in inflammatory responses. PPARγ reprogramming is altered in mice with cell-specific ablation of the dopamine D2 receptor (D2R) in the striatal medium spiny neurons (MSNs) (iMSN-D2RKO). Administration of a specific PPARγ agonist in iMSN-D2RKO mice elicits substantial rescue of cocaine-dependent control of circadian genes. These findings have potential implications for development of strategies to treat substance abuse disorders.
Highlights
Substance abuse disorders are linked to alteration of circadian rhythms, the molecular and neuronal pathways implicated have not been fully elucidated
Using combined metabolomic and transcriptomic approaches, we show that D2 receptor (D2R) in iMSNs contributes to cocaine-induced activation of peroxisome protein activator receptor gamma (PPARγ), a nuclear receptor implicated in inflammatory responses[30,31]
Circadian motor activity of iMSN-D2RKO mice was decreased with respect to WT mice in the active phase before (p < 0.0001) and after (p = 0.0004) cocaine administration (Fig. 1d, e), consistent with results obtained in non-circadian behavioral settings[27,29,33]
Summary
Substance abuse disorders are linked to alteration of circadian rhythms, the molecular and neuronal pathways implicated have not been fully elucidated Addictive drugs, such as cocaine, induce a rapid increase of dopamine levels in the brain. Administration of a specific PPARγ agonist in iMSN-D2RKO mice elicits substantial rescue of cocaine-dependent control of circadian genes These findings have potential implications for development of strategies to treat substance abuse disorders. Peripheral clocks are present in virtually all organs and cells within the body and recent findings have revealed that clocks communicate in order to achieve systemic homeostasis[5,6] Diverse environmental cues, such as feeding behavior, act as robust zeitgebers for peripheral clocks in metabolic tissues through mechanisms that appear SCN-independent[7,8]. Drugs of abuse have been shown to induce severe perturbation of circadian rhythms[10,11,12], such as disruption of the sleep/
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