Loss of striatal cannabinoid CB1 receptor function in attention-deficit/hyperactivity disorder mice with point-mutation of the dopamine transporter

Maura Castelli, Mauro Federici, Silvia Rossi, Valentina de Chiara, Francesco Napolitano, Valeria Studer, Caterina Motta, Lucia Sacchetti, Rosaria Romano, Alessandra Musella, Giorgio Bernardi, Alberto Siracusano, Howard H. Gu, Nicola B. Mercuri, Alessandro Usiello, Diego Centonze

Research output: Contribution to journalArticle

Abstract

Abnormal dopamine (DA) transmission in the striatum plays a pivotal role in attention-deficit/hyperactivity disorder (ADHD). As striatal DA signalling modulates the endocannabinoid system (ECS), the present study was aimed at investigating cannabinoid CB1 receptor (CB1R) function in a model of ADHD obtained by triple point-mutation in the dopamine transporter (DAT) gene in mice, making them insensitive to cocaine [DAT cocaine-insensitive (DAT-CI) mice]. DAT-CI mice had a marked hyperactive phenotype, and neurophysiological recordings revealed that the sensitivity of CB1Rs controlling GABA-mediated synaptic currents [CB1Rs (GABA)] in the striatum was completely lost. In contrast, CB1Rs modulating glutamate transmission [CB1Rs (Glu)], and GABA B receptors were not affected in this model of ADHD. In DAT-CI mice, the blockade of CB1R (GABA) function was complete even after cocaine or environmental manipulations activating the endogenous DA-dependent reward system, which are known to sensitize these receptors in control animals. Conversely, the hedonic property of sucrose was intact in DAT-CI mice, indicating normal sweet perception in these animals. Our results point to CB1Rs as novel molecular players in ADHD, and suggest that therapeutic strategies aimed at interfering with the ECS might prove effective in this disorder.

Original languageEnglish
Pages (from-to)1369-1377
Number of pages9
JournalEuropean Journal of Neuroscience
Volume34
Issue number9
DOIs
Publication statusPublished - Nov 2011

Keywords

  • CB1 receptor
  • D2 receptor
  • Endocannabinoids
  • EPSC
  • IPSC

ASJC Scopus subject areas

  • Neuroscience(all)

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