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

• Published in: The European journal of neuroscience Vol. 34; no. 9; pp. 1369 - 1377
• Main Authors: Castelli, Maura, Federici, Mauro, Rossi, Silvia, De Chiara, Valentina, Napolitano, Francesco, Studer, Valeria, Motta, Caterina, Sacchetti, Lucia, Romano, Rosaria, Musella, Alessandra, Bernardi, Giorgio, Siracusano, Alberto, Gu, Howard H., Mercuri, Nicola B., Usiello, Alessandro, Centonze, Diego
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.11.2011
• Subjects: Animals; Attention Deficit Disorder with Hyperactivity - genetics; Attention Deficit Disorder with Hyperactivity - pathology; Attention Deficit Disorder with Hyperactivity - physiopathology; Attention deficit hyperactivity disorder; Cannabinoid CB1 receptors; CB1 receptor; Cocaine; Cocaine - administration & dosage; Corpus Striatum - metabolism; D2 receptor; Disease Models, Animal; Dopamine Plasma Membrane Transport Proteins - genetics; Dopamine transporter; Dopamine Uptake Inhibitors - administration & dosage; Dronabinol - analogs & derivatives; Dronabinol - pharmacology; ECS; endocannabinoids; EPSC; Excitatory Amino Acid Antagonists - pharmacology; Food Preferences - physiology; gamma -Aminobutyric acid B receptors; Gene Expression Regulation - genetics; Glutamic acid; In Vitro Techniques; Inhibitory Postsynaptic Potentials - genetics; IPSC; Male; Methoxyhydroxyphenylglycol - analogs & derivatives; Methoxyhydroxyphenylglycol - pharmacology; Mice; Mice, Inbred C57BL; Mice, Transgenic; Motor Activity - genetics; Neostriatum; Nervous system; Neurotransmission; Perception; Point Mutation - genetics; Receptor mechanisms; Receptor, Cannabinoid, CB1 - genetics; Receptor, Cannabinoid, CB1 - metabolism; Receptors, GABA-B - metabolism; Reinforcement; Sucrose; Sucrose - administration & dosage; Sweet taste
• ISSN: 0953-816X; 1460-9568
• DOI: 10.1111/j.1460-9568.2011.07876.x

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 GABAB 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. 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].