The endocannabinoid system misfires in ADHD mice (Commentary on Castelli et al.)

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Attention-deficit hyperactivity disorder (ADHD) is characterized by short attention span, hyperactivity and impulsiveness and affects both children and adults. Its social and economic significance can hardly be overrated, with a recent literature review estimating a worldwide prevalence of more than 5% (Polanczyk et al., 2007). With importance comes controversy, and the biological basis of ADHD, its diagnostic criteria and its treatments continue to divide opinions.

Neuroscientists have tackled ADHD at several levels. Brain imaging has revealed abnormalities in ADHD patients, particularly in the neural networks linking the frontal cortex to the basal ganglia (Cubillo et al., 2011). The genetic factors underlying ADHD are also being unravelled. Several lines of research point to an involvement of the dopaminergic system, and the dopamine transporter (DAT) in particular. DAT polymorphism is correlated with ADHD (Gizer et al., 2009). Intriguingly, abnormalities of the DAT and its pharmacology may explain the apparent paradox that stimulants such as amphetamine and methylphenidate (Ritalin), which inhibit DAT activity and increase extracellular dopamine, are effective (and widespread) treatments for ADHD symptoms.

Given these findings, the use of animal models of ADHD carrying mutations in the DAT gene holds great promise. In a study published in this issue of EJN, Castelli et al. (2011) used a knock-in transgenic mouse in which a mutant version of the DAT gene results in a protein that becomes insensitive to cocaine, while retaining at least in part its functionality (Chen et al., 2006). These DAT mutant mice are hyperactive and respond paradoxically to both cocaine and methylphenidate: these drugs, which induce hyperlocomotor states in normal mice, reduce motor activity in the DAT mutants (Tilley & Gu, 2008).

Castelli et al. (2011) focused on the endocannabinoid system in the striatum of these DAT mutant mice. There are good reasons to investigate in this direction. Dopamine promotes endocannabinoid release in the striatum (Yin & Lovinger, 2006) and striatal dopamine levels are elevated in DAT mutant mice.

In normal animals, striatal projection neurons release endocannabinoids in response to ionotropic and metabotropic receptor activation. Endocannabinoids then act as retrograde messengers, diffusing in the extracellular space and binding presynaptic CB1 receptors located on glutamatergic and GABAergic terminals. In both cases, this decreases neurotransmitter release.

Castelli et al. (2011) found that endocannabinoid signalling is dramatically impaired in DAT mutant mice. Surprisingly, the mice present a specific deficit of the endocannabinoid-mediated control of GABA release, while control of glutamate is unaffected. The potential implications of these findings are fascinating: the striatum, whose intrinsic circuits are mostly GABAergic, is involved in the action selection process (Kimchi & Laubach, 2009). Thus, the inability of striatal projection neurons to suppress inhibition may be directly linked to abnormal action selection – a cardinal feature of ADHD.

This is one of several changes induced by the mutated DAT gene in the striatal network, including those of dopamine signalling previously described by the same group (Napolitano et al., 2010). However, this is the first indication that the endocannabinoid-mediated control of synaptic inhibition may be selectively impaired in ADHD, and raises the possibility that drugs able to restore this process may prove effective in its treatment.

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