In the current study we find support that variants at CNR1 are associated with ADHD and PTSD. The findings are similar to those of other investigations of this gene, in that they are of relatively small effect size, and do not replicate necessarily across samples. In the current study, we see support for an association of CNR1 and PTSD but findings require replication in larger samples. The failure to replicate across samples may reflect shared underlying constructs embedded in diagnostic classifications (e.g., emotional regulation difficulties) and/or inadequate power to detect small effect sizes. There may be an important role of gender in mediating the association of CNR1 and psychiatric illness, however, and future research needs to include a possible role of genotype by gender interactions.
ECs play an important role in neural plasticity, stress response, and learning and memory. CNR1
receptors are found in particularly high density in the hippocampus and amygdala, regions known to play a role in emotional regulation and memory, and regions suggested to play a role in ADHD [Plessen et al., 2006
], emotional regulation [Urry et al., 2006
], and other psychiatric disorders (e.g., bipolar, mood, anxiety disorders). They are found on axonal terminals of GABAergic inhibitory neurons containing neuropeptide cholecystokinin (CCK), a neuropeptide known to bind to CCKB
receptors and play a role in anxiety. ECs are known to increase CCK release and also have interactions with other neurotransmitter systems including dopamine [Price et al., 2007
] and serotonergic systems [Braida et al., 2007
]. Genes involved in dopamine and serotonin regulation have already been implicated in both ADHD [Kim et al., 2005
], anxiety and mood disorders [Hariri et al., 2006
] and are also associated with variation in hypothalamic-pituitary-axis (HPA) stress response [King et al., 1998
In rodents, endogenous cannabinoids have numerous influences on cognition and behavior as evident by the use of antagonists and agonists of cannabinoids. Agonists impair memory in rats, increase slow wave sleep and rapid eye movement sleep at the expense of wakefulness, impair prepulse inhibition, and recognition memory [Castellano et al., 2003
]. The specific mechanism of ECs and CNR1
activity in the brain are currently being delineated but it is well known that many psychiatric disorders, including ADHD, schizophrenia, PTSD, anxiety, and mood disorders have various memory and inhibition impairments. The potential involvement of reward systems in multiple psychiatric disorders, including ADHD, again suggests the plausible association of CNR1
and a range of conditions.
These data provide support for a putative role of endogenous cannabinoids in ADHD, and PTSD. The CNR1
gene may contribute to shared underlying risk continua, such as emotional dysregulation in response to stress, across these diverse diagnostic groups. Increased amygdala activity, poor stress reactivity as reflected by HPA response, and poor prefrontal cortical modulation is a plausible underlying mechanism of liability that may be shared across disorders. Recent imaging studies support amygdala and hippocampal differences in ADHD [Plessen et al., 2006
], studies of siblings of ADHD individuals support prefrontal-limbic circuitry differences as a putative endophenotypes [Durston et al., 2006
], and studies of stress response in ADHD support abnormalities in HPA axis responsivity [King et al., 1998
]. Taken together with the current findings, we suggest that this gene may be an important risk variant in the emotional regulation difficulties underlying ADHD, PTSD, and possibly other co-morbid conditions (such as mood disorder); however, the role of CNR1
is likely small, particularly at the level of psychiatric diagnosis, so future work using more refined phenotypes or endophenotypes of affect regulation are necessary.
The current findings require additional work and replication. Further investigation of affect related traits associated with ADHD may improve our understanding of the role the CNR1 gene may have in this condition and co-morbid disorders. Further refinement of putative DNA variants in CNR1 with functional outcomes is needed to delineate the causal variants contributing to psychiatric illness.