By Anand Gururajan
Autism and autism spectrum disorders (ASD) are neurodevelopmental psychopathologies affecting individuals across the lifespan and which have a significant burden on society. Current therapeutic strategies are mostly ineffective or have side-effect profiles which make their use problematic. However, one molecule which has shown promise for the treatment of social dysfunction associated with these disorders is the endogenous neuropeptide oxytocin and this is consistent with evidence in support of its role as the ‘social peptide’. However, another molecule which also influences social behaviour and has shown preclinical potential is the endogenous cannabinoid known as anandamide (AEA). Against this background, the research group led by Daniele Piomelli investigated interactions between the endocannabinoid system and oxytocin in the context of social reward.
AEA as a molecular mediator of social reward
Social interaction is an inherently rewarding process for humans unless of course you’re dealing with some people in the mornings before they’ve had their caffeine hit. This reward gained from interacting with conspecifics is also observed in rodents, which are just as social as human beings if not more. In their first experiment, the investigators isolated group-housed juvenile mice for 24 hours before returning them to their home cages or subjected them to an additional 3 hours of social isolation. They observed that in mice that were returned to their groups the levels of AEA increased in the nucleus accumbens (NAc), a region involved in motivation and reward processing, and the ventral hippocampus (vHIP), a region which regulates mood and social behaviour. C-fos activation increased in both the shell and core regions of the NAc in mice that were returned to their groups. Previous work by the Vanderschuren lab has shown that social reward was associated with increased AEA levels in the amygdala, which was not observed in this study. A possible explanation for this discrepancy, apart from the choice of species (rat vs. mouse), could also be the duration of the isolation period prior to testing. In the work by Vanderschuren and colleagues, isolation time was only 3.5 hours.
They then further studied the role of AEA as a mediator of social reward by using transgenic mice that were unable to produce fatty acid amide hydrolase (FAAH), the main enzyme responsible for AEA degradation. They used a social conditioned place preference testing paradigm which consisted of the following phases. In phase 1 (pre-conditioning), the test mouse was placed in a two-chambered box with different types of bedding on either side of a transparent divider. In phase 2 (conditioning), the test mouse was placed in a cage with its cage-mates with one type of bedding for 24 h and then placed in another cage on its own with the other bedding for 24 h. In the final phase (post-conditioning), the mouse was placed backed in the two-chambered box and preference for the type of bedding was determined. Results showed that faah-/- mice exhibited increased preference for the social bedding compared to wildtypes and interestingly, this phenomenon was not observed in other setups for the conditioned place preference test using food or cocaine. Social preference in faah-/- mice was blocked by treatment with a cannabinoid receptor antagonist.
Both faah-/- and wildtype mice showed similar results in the three-chambered social approach task. This effect of inhibiting AEA degradation on social preference was reproduced in wildtypes, which received systemic injections of a FAAH inhibitor during the conditioning trial but not the pre-conditioning trial. Notably, social approach as measured using the three-chambered task was the same for wildtype, URB-treated and faah-/- mice.
Social reward-induced release of AEA is regulated by oxytocin
In the second set of experiments, the authors studied the influence of oxytocin neurotransmission on AEA signaling specifically in the NAc. Systemic injections of an oxytocin receptor antagonist prevented the increase in AEA levels following social contact after the 24 h deprivation that were seen in the first experiment. Intracerebrovascular infusions of an oxytocin receptor agonist also increased NAc AEA levels but in the absence of any specific social incentive. The authors also showed that chemogenetic activation of oxytocin-secreting neurons in the paraventricular nucleus increased AEA in the NAc. In the last set of experiments, they showed that faah-/- mice were less sensitive to treatment with an oxytocin receptor antagonist in the social conditioned place preference test. Also, while treatment with the antagonist decreased c-fos activation in the shell and core regions of the NAc of wildtype mice following social contact (first experiment), it had no effect in faah-/- mice.
So overall, results from these experiments firstly confirmed the role of AEA as a mediator of social reward and secondly, that its release in this context is dependent on oxytocin neurotransmission in the NAc.
Oxytocin and endocannabinoid signaling
Endocannabinoids such as AEA are released on-demand from post-synaptic terminals and act on presynaptic cannabinoid receptors (CB1 or CB2) to modulate neurotransmission. In this regard, it has been reported that oxytocin induced presynaptic long-term depression of excitatory synaptic transmission on GABAergic medium spiny neurons (MSN) in the NAc, which could be achieved through retrograde action of AEA, released from post-synaptic terminals, on presynaptic CB1 receptors. Glutamatergic afferents to the NAc stimulate GABA release by MSNs, which in turn inhibit dopaminergic neurons in the ventral tegmental area. Thus, oxytocin-induced presynaptic long-term depression could indirectly disinhibit ventral tegmental dopaminergic neurons. However, as the authors point out, this explanation for how oxytocin regulates endocannabinoid signaling in the context of social reward behaviour will require refinement to take into account other molecular mediators of social reward such as serotonin as well as endogenous opioids .
While this is an interesting study, the results raise further questions. Firstly, inhibition of FAAH can lead to increased levels of N-acylethanolamines such as olealethanolamide and palmitoylethanolamide; what are their effects on social behaviour and reward? Secondly, how effective is FAAH inhibition in an animal model of autism? Prenatal exposure to the anti-epileptic drug valproate is known to induce an autistic-like behavioural phenotype which includes deficits in social approach but this model would need to be put through the social conditioned place preference paradigm to determine the effect of prenatal valproate exposure on social reward before determining the therapeutic benefits of treatment with a FAAH inhibitor. Thirdly, if increased AEA signaling is the main goal, how effective would the use of AEA transport inhibitors be? And lastly, are the side-effects associated with endocannabinoid modulation worse or better than treatment with oxytocin?
As a behavioural pharmacologist with a keen interest in the role of endocannabinoids in modulating mood and behaviour, I found this to be an important paper as it sheds light on a potential mechanism of action by which treatment with oxytocin exerts its therapeutic benefits on patients with autism and ASDs. But of course, larger scaled clinical trials and more thorough preclinical investigations will ultimately determine its transition from a candidate drug to one that is available in the dispensary.
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Anand Gururajan is a postdoctoral researcher in the Department of Anatomy & Neuroscience, University College Cork in Ireland. His current research focus is in the role of microRNAs in psychiatric disorders.