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The necessity of social interaction make it a pressing target for possible therapeutic enhancement. Common conditions like autism, depression, and PTSD are all characterized in part by a depressed or reduced level of social interaction. The authors noted that Swiss mice showed extra sociability when given doses of acetaminophen (paracetamol, marketed in the USA as Tylenol).
To investigate this effect, they first hypothesized that other strains of mice might not have this effect because of “CB1 receptor-mediated inhibition of serotonin (5-HT) transmission” in areas of the brain that control social interaction. In order to test their hypothesis, they examined the effects of acetaminophen on “socially-deficient” mice against a cannabinoid agonist. The cannabinoid agonist was not found to increase sociability but acetaminophen did have a positive effect on social interaction, social novelty preference, and marble burying in socially-deficient mice.
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The authors conclude that modulating endogenous cannabinoids in the frontal cortex could potentially be useful for human sociability disorders or impairments, and the use of CB1 agonists could be useful for “treating repetitive behaviours”.
Rats generated to have abnormally low levels of social interaction were administered acetaminophen to gage whether the drug did have the effect of increasing sociability, as was shown in Swiss mice. A control of a cannabinoid agonist was used for the purposes of establishing the role of the cannabinoid system in the rats’ social interaction.
On the standard measures of social interaction, the normally socially-deficient rats were reported to have higher test results when administered with acetaminophen than the controls. CB1 agonists were shown to have no significant effect. This implies that acetaminophen upregulates 5-HT (serotonin) neurotransmission, leading to more social behaviors.
The mechanism by which acetaminophen achieves this effect is thought not to be through direct interaction with the CB1 receptors. Instead, a chain or cascade effect is promoted, activating CB1 receptors through a series of reactions. The interactions of acetaminophen are complex, and possibly involve the CB2 receptors, as well as vanilloid receptors.
It is clear that acetaminophen acts on 5-HT receptors for its analgesic effects, and the effects of endocannabinoids on the 5-HT system is explored elsewhere but they are thought to mediate and regulate some interactions of other neurotransmitters, as well as some of them directly binding to them. The exact interactions of these chemicals is still patchy.
Rat Models of Sociability Are Different from Humans
Rats have similar metabolisms and even arrangements of their brains but they are necessarily very different in their social interactions. While the standard models of social interactions do have some considerable overlap, it remains to be seen whether the sociability differences seen in this experiment will carry over to the much more complex social brain of a human.
The authors indicate that CB1 deficient mice have impaired social behaviors, something that was already known. However, this research highlights the importance of endocannabinoid receptors in the normal social functioning of brains. It is hoped that through interaction with the endocannabinoid system, tolerable and safe ways of increasing sociability and perhaps other important human characteristics.
Although this is preliminary data, it does strongly indicate the importance of the endocannabinoid system in social brain structures and interactions. That social interaction can be increased through administration of a simple and tolerable drug is hopeful for the potential treatment of autism, schizophrenia, post-traumatic stress disorder and depression.
However, until the exact mechanisms by which this effect is mediated, acetaminophen will not be used in this way. A lack of existing data from socially-deficient humans who take acetaminophen implies that it might be more complex in humans than for rats.