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Oxytocin Attenuates Amygdala Reactivity to Fear in Generalized Social Anxiety Disorder

?OXT ?s role could be to specifically modulate the amygdala under pathological rather than normal physiological states (eg, to reduce the processing of threatening social cues after the initial threat has been detected), as it would be undesirable to have a general dampening of the amygdala to all emotional cues? (2410)

1. What neuromodulatory effect does OXT have on the neurons in the amygdala (ie. As a neuropeptide, HOW would its presence increase or decrease activation in the region of interest?)

2. Propose an experiment to further investigate the apparent fear-specific attenuation of amygdala activity by OXT in GSAD patients (behavioral tasks, imagining, ect) Eg. how could you control for varied sensitivities to emotional recognition?

3. What effects might long-term administration of OXT have on the brain (good or bad?)

4. Only males were included in this study ? would you expect females to demonstrate different amygdalar activation? Would this be affected by hormonal cycles?

I thought the article presented an interesting new finding on the use of oxytocin as a means of treating social anxiety. The researchers claim that the reduced activation in the amygdale following exposure to fearful faces indicates that oxytocin has a modulatory, inhibitory effect on the neurons of the amygdala where a number of oxytocin g-protein coupled receptors are located.

An additional experiment to help further elucidate oxytocin?s role would be to condition patients with a mild shock when a tone is played for one group and condition another group to be exposed to a shock in response to various faces (sad, angry fearful). Ideally there would be both controls and patients with GSAD in both groups, and we could then conduct fMRI imaging before and after administration of intranasal oxytocin to determine relative activation in the amygdale. This would help determine if the reduced fear response in the amygdale is limited solely to face recognition or if it is a more general response to any sort of fear or stress stimuli.

It is difficult to say what precisely the effects of long-term oxytocin use could be. As a neuromodulatory chemical, it has an effect on a very widespread amount of systems so increasing the synaptic levels of oxytocin could cause a number of side effects from increasing arousal to potentially hindering memory. Additionally, it may be that some sort of compensatory mechanism would be engaged by continual influx of oxytocin (endocytosis of oxytocin receptors, decreased production of oxytocin, etc.) which could reduce its efficacy in treating GSAD.

As to why only males were used in this study, reading the abstract from the Domes paper referenced in the study, it appears that there is in fact significant difference in the response to oxytocin, with there actually being activation in the amygdala following exposure to oxytocin; this is of course the exact opposite of what is reported in males. It is possible that hormonal cycles might have something to do with the difference but as oxytocin cannot cross the blood-brain barrier, I?m not entirely sure what accounts for the observed difference ? perhaps different genes are enhanced or inhibited (oxytocin itself, its receptor, various enzymes that catalyze its formation, etc.) between the sexes.

As I looked up oxytocin, it became increasingly more clear of it's purposes and role. As research and data shows, oxytocin reduces anxiety and makes people more calm, effects that occur through activation or suppression n of the amygdala. The amygdala is activated in times of fear so if oxytocin is suppressing the fear or reducing anxiety, it is inhibiting activity in the amygdala.

As Drew said, pairing the faces with a mild shock may control the variables more. Many times this is done to lab rats and other animals being tested, specifically for fear, so this may have a similar effect on humans as well if used properly. This could also be applied to other senses such as a loud noise or a smell. These would connect fear to the olfactory and auditory systems, and help determine if they play a role in fear as well.

I imagine that the long term administration of oxytocin would do more harm than good. Though it may work in short periods of time in reducing fear and anxiety, things could be different in the long run. Perhaps the amygdala would become less sensitive to oxytocin and would then require more and more to be effective as the receptors in the amygdala could become desensitized. This would mean that those receiving oxytocin as a treatment would require higher doses and other complications could arise.

Since oxytocin primarily effects and is found in women, it is understandable why men were used in this experiment. They can receive oxytocin without getting the side effects that women get when oxytocin is present in their systems. Though it may not affect the amygdala in a different way, women may see other, unwanted effects. I am not sure if it would disrupt the hormonal cycle or have the hormonal cycle affect it, but there is that possibility. It seems that in most of the information presented about oxytocin, the effects are primarily affecting women, making it harder to conduct this test to see if the efficiency is the same.

Hannah and Drew have definitely hit the nail on the head when they explained that oxytocin suppresses anxiety via inhibiting the amygdala, among other neurophysiological processes. In fact, considering that oxytocin plays a large role in orgasms, we may be underscoring it by merely saying it has ?calming effects.? However, I?m slightly confused about oxytocin?s mechanisms of action in the central nervous system. I can visualize in my head (to some extent) the physiological role oxytocin acts out in lactation and orgasm, but what pathway does it follow to inhibit the amygdala as it cannot cross the blood-brain barrier (according to wiki). I?m a little frustrated with this, as oxytocin?s mode of action on the brain itself is consistently neglected in all the literature I can find (with the exception of its negative feedback roles on the hypothalamus).

This brings up another important point. While I feel oxytocin would initially reduce anxiety and fear in GSAD patients, I believe the hypothalamus would attempt to compensate for the excess foreign oxytocin in the system by reducing the pituitary and its production of this neuromodulator. Thus, patients sole source of OXY may eventually be this nasal spray in cases of extremely extended use. I would not be surprised if oxytocin?s target cells down-regulated its receptors as well.

I also agree with Hannah as to why women were not included in this study. To put it simply, to inject females with oxytocin would be fiddling with far more systems than just the limbic, its primary target in men. Our sex cycles, lactation, etc would all be thrown off. Additionally, this study paid large attention to subjects? mood changes. Women have a larger fluctuation in sex hormones throughout the month than males, to state the obvious, which consequently can affect female emotions. One could argue that including only males creates a better control in terms of mood.

Oxytocin, being a neuropeptide, cannot cross the phospholipid bilayer that forms the cell membrane. This means that it must have receptors on the extracellular side of the neurons of the amygdala to have an effect. As far as the effects that it has on the amygdala, it appears to act in an inhibitory manner since it reduces activity triggered in the amygdala by anxiety. Therefore, oxytocin is acting as a neuromodulator and modulating the activity in the amygdala by repressing the response it makes a little bit.

Drew's idea for an experiment controlling for varied sensitivities to emotional recognition seems very plausible to me: exposing both the "control" and experimental groups to the shock along with various stimuli would serve to eliminate the shock as the true "fearful" factor in the test, showing whether the amygdala lights up in response to generally fearful stimuli in patients with GSAD or whether it is just in recognition of fearful facial expressions. Hannah's idea of pairing auditory and olfactory stimuli also seems like a good idea to me in that it could further explore the role of other stimuli in GSAD, such as whether certain smells from one's memory might be linked to episodes of anxiety.

As far as long-term administration of intranasal oxytocin goes, I think it would not be a good idea. As much as it might help GSAD patients in the short term, my theory is that after a period of use, receptors for oxytocin on the amygdala might get downregulated to decrease its modulatory effect. The use of exogenous oxytocin might also cause the body to decrease or even cease altogether its production of natural oxytocin, making the user completely dependent upon the intranasal spray to keep their hormone levels in balance. Throwing off oxytocin levels in the body might also have downstream effects as well which, unless studied further, could prove to be extremely hazardous to the user. The endocrine system is not something to mess around with.

This being said, I believe this is why women were not included in the study. Women show more of a biological response to oxytocin in that it has a role to play in the birthing cycle as well as milk let-down during lactation, both processes that could be affected by use of exogenous oxytocin. Being more of a female sex hormone, I feel its effects on female users could be much more drastic and varied than in males simply because of the different chemical makeup of females. It could even have effects on mood and the menstrual cycle which I feel would not (in my case) justify use of the drug. As far as I'm concerned, the endocrine system is a very delicate system that works hard to keep itself in balance, and putting something "foreign" into the system such as exogenous oxytocin could have long-term effects that, early in such a study, could be hard to predict or observe. Because of this, only after extensive study would I say this drug could be used by male patients, and only after very long-term and all-encompassing studies would I consider okaying it for women.

OXT seems to have inhibitory on the neurons in the amygdala since it attenuates the hypersensitive fear response in patients with GSAD. However, it doesn?t seem to cause any difference in healthy controls, so it has a ?normalizing? effect rather than just completely inhibit.
To conduct a study on the neuromodulatory effect of OXT on the amygdala, I would use animal models. Create KO models for OXT receptors in the anterior amygdala. Measure their basal activity to fearful responses by giving a fearful stimuli and measuring heart rate, breathing, muscle responses etc? Then rescue the KO model by inducing downstream OXT activity in those regions and measure the physiological differences, compare all with control mice.
It?s not really known what over-expression of OXT would have on an organism; it will probably make them a very loving person. It is not evolutionarily advantageous to survival in wild conditions because fear is a tool that we developed in order to survive. If our ancestors tried to hug the sabertooth tiger in the wild, they probably wouldn?t last long enough to give us their genes. On the other hand, I guess it would be possible for prolonged OXT exposure in the brain to create some LTD in the corresponding amygdala regions. In women, perhaps it could create uterine contraction and sexual arousal problems.
It is known that vasopressin and oxytocin strongly modulate autonomic fear responses. In class, we learned that inducing vasopressin holds different effects for men and women. So I wouldn?t be surprised if Oxytocin also had different effects for men and women due to physiological differences. Women also have constant change in the balance of hormones in their bodies, since oxytocin is linked to pair bonding activity and maternal behaviors, perhaps there would be a fluctuation of oxytocin depending on what stage of the hormonal cycle the female is in at a certain point in time. However, a study done by Stock et. al. looking for the plasma levels of oxytocin during menstrual cycle found no significant differences. Overall though, It is much easier to conclude data from a group of subjects who do not have these potential unknown variables.

The discussion of the paper tackles the mechanism of oxytocin in the brain. Accoridng to this, activated oxytocin receptors stimulate gabaergic internuerons in the amygdala. Activation of these neurons by oxytocin normally serves to regulate the output of the central nucleus of the amygdala. In the case of GSAD, the amygdala is hyperactive, so an increase in oxytocin leads to an increase in GABAergic activation and therefore a decrease in the output of the amygdala resulting in normalizing the originally hyperactive amygdala.
What this experiment failed to do was isolate the difference between reaction to a neutral face and a fearfull/ angry face. Instead, the experiment used shapes as a control for the baseline of amygdala activity. I think for a more succesfull fMRI study, I would establish the baseline of facial recognition using a neutral face and then compare the results of amygdala activation with fearfull, angry, and happy faces. Everyone has contributed an experiment already that would provide further insight into the amygdala response to fearful expressions an I would like to agree to doing most of them. The biggest issue with the experiments involving social anxiety is accounting for the diffferences in emotional sensitivities. The only reasonable conclusion I can come up with for addressing this issue is to use a very large sample size that could potentially create a statistically valid average of amygdala activity in both normal individuals and people with GSAD.
Most people have said that they fear LTD of neurons or dependence on oxytocin levels, but this experiment seems to show that oxytocin has a normalizing effect on amygdala output. Downstream components, such as the LTP of GABAergic internuerons may balance out the sudden increase in oxytocin levels and allow for better self regulation, reducing hyperactivity of the amygdala. So I do not think that long term use of Oxytocin will have negative effects on the brain, but the mechanisms of action and self-regulation are unknown. Further studies will give us insight into the matter, but I think that synthetically increasing oxytocin levels will be beneficial in promoting normalization of amygdala function
The emotional state of males is more consistent than that of females. We do not use female rats for behavioural testing in our lab for the sole reason of inconsistent behaviour and data depending on hormonal cycles. I am not a woman, but I am dating one who responds drastically different to my facial expressions based on hormonal cycles. I would expect the amygdala, responding to recognition of different facial emotional cues, to react differently to threatening faces in a more inconsistent manner than male amygdala activation. I would argue that a woman may respond to a threatening face with higher amygdala activation due to the constant external threats faced by women on an day to day basis, such as the threat of physical violence from a male. While it may seem slightly politically incorrect to bring that point up, we have to face that we still live in a society where women feel threatened by physical violence from untrustworthy men by a much higher degree than men feel threatened by physical violence or rape. I would argue that this existence leads females to exist in a state of untrustworthiness that could be more severely effected by increasing oxytocin levels. This would be a large issue for accounting for emotional sensitivity. The main issue with using women in the study is the side effects that exist outside the amygdala.