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* Department of Anatomy, Indiana University School of Medicine, Indianapolis, Indiana 45202; Department of Human Anatomy & Medical Neurobiology, College of Medicine, Texas A&M University System Health Science Center, College Station, Texas 77843-1114; and Department of Cell & Developmental Biology & Anatomy, University of South Carolina School of Medicine, Columbia, South Carolina 29208
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Timothy A. Cudd, Texas A&M University, College Station, Texas
Michael D. Gershon, Columbia University College of Physicians and Surgeons, New York, New York
Charles R. Goodlett, Indiana University-Purdue University at Indianapolis, Indianapolis, Indiana
Steven R. Goodman, University of Texas at Dallas, Richardson, Texas
Gordon S. Mitchell, University of Wisconsin School of Veterinary Medicine, Madison, Wisconsin
Edward P. Riley, San Diego State University, San Diego, California
Michael T. Shipley, University of Maryland School of Medicine, Baltimore, Maryland
Peter J. Stambrook, University of Cincinnati College of Medicine, Cincinnati, Ohio
Kathleen K. Sulik, University of North Carolina School of Medicine, Chapel Hill, North Carolina
Joanne Weinberg, University of British Columbia Faculty of Medicine, Vancouver, British Columbia, Canada
James R. West, The Texas A&M University System Health Science Center, College Station, Texas
Feng C. Zhou, Indiana University School of Medicine, Indianapolis, Indiana
F. C. Zhou: Alcohol, like sugar, has been associated with every form of life since the beginning of evolution. Life forms depend on sugar to survive. Numerous mutations and selections through evolution have built this dependence into genes, so the tendency to seek sweetness does not require new learning, but is an engrained instinct. Since alcohol is not a commodity for survival, evolution has kept tenacious alcohol-seeking behavior through other means, such as pleasure. If the hedonic propensity does not eternally keep alcohol seeking in place, evolution has other layers of reinforcement, such as addiction. Alcohol addiction obviously prevails not only in humans, but also in many other life forms such as the monkey, pig, rodent, and fruit fly. Through mutations and selections in evolution, the "alcohol-preferring" trait may have been incorporated into genes of life, such as are exhibited in alcohol-preferring rats and C57 mice used in research.
As we learned today, excessive alcohol drinking not only affects individuals, but also their offspring. This is evident not only in humans, monkeys, sheep, and rodents, but also in amphibians like Xenopus. Since alcohol is preferred over, or even inseparable from, life throughout evolution, and alcohol affects many phyla of the animal kingdom throughout different stages of their development, alcohol must have fundamental and complex effects on the cell biology and genetics that control development as demonstrated by today’s speakers. I anticipate that you have many burning questions. With this, I turn the floor over to you for questions and discussion.
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K. K. Sulik: One way in which we have dealt with that issue is to use an in vitro system. Using whole-embryo culture, for example, we can create the same kinds of alcohol-induced abnormalities as are induced using in vivo systems. This indicates that maternal withdrawal is not responsible for causing the defects.
M. T. Shipley: How do you know that there aren’t the same consequences of withdrawal in the fetuses that would have occurred in the mother? What are the metabolic changes during withdrawal?
K. K. Sulik: At the early stages of embryonic development that we have studied, evidence of ethanol-induced cell death is evident within 6 to 8 hours and gene expression changes have been documented within 2 hours of maternal ethanol treatment. Others working with these model systems can see ethanol-induced changes in calcium concentrations within minutes. This time frame argues against withdrawal as a major player.
J. R. West: There are a couple of things that one can do. One can taper the alcohol and, if you do that, you prevent any precipitation of withdrawal symptoms. Another thing is to sacrifice the fetuses at the end of an initial period of alcohol exposure, before there is any chance of withdrawal before any symptoms are initiated.
C. A. Blake: I have a two-part question that might be addressed by Dr. Sulik or Dr. Riley. Parts of the inferior portion of the temporal cortex on one side of the body connect with similar areas on the other side by axons traveling through the anterior commissure rather than through the corpus callosum. The corpus callosum is considerably smaller in a number of individuals with FAS [fetal alcohol syndrome]. Is the anterior commissure smaller in individuals with FAS, particularly those who have a smaller corpus callosum? The second part of my question relates to the fact that some of the axons traveling through the anterior commissure are connecting the olfactory bulbs on both sides. Do these individuals have an impaired sense of smell in addition to visual and auditory problems?
K. K. Sulik: I’d like to address the issue of the anterior commissure, but I’ll defer to Ed on the sense of smell. I would expect the anterior commissure to be hit very hard. But I would guess that it has not been examined in MRI [magnetic resonance imaging] studies.
E. P. Riley: The smell question is under investigation. Some of the kids report a heightened sense of smell or being very responsive to odors. In general, they are overreactive. But when you look at thresholds, they seem to have deficits in thresholds.
M. T. Shipley: As in many fields, when one begins to assay the effects of some early event on behavior or brain function, one often begins looking at synaptic function. Are there neurons there, are they dying, are they synaptically interactive with each other? But another extremely important determinant of the behavior of neurons and how they respond to synaptic interactions is the constellation of intrinsic currents that the neurons possess: their channel properties. Depending upon the balance of channels and currents present in the neuron, their intrinsic firing rates may be extremely varied. So, my question is what do we know about the role of alcohol exposure during the fetal period on the expression of genes that encode channels that are relevant to neuronal function? Sodium channels, potassium channels, pick your flavor. And, how are these developmentally expressed in the embryo or developing brain and how do they impact ultimately on the behavior?
F. C. Zhou: Obviously, alcohol effects are very common in the nervous system at all phases, from neurogenesis to differentiation to neuronal deficits and on to the neuronal circuitry. Many of the neuronal behavioral deficits are really an overall global symptom of the circuitry problem. One of the examples is the serotonin system, which is affected from neurogenesis and neuronal maturation to forebrain innervation and transporter uptake. And, long-lasting serotonin system deficits have quite profound consequences for affected disorders, cognitive deficits, and other hyposerotonin neurobehavioral deficits. Other systems, such as the cholinergic system, are also among the targets. Today, we have less information on how receptor-and channel-mediated signal transduction are being affected in FAS.
C. R. Goodlett: If I might just add that there is not much known about the developmental regulation of ion channels in any of these systems relative to fetal damage. In Purkinje cells, Donna Gruol of the Scripps Institute has studied the development of Purkinje-cell cultures that have permitted analysis of channel functioning using patch clamp, and it’s clear that there are changes in calcium currents with alcohol exposure. One of my favorites is whether the GABA-A receptor may be changing in Purkinje cells in a way that may cause some of the cell death that we see. As you probably know, the developmental regulation of GABA-A in Purkinje cells changes from excitatory to inhibitory at the time in the neonatal period of enhanced vulnerability of Purkinje cells. It may be that alcohol could actually enhance GABA-A that is functioning as an excitatory channel at that point. And, it is clear that you can induce calcium spiking under those conditions, and that might be leading to some of the primary damage.
M. T. Shipley: It was interesting that the example you gave was serotonin because near and dear to my heart are a couple of neurons that we are studying currently in which serotonin acting on identical receptors modulate two very different currents in two cell types that are involved in the circuit. So, relatively subtle changes in the channel-density channel expressions that alter the currents in the cell are really going to alter the responsiveness of the cell transmitters and, therefore, how they operate in the system. So, I would only, of course, agree that looking at the influence of alcohol on channel properties would be an interesting area for future research.
F. C. Zhou: I agree.
G. S. Mitchell: I actually have a series of questions that I think will lead to a speculation. I was struck by two particular findings. One is that there is such a deficit in serotonergic function after fetal alcohol exposure. That, coupled with the cranial facial abnormalities, leads me to a speculation, and that speculation is that these kids that have had ethanol exposure during development may have a higher propensity for sleep-disordered breathing. If that is the case, it can lead to some very severe consequences. On the one hand, it can lead to death, possibly sudden infant death syndrome [SIDS]. On the other hand, a lot of neurocognitive deficits that sound a lot like has been described here today, learning disabilities, hyperactive symptoms, that kind of thing, are now known to be a consequence of sleep-disordered breathing. I have a series of questions that will take me through this. One is if the serotonergic system was affected, is it also affecting the caudal raphe nuclei? Raphe obscurus? Raphe pallidus? Is it a general effect on raphe neurons, or is it just the more rostral groups?
F. C. Zhou: Yes, it does affect the general ascending system as well as the descending system, as we have seen in our paradigm.
G. S. Mitchell: A deficit in serotonergic function is very highly associated with sleep-disordered breathing, particularly when it’s interacting with abnormal upper airways. So, one question I have for Dr. Sulik is: with these craniofacial abnormalities that are characteristic of FAS, is there a congenital narrowing of the airways that goes along with the other features that you talked about?
K. K. Sulik: I don’t think that anyone has really looked at that. You would expect that there would be a narrowing of the airways.
G. S. Mitchell: So, if you did, in fact, have narrowed airways, this may be a bit like inadequately bred bulldogs, which almost always snore because they have narrow airways due to the structure of the face. However, snoring is also, in part, a neural event. The neural event is probably deficient motor tone in the upper airway muscles that normally keep the airway open. With inadequate serotonergic function, you interrupt important forms of plasticity that may be involved in keeping those airways open. Has anyone looked at sleep-disordered breathing in these kids with FAS?
F. C. Zhou: There is a consortium study on SIDS that looked into the involvement of alcohol and the serotonin-1A receptor on infant sleep disorder with obstructed respiration, which causes sudden infant death. The cause of respiratory obstruction has a central component involving serotonergic neurons in the caudal raphe.
G. S. Mitchell: Right. So, there is a very strong association with alcohol, and there’s also a phenotype that Hannah Kinney at Harvard has identified. The one thing she can find is that babies that did die from SIDS had deficient serotonergic neurons in one form or another, at least the serotonin-1A receptor on those neurons is hypoexpressed. So, something is abnormal with the serotonergic system in babies that died from SIDS, consistent with observations after fetal alcohol exposure.
E. P. Riley: There is now a planning grant investigating the relationship between fetal alcohol syndrome and SIDS. It’s sponsored by NICHD and NIAAA. And, I don’t know anything about SIDS, but if you talk to the parents about sleep disturbances of these kids, it’s one of the biggest problems the parents encounter. They sleep for brief periods of time. They’re up every two hours.
G. S. Mitchell: Of course that [sleep disturbances] is a symptom of individuals with sleep-disorder breathing as well.
E. P. Riley: I don’t know of anyone who has brought them in to a sleep clinic to look at this.
G. S. Mitchell: So, fetal alcohol exposure could lead to SIDS as one possible outcome. But, there is another possible outcome of interest. David Gozal at the University of Louisville has shown that sleep-disordered breathing at critical developmental stages leads to profound neurocognitive deficits. For example, rats exposed to simulated sleep-disordered breathing, intermittent hypoxia, really have trouble finding their way in a Morris water maze, suggesting spatial learning deficits. Collectively, there seems to be a convergence of a lot of associated symptoms between FAS and sleep-disordered breathing.
J. R. West: If I may interject something. The other side of that is that we, in conjunction with Dave Earnest at Texas A&M, have found alterations in circadian rhythms. That’s something that can affect sleeping patterns as well.
C. R. Goodlett: Just to follow up because I was going to mention that as well. That’s a model system as well—a functional system of circadian rhythmicity that animal and human studies can go hand in hand. It’s fairly clear now from the current fetal alcohol research that the disruption of circadian rhythms is fairly robust, and it’s at the level of molecular regulation.
S. R. Goodman: I don’t work in your field so I apologize in advance for a naive question. In the animal-model studies, where does the field stand in terms of correlating the structural changes that you are showing to both genomic and proteomic changes at the same time?
K. K. Sulik: I think it is an area where we certainly need to do more. There have only been a few microarray studies that have looked at gene-expression changes that occur shortly after ethanol exposure. A problem inherent to the microarray technique is the difficulty in sorting out relevant information. However, developmental biologists are providing us with an enormous amount of information regarding patterns of gene expression. So, we can begin to correlate the known changes in gene expression as determined with microarrays to cells and tissues that are really sensitive or resistant to alcohol and their specific patterns of gene expression as illustrated by in situ hybridization techniques. This type of analysis should give us a good handle on genetic pathways that play important roles in ethanol-induced teratogenesis.
C. R. Goodlett: I want to make one other follow up to that point. Part of the problem with using so-called unbiased screening microarrays and proteomics in a developing system like this are that changes occur so quickly and you’ve got to do so many different time points to have any kind of handle on what you are doing, that I think it becomes untenable until you really know the system with some sense of what’s going on. And, that sort of defeats the purpose of doing microarrays. It’s not that it can’t be done, but it’s not like it’s being done in a mature nervous system, which is complex enough.
P. J. Stambrook: The question is actually addressed to Dr. Weinberg. I was intrigued by the concept of epigenetic changes that may occur as a consequence of fetal exposure to alcohol. One would predict that if one took a fetally exposed animal and then later crossed it with an animal that has not been exposed at all, the progeny would not have the same syndromes as the originally exposed parent. Is that correct? Secondly, if you now expose the second generation to alcohol, would you exacerbate the original effects or would they be synergistic, additive, or would the severity remain the same as that seen with the original exposure?
J. Weinberg: Those are great questions. Actually, in terms of the immune system, there is now some evidence that the effects of alcohol can be additive over generations. So, if you take the offspring who were exposed to alcohol in utero, let them grow up and then expose them to alcohol during pregnancy, the immune deficits in terms of T-cell function are worse. You see immune deficits in T-cell function in the first generation of the type I’ve been talking about, and they are worse in the second generation. So, at least in terms of immune function, there are some additive effects over generations. In terms of understanding how prenatal alcohol exposure causes long-term changes in the offspring HPA [hypothalamic-pituitary-adrenal] axis, what we think is happening is epigenomic mediation of effects. There are changes in gene expression, but not specifically in genes themselves. One model we’re working with is based on work of Michael Meaney, Moshe Szyf, and colleagues who have shown that differences in maternal behavior can serve as a mechanism for nongenomic transmission of differences in HPA function across generation. That is, maternal behavior appears to mediate long-term changes in the offspring’s HPA function throughout the life span. What they found is that a high level of maternal behavior, defined as maternal licking, grooming, and arched-back nursing, will actually produce offspring that have better-modulated HPA regulation. And, when they look at mechanisms, there appear to be two major mechanisms that mediate this long-term effect. The first is demethylation at one site of the glucocorticoid-receptor gene, which allows increased expression of glucocorticoid receptors themselves, and the second is increased histone acetylation, which allows increased access of transcription factors to the glucocorticoid-receptor gene. So that by changing methylation and histone acetylation, at least in their model of maternal behavior, there appears to be a long-term alteration in HPA regulation at the level of the glucocorticoid-receptor gene. We hypothesize that these same types of epigenomic mechanisms may be mediating the changes in HPA activity that we see in our animal model. In our case, it’s not a difference in mothering that is causing the alterations in HPA activity. It is alcohol that is the environmental agent that changes HPA regulation throughout the life span of the organism.
P. J. Stambrook: Just a quick follow up. Are those changes in glucocorticoid-receptor methylation, demethylation, histone demethylation generational?
J. Weinberg: For the Meaney-Szyf maternal behavior model, the answer is yes. That is, offspring of high-licking, grooming, nursing mothers become high-licking, grooming mothers themselves when they are mated. So, in their maternal behavior model, those effects are multigenerational and they seem to be at the level of gene expression. Whether that’s the case in our model of prenatal alcohol exposure we don’t know, but within the context of fetal programming, that’s one hypothesis of how we think these changes may be occurring.
C. A. Blake: A number of years ago, during the conduction of experiments in rats in which we were testing a variety of central nervous system–acting drugs on blocking the preovulatory surge of gonadotropins in blood during a described window on the afternoon of proestrus, we found that ethanol was very effective. However, the doses required to do this were very large and often associated with hemolysis showing up in the urine. While listening to some of the talks today, it seems that the doses of ethanol that some of you administered are very large. First of all, I wanted to ask whether you’ve experienced hemolysis in the rodents administered ethanol. Secondly, I wanted to ask if someone could discuss just how high the concentrations of ethanol are elevated in the blood in these experiments and in pregnant women who have FAS offspring and whether a one-time elevated exposure is more effective than maintaining reasonably high levels over a long period of time.
J. R. West: One of the things that we found in the laboratory that was probably more consistent than anything else was that peak blood alcohol concentration [BAC] was the best predictor of damage. In fact, we did some studies that showed that less alcohol could be more harmful than a greater amount, provided it is consumed over a shorter period of time to produce higher blood alcohol concentrations. The BACs that are produced in animal models are high. However, I gave a talk a few years ago in Austin to some recovering pharmacists and part of their treatment required that they listen to certain scientific talks related to drug abuse. I was talking about the amount of alcohol consumed by pregnant women that appeared in some case reports. Someone came up to me afterwards and said that a pint or a fifth of alcohol a day is not so much for an alcoholic to drink. One of the problems is there is a tremendous amount of behavioral tolerance that occurs. I’m reminded of a study that was done, I believe, in Pittsburgh back in the early ’80s by David Van Thiel’s group. They went into emergency rooms and got permission to take blood-alcohol levels from people who came in from accidents, from car wrecks to running over their foot with a lawn mower. They took blood levels from those who did not appear to be intoxicated. They found that the average BAC was almost 300 mg/dl and they had one or two that were the 400 to 500 mg/dl range and, not only were they walking in under their own power, but they did not appear to be intoxicated. So, that’s one of the problems when you’re talking about long-term alcoholics. They can acquire so much behavioral tolerance that they can reach just incredible high blood-alcohol levels.
J. Weinberg: I’ll just reemphasize that. Most of us working with rats are working with blood-alcohol levels in a range of about 50 mg% to 200 mg%. That’s about twice the drunk-driving level. So, that’s a high level, but it’s probably not the level you have in women who are producing children with FAS. They achieve blood-alcohol levels that would kill a naive person. We have heard descriptions of women who drink until they pass out and then wake up and keep drinking. Often, the incidence of FAS increases with each pregnancy because the level of alcoholism increases. So, the blood-alcohol levels used in these animal models are absolutely reasonable if you’re looking at models of fetal alcohol syndrome or even lower levels of alcohol exposure. They mimic that. They’re not outrageously high, although they would be outrageously high for a naive person taking one drink. So, if you’ve done an experiment where a single dose of alcohol results in hemolysis, then that probably is a very high dose for a first-time exposure. In a chronic exposure model, it would not be considered an excessively high dose.
M. D. Gershon: I wanted to make a point in regard to the use of animals. In one of your slides you pointed out that animal models are useful because they allow experiments to be carried out that would be ethically forbidden in humans. Now, I know exactly what you mean. And, I am thoroughly sympathetic with your meaning! However, the way you have phrased the point on your slide, I think, can get this entire field into grave difficulty.
T. A. Cudd: I beg your pardon. I should have said "not as limited."
M. D. Gershon: I think what you should say is there are different ethical considerations.
T. A. Cudd: Your point is well taken.
M. D. Gershon: As we all know, the barbarians are at the gate. The other thing I’d like to ask is the teaser was thrown out that 5HT agonists are now being thought of or investigated for use in therapy here. But, nothing was said further about what agonists and what the data were. I was wondering if someone could say something further about what you mean by that or what the theory is as to why it would work?
F. C. Zhou: The effect of serotonin 1A on development has been shown by two independent laboratories, including ours. Serotonin plays very interesting roles: one as a neurotransmitter throughout life, the other in signaling during development. Serotonin has a critical role in the development of the CNS. If there is a deficiency of serotonin during development, there would be cascaded deficiencies in forebrain development. The timing of arrival of serotonin innervation in the brain falls on a very specific window when serotonin 1A has its highest level of expression. This window is approximately between gestation Day 16 to postnatal Day 20 in mice and rats, and then it quickly subsides. So, one of the roles of the serotonin-1A receptor is that it has been implicated in mediating serotonin signaling to produce differentiation and maturation and even migrations of postmitotic neurons. We have shown that serotonin 1A is expressed immediately after the last division of neuroepithelial cells in forebrain. So, in FAS models where serotonin neurons are compromised, serotonin-1A agonists can be used to boost the reduced serotonin signaling. It has been shown now by Dr. Mary Druse that serotonin-1A ligand buspirone or isapirone can increase serotonin levels and uptake. We are also looking as whether 1A can boost the signaling of compromised serotonin on the development of their target neurons in the forebrain.
M. D. Gershon: With regard to serotonin, why pick one of a whole ton of serotonin receptors? The 5-HT2B is very involved in development in the periphery. It exerts developmental effects on neurons and other systems. Is there much known about the role played by SERT [the serotonin reuptake transporter] in development? SERT is the inactivator of serotonin.
F. C. Zhou: There are two transporter proteins. One is identified in the gut. The other is for serotonin neurons, as well as for the sensory neural systems.
M. D. Gershon: The one in the gut is exactly the same as the one in the brain. The same molecule is the serotonin transporter, SERT.
F. C. Zhou: The other I was referring to is the serotonin-binding protein. It has not been understood whether alcohol directly targets the serotonin-transporter protein. However, the transporter expression in the sensory system is affected by fetal alcohol exposure. The sensory system during development expresses serotonin transporter as a required mechanism for wiring, and only during the period when it makes synaptic connections. It has been shown that serotonin-transporter expression on sensory neurons was reduced. So, the uptake of the serotonin into sensory system is reduced in the fetal alcohol–treated mice, which would have potential consequences for sensory development. This paper just came out.
C. A. Blake: This question relates to the time of onset of parturition. Dr. Weinberg presented data to show in her model that the time of onset of parturition in the rat is delayed by about a half a day, and Dr. Cudd referred to the outdated process of infusing ethanol in women to delay birth. Then Dr. Weinberg presented evidence that the plasma ACTH and glucocorticoid concentrations were elevated in the model that she was using. One might predict that hypothalamic CRH [corticotropin releasing hormone] secretion might be increased by the elevations in blood-alcohol concentration despite the elevated glucocorticoid concentrations. However, this doesn’t tell us anything about what is going on with fetal CRH secretion. One might predict that alcohol stimulates its release as well. In humans, one of the prominent theories as to what causes birth centers on the fetus telling the mother when it is time to be born by the increased release of fetal CRH. This, in turn, releases fetal ACTH, which acts on the fetal adrenal cortex to release sulfated androgens that travel to the placenta where they are aromatized to estrogen. The estrogen then increases the production of prostaglandins that increase uterine contractions. In that scenario, one would expect advancement in the time of birth. Has any research been conducted to determine the mechanism by which alcohol delays parturition?
J. Weinberg: In terms of the HPA axis, there is a dual effect of maternal alcohol consumption on the offspring. There is a direct effect of alcohol on the fetal HPA axis, which is functional before birth, around Day 16 to 17 of gestation in the rat. So, alcohol can directly stimulate the fetal HPA axis. But, alcohol also stimulates the maternal HPA axis, and glucocorticoids can cross the placenta to some extent despite some enzymes that block them. Maternal glucocorticoids that cross the placenta have the effect of inhibiting the fetal HPA axis. So, you have this dual effect on the fetus. The Day 1 neonate has elevated levels of glucocorticoids and ACTH compared to controls, and no one has ever looked at CRH or CRH expression. During the stress-hyporesponsive period that follows birth, all pups show reduced stress responsiveness, but fetal alcohol–exposed pups show an even greater blunting of the corticoid stress response than controls. The HPA stress response then recovers to approximately normal levels shortly after weaning. From then on, however, alcohol-exposed offspring are hyperresponsive to stressors. So, there is a very complex multifactorial effect on fetal HPA. Why is parturition delayed rather than advanced? I don’t know the answer to that.
C. A. Blake: If the maternal glucocorticoids are elevated sufficiently and cross the placenta in substantial amounts to exert some effect on the developing negative feedback system in the fetus, the steroids could exert negative feedback on fetal CRH and ACTH and act to delay parturition.
T. A. Cudd: I just wanted to add that the reason people used intravenous ethanol infusions is because of the inhibitory action on oxytocin release [resulting in tocolysis]. Ethanol also inhibits vasopressin release, as we all know when we have to visit the restroom more frequently after drinking.
G. S. Mitchell: Serotonin, even in adults, is pretty potent in initiating and orchestrating neuroplasticity. In most cases, serotonin-dependent plasticity is highly pattern sensitive, episodic serotonin exposure being much more effective than continuous exposure. So, when these serotonergic drugs have been given, the serotonin agonists in particular, has any thought been given to using pulsatile administration versus continuous administration?
F. C. Zhou: It has not been looked into with much detail. As you know, the FAS model itself is very complex because of the patterns and the dose of alcohol exposure and the dynamic pace of the developing phase. So, the treatment studies are just beginning. It is certainly a good thing to keep in mind.
G. S. Mitchell: With a drug like 8-hydroxy-DPAT, which is 1A agonist, one of the expected effects is that it shuts down the raphe neurons. Therefore, every other serotonin receptor is probably downregulated in its function rather than upregulated. So, have other receptors been considered? Or is the 1A receptor really the most important one?
F. C. Zhou: Your guess is as good as mine. The serotonin-1A receptor, besides its effect on target neurons, is also an autoreceptor for serotonin neurons. The serotonin-1A agonist, which increases transmission of target neurons can, as a side effect, reduce serotonin release. However, there are drug companies investigating the second generation of 1A agonists, which will have differential effects on target neurons versus the serotonin neurons themselves.
C. R. Goodlett: I understand that one of the ideas behind the experiments on early development, as Mary Druse proposed, is that these agonists are actually acting on 1A receptors on astrocytes near the serotonin neurons and, thereby, stimulating the release of S100, and that’s the trophic support that’s being provided to the developing serotonin neurons.
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