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PERINATAL DRUG/ALCOHOL EXPOSURE AND NEURONAL SUICIDE PUBLIC HEALTH IMPLICATIONS
John W. Olney
Drug-Induced Neuronal Suicide in the Developing Brain
In a series of recent studies (1-5), it has been shown that several major classes of drugs, when administered
to immature rodents during the period of synaptogenesis, trigger widespread neuronal suicide throughout
the developing brain. The period of synaptogenesis, also known as the brain growth spurt period, occurs
in different species at different times relative to birth. In rats and mice it is a postnatal event, but in
humans it extends from the sixth month of gestation to several years after birth. Thus, it appears that there
is a period of several years, encompassing portions of both pre and postnatal human development, during
which immature neurons are prone to commit suicide if exposed to certain drugs that interfere with their
developmental program.
Converting Natural Neuroapoptosis into Pathological Neuroapoptosis
In the developing nervous system of all species, including humans, neurons live or die at the mercy of a
gene regulated program. For example, during synaptogenesis, the program requires that neurons form
synaptic connections and become integrated into complex neural networks; and, for any neuron that fails
to become properly integrated, the program dictates that it shall commit suicide (undergo “programmed
cell death”). Programmed cell death (currently referred to as “apoptosis”) is recognized as a natural
spontaneous process whereby redundant or unsuccessful neurons commit suicide and are deleted from the
developing brain. Under normal circumstances, only a small percentage of neurons are deleted by this
natural process.
The above scenario begs an important question - what happens if environmental factors intercede and
cause neurons to fail to make the appropriate connections? Presumably, this could cause large numbers of
neurons that would otherwise have survived, to receive a suicide signal, causing them to self-destruct and
be removed from the brain. In recent research, we are beginning to identify powerful environmental
factors that can act in this manner and cause millions of immature neurons to commit suicide, thus
converting a natural process for keeping the brain tidy, into a pathological process that rids the brain of
millions of neurons that were otherwise destined to become successfully integrated into the developing
nervous system and make positive contributions to its functional capacity.
Drugs that Trigger Neuroapoptosis
What types of drugs can cause developing neurons to commit suicide? Those that have been identified
thus far act by several different mechanisms but have a single property in common - they all suppress
neuronal activity. Four separate classes of drugs (NMDA glutamate antagonists, GABAmimetics, sodium
channel blockers, and alcohol) have been shown to trigger neuroapoptosis in the developing animal brain.
The activity level of a neuron is determined by the amount of excitatory versus inhibitory transmitter input
it receives. NMDA glutamate antagonists and sodium channel blockers reduce neuronal activity by
decreasing the amount of glutamate excitatory transmitter input; GABAmimetics reduce neuronal activity
by increasing the amount of GABA inhibitory transmitter input. Alcohol is unique in having both NMDA
antagonist and GABAmimetic properties. Thus, alcohol suppresses neuronal activity by a dual
mechanism, and this makes it particularly effective in triggering neuroapoptosis in the developing brain
(2, 4).
Under what circumstances might the developing human nervous system come in contact with these
apoptosis-promoting agents? Many drugs that trigger developmental neuroapoptosis in animal brain are
used as sedatives, anticonvulsants or anesthetics in obstetric and pediatric medicine, and many also are
drugs that are sometimes abused by pregnant women.
Alcohol
Alcohol deserves special consideration because of the frequency with which it is used/abused by pregnant
mothers, and because it is well established that alcohol can have serious deleterious effects on the
developing human brain (fetal alcohol syndrome, FAS) (6, 7). Although the devastating effects of alcohol
on the human fetal brain have been recognized for 3 decades (6), the mechanism(s) underlying these
effects have remained shrouded in mystery. The recent observation (2, 4) that a single alcohol intoxication
episode can cause millions of neurons to commit suicide and be deleted from the developing rodent brain,
provides a much more promising explanation than has heretofore been advanced, for the micro-encephaly
(reduced brain size) and lifelong neurobehavioral disturbances associated with FAS.
Other Drugs of Abuse
Alcohol, although the most frequently abused drug in human society, is not the only drug with apoptogenic
properties that is abused by pregnant women. Other examples, include phencyclidine (PCP, angel dust),
ketamine (Special K), nitrous oxide (laughing gas) and many drugs classified as barbiturates and
benzodiazepines. It is a common practice in a club drug setting to imbibe alcohol while abusing various
other drugs, such as ketamine. This seemingly harmless recreational behavior is ill advised for pregnant
women, because we have found in animal studies that alcohol, even at low doses, substantially enhances
the apoptosis-promoting activity of ketamine.
Use of Apoptogenic Drugs in Obstetric/Pediatric Medicine:
Numerous drugs that have recently been shown to trigger neuroapoptosis in the developing animal brain
have been used in obstetric and pediatric medicine for many years. These drugs are considered essential
for meeting the therapeutic needs of patients who are seriously ill, and there has not previously been any
basis for suspecting that they might quietly delete normal neurons from the developing brain.
Anesthetic Drugs
Obstetric and pediatric patients sometimes have to undergo complex surgical procedures that require
prolonged anesthesia. In essence, the nervous system must be put to sleep, sometimes for many hours, by
drugs that suppress neuronal activity. All drugs that have proven useful for this purpose are either NMDA
antagonists or GABAmimetics, and the most effective anesthetic protocols are based on the use of
multiple agents from each of these two categories. Thus, the most effective anesthetic drug protocols act
by the same combination of mechanisms as alcohol and, therefore, would presumably cause alcohol-like
effects in the developing brain. Consistent with this expectation, it was shown in a recent study (5) that
exposure of infant rats for a period of 6 hours to a combination of anesthetic drugs commonly used in
pediatric anesthesia, produced an alcohol-like pattern of neuroapoptosis throughout many brain regions,
and subsequent learning deficits that were demonstrable as the animals grew to adulthood.
Antiepileptic Drugs
The only known method for controlling epileptic seizure activity is to administer drugs that suppress
neuronal activity. Most antiepileptic drugs (AEDs) are either GABAmimetics or sodium channel
blockers. In a recent study (3), it was shown that AEDs in either of these categories trigger
neuroapoptosis in the developing rat brain, and that blood levels of AEDs required to induce
neuroapoptosis in the infant rat brain are in the same range as those required for effective anti-epileptic
therapy. In addition, it was found that combinations of AEDs, at doses in the therapeutic range, trigger
more severe neuroapoptosis than individual AEDs.
Threshold Conditions
Much of the developmental neuroapoptosis research performed thus far has addressed the question
whether various drugs, when administered in relatively high doses, can cause large numbers of neurons to
commit suicide. More recently we have begun addressing the more subtle question - what is the minimal
dose or duration of exposure required for a drug to cause a small but statistically significant number of
neurons to commit suicide.
In a study addressing this question for alcohol we found (9) that transient blood alcohol elevations
hovering in the 80 mg/dl range for approximately 60 minutes is a sufficient condition for triggering
apoptotic neurodegeneration at a significantly higher rate than occurs naturally in saline-treated control
animals. In a human context, a blood alcohol elevation of this magnitude would be produced by drinking
about 2 cocktails.
We have conducted a similar study pertaining to ketamine, which is both a drug of abuse and a drug used
frequently in pediatric medicine to provide sedation or for induction of anesthesia. In this study, we found
(10) that a single dose of ketamine that is sedating for an infant mouse, but does not render the animal
immobile or unconscious, triggers a significant increase in neuroapoptosis in several regions of the
developing brain.
Extrapolating from Rodents to Humans
Evidence documenting that drugs commonly used in obstetric or pediatric medicine can cause extensive
apoptotic neurodegeneration in the developing rodent brain raises the important question whether a
similar neurotoxic phenomenon occurs in the developing human brain following exposure to such drugs.
This is a very difficult question to answer conclusively, because if a similar phenomenon did occur in
humans the manifestations, except in extreme cases, would be subtle and would only become evident on a
delayed basis. To document that brain injury has occurred, one must rely largely upon epidemiological
evidence because, unlike the experimental animal situation, one cannot histologically examine the human
brain immediately after drug exposure to obtain unequivocal evidence that an increased number of
neurons are committing suicide. At the present time we do not have adequate epidemiological evidence
addressing this question and we consider it unwise to speculate based on the animal data presently
available. These data pertain only to rats and mice, and it is axiomatic that rodent data provide an
imprecise basis at best, and irrelevant basis at worst, for evaluating human risk.
An important reason for not prematurely extrapolating from rodents to humans in this particular case is
that rodents and humans have a very different developmental time scale. Disruption of synaptogenesis is
the proposed mechanism by which anesthetic drugs trigger neuroapoptosis. In rodents, synaptogenesis is
completed within a period of weeks whereas in humans it is completed within a period of several years.
Neurons are programmed to commit suicide if their synaptic mission is thwarted to some critical degree.
For the rodent neuron, perhaps 2 hrs of disruption exeeds the critical time limit, but for the human neuron
maybe the critical time limit is much longer, just as the life span and period of synaptogenesis is much
longer. This is a credible hypothesis, and fortunately it is a testable hypothesis, because there are other
species, including non-human primate species, that have substantially longer periods of synaptogenesis
than rodents. Obtaining an answer to this question is an important goal of currently ongoing research.
Every Cloud has a Silver Lining
We think it is likely that anesthetic drugs put neurons to sleep by one mechanism, and put neurons to
death by another. The mechanism by which neurons are put to death involves a chain of intracellular
biochemical steps which ultimately culminate in the activation of a suicide signal. If we can identify each
of the biochemical steps, it may be possible to develop blocking agents that intercede at one or more
critical step and halt the chain reaction before the suicide signal is activated. Therefore, it may be possible
to retain the therapeutic benefit of putting neurons to sleep (anesthesia), while selectively blocking the
mechanism by which anesthetic drugs accidentally activate a suicide signal that puts neurons to death.
Current research is aimed at identifying the steps that will have to be blocked in order to prevent the
suicide signal from being activated.
Developmental Neuroapoptosis and the Origins of Neuropsychiatric Disorders
We consider it likely that the developmental neuroapoptosis phenomenon we are studying may contribute
to a wide range of neuropsychiatric diosorders. We have observed for both alcohol and related
apoptogenic drugs that, depending on whether exposure occurs during the early, mid or late phase of
synaptogenesis, these agents trigger different patterns of neuronal deletion, and it follows that each pattern
of neuronal loss has the potential to give rise to its own unique constellation of neurobehavioral
disturbances. In a recent study by Ann Streissguth’s research group (7, 8) it was found that 72% of FAS
patients, after having experienced hyperactivity/attention deficit and/or learning disorders in childhood,
required psychiatric care for adult-onset disturbances, including a 44% incidence of major depression and
40% incidence of psychosis. Assuming that developmental neuroapoptosis was the mechanism by which
alcohol damaged the brains of these FAS patients, these finding document that this mechanism can give
rise to a wide spectrum of neuropsychiatric disorders.
It is currently believed that major psychiatric disorders have a genetic predisposition that may or may
not be expressed as a clinical illness, depending on the influence of relevant environmental factors. The
search for relevant environmental factors is an ongoing challenge being pursued in epidemiological
studies by psychiatric researchers such as Ezra Susser and colleagues. We believe that developmental
neuroapoptosis is an interesting phenomenon that may be able to shed new light on this problem. This is a
genetically driven phenomenon that normally does not cause unwanted deletion of neurons from the brain,
but if certain environmental factors intercede, it can result in the accidental deletion of large numbers of
neurons from many different brain regions. Animal studies are useful for identifying environmental
factors that can trigger developmental neuroapoptosis, but the eventual proof that such factors contribute
to human neuropsychiatric disorders must be established through research focused on human subjects.
Environmental factors identified thus far (and there may be many more waiting to be identified) seem to
trigger neuroapoptosis by interfering with the glutamate and/or GABA neurotransmitter systems.
Glutamate and GABA are ubiquitous neurotransmitter/neurotrophic systems that have vitally important,
but incompletely understood, roles in brain development. It is possible that many instances will be
discovered whereby either an aberrant genetic or environmental factor interferes with these glutamate or
GABA functions in the synaptogenesis stage of development. According to the evidence now unfolding,
if such interference occurs, it will silently drive neurons in large numbers to commit suicide and cause a
child to be born with neurobehavioral disturbances of occult origin that may manifest either in childhood
or adulthood, or both (8).
Ultimate Significance
We consider it likely that the significance of the developmental neuroapoptosis phenomenon we are
studying will eventually transcend the context of fetal alcohol neurotoxicity and drug abuse or iatrogenic
brain damage. We view this as a "final common pathway" type of mechanism which, regardless how it is
activated, has considerable potential to disrupt brain development and give rise to a wide variety of
neuropsychiatric disturbances.
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