Leptin-endocannabinoids-dopamine dysfunction: The univeral link in the Sudden Infant Death Syndrome (S.I.D.S.) riddle?

"All truth passes through 3 phases: First, it is ridiculed. Second, it is violently opposed, and Third, it is accepted as self-evident."

Arthur Schopenhauer, 1788-1860

Sudden Infant Death Syndrome (S.I.D.S.) is the most common cause of death of infants under one year of age in developed countries. While its prevalence has significantly decreased with the "Back to Sleep" program instituted in the 1990s, no internal "cause and effect" abnormality in the infant brain has been discovered in SIDS infants. The riddle of SIDS involves consideration of many factors that predispose an infant to be more likely to die from SIDS, including stressors such as sleeping in a prone ("on the stomach") position. For three decades, the author believes the "reverse Trendelenberg position" decreases the likelihood of SIDS more than simply placing infants to sleep on their back...and the potential for the "flat head" syndrome is eliminated. See Sit to Survive or www.SitToSurvive.com.

Male infants, premature and low birth weight infants have a greater likelihood of dying from SIDS as well as infants who are borne to parents who have abused or continue to abuse tobacco, marijuana, cocaine, methadone, and heroin after the infant's birth. These abused substances are associated with pronounced dopaminergic neuronal activity in developing, actively remodeling infant, adolescent and adult brain reward/pleasure, appetite, arousal, and respiratory centers and systems. The number of neurons in the developing fetal and infant brain and peripheral nervous system expressing dopamine likely increases due to repetitive exposure to abused substances and other environmental factors associated with SIDS. The increased number dopaminergic neurons may arise de novo or result from a change in the type of neurotransmitter secreted by pre-existing neurons. As long ago as 1984, Canadian researchers (D.G. Perrin, M.D. Hospital for Sick Children, Toronto) discovered dopamine excess was found in two infants' carotid bodies who died of SIDS.

Much work has been done on brainstem arousal, respiratory and cardiovascular system etiologies with regards to SIDS. The author's review of the medical literature to date finds little information available regarding SIDS deaths due to abnormalities between leptin, endocannabinoids and dopamine. Can one define a "universal" link in the nervous system (central or peripheral nervous system, such as the carotid bodies) neurophysiologically that explains the diverse predisposing factors and conditions known to be associated with a higher likelihood of SIDS occurrence? Perhaps quantitative or qualitative abnormalities of interactions among CNS leptin, endocannabinoids and dopamine levels, bioavailability or activity is the universal link that causes SIDS at a certain developmental age of the infant nervous system (between one and six months of age)?

Leptin effects and endocannabinoid (anandamide) effects are inversely correlated. When leptin levels are high, as in the hypothalamus, regional anandamide activity is low. Low birth weight infants have lower levels of leptins than normal birth weight infants. One might suspect that endocannabinoid levels are higher in low birth weight infants. Low birth weight infants do not have normal adipose tissue mass and because leptin levels are positively correlated with adipose tissue mass, the paucity of adipose tissue in low birth weight infants directly correlates with a paucity of leptin in low birth weight infants. Since Afro-American infants have the highest infant mortality due to SIDS and also the highest percentage of low birth weights as compared to all other ethnic groups, low leptin levels iin low birth weight infants forebode a greater likelihood of Afro-American infants and other infants of low birth weight to die from SIDS.

Endocannabinoids are powerful appetite stimulants, esp. in marijuana users who "get the munchies", and in laboratory experimental models. Endocannabinoid activity in the CNS is mediated through interaction with a membrane bound receptor (CB1). Antagonists of endocannabinoids result almost 100% mortality in rodents, due to lack of suckling and feeding, when administered within 24 hours of birth. Obese rats lacking leptin receptor have higher levels of endocannabinoids than normal rats. If one assumes endocannabinoid levels are higher in low birth weight infants (because leptin levels have been demonstrated to be lower in low birth weight infants) or if CB1 receptor agonists (tetrahydrocannabinol, THC) are present in fetal and infant blood and brains of marijuana abusers, esp. marijuana smoking mothers who smoked during gestation and subsequently smoked marijuana while breastfeeding their infants, then excess endocannabinoid mediated anatomic, physiological or pharmacological effects at multiple fetal and infant CNS sites and systems have probably occured from early fetal CNS development to age 12 months of life.

So, if one assumes excess endocannabinoid system activity with the participation of excess dopaminegic CNS activity contributes significantly to the occurrence of SIDS, then are there preventative and interventional measures to be take to further decrease the likelihood of SIDS? Avoiding prenatal exposure to substance abuse is already recommended. Illicit drug use during breastfeeding is strongly discouraged. Attempts to decrease the number of pre-term and low birth weight infants are also helpful.

Excess Endocannabinoid Signaling: The root cause of Sudden Infant Death Syndrome?

But, can SIDS preventive measures, other than "Back to Sleep" and environmental control, be instituted in the majority of infants who die from SIDS whose mothers do not abuse tobacco, illicit substances, etc.? Perhaps the answer to further decreasing the number of SIDS deaths lies in preventing inappropriate overactivity of the endocannabinoid system and dopamine in defined "at risk" SIDS infants? Medications may be developed that affect endocannabinoid synthesis, metabolism, reuptake or degradation or beneficially affect neurotransmitter harboring neurons (serotonin) that may need to be augmented or facilitated to counteract inappropriate endocannabinoid system and dopamine overactivity. There is speculation that endocannabinoid system overactivity may directly or indirectly contribute to decreased levels of serotonin and tryptophan hydrolase in the brainstem of infants who die of SIDS. Solving the riddle of SIDS in developing nations is slowly making progress. A research oriented pursuit of an abnormal and dysfunctional leptin-endocannabinoid-dopamine interactive role in SIDS may well pave the road for a further significant decline of SIDS deaths globally.

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© Copyright, 2010. Byron L. Barksdale, M.D. All rights reserved worldwide.