Intellectual disability more common in families with substance use disorder
Children of a parent with alcohol or drug use disorder have a greater risk of intellectual disability, even if the problem only lies with the father, researchers from Karolinska Institutet in Sweden report. According to the study, which is published in the journal eClinicalMedicine, preventive measures should be directed at both parents.
It is well known that a woman’s alcohol consumption during pregnancy can increase the risk of her child developing an intellectual disability. Research from Karolinska Institutet now shows that all forms of substance abuse, both in the mother and the father, and not only during pregnancy, can constitute a risk factor.
Have mainly focused on mothers
“Preventative measures, such as educating healthcare professionals and public health recommendations, have focused for decades on mothers with alcohol-related problems,” says Lotfi Khemiri, researcher at the Departments of Medical Epidemiology and Biostatistics and Clinical Neuroscience, Karolinska Institutet. “Our findings highlight the importance of also directing such measures towards fathers with different types of substance use disorder.”
The study, which is based on data from Swedish registries, comprised almost two million babies born between 1978 and 2002 and their parents. The researchers found that 1.2 per cent of babies born to parents without such a disorder were diagnosed with an intellectual disability, compared with 3 per cent of the babies who had one parent with a diagnosis related to a substance use disorder (alcohol or drug abuse).
Higher risk before birth
The elevated risk was greater if the parent had received a diagnosis before or during pregnancy rather than after birth. A substance use disorder diagnosis registered before birth was associated with more than twice the risk of intellectual disability in the baby, regardless of which parent had the diagnosis. The correlation was weaker but still statistically significant after adjustment of socioeconomic factors and psychiatric comorbidity in the parents.
“Since it was an observational study, we can draw no conclusions about the underlying mechanism, but we suspect that both genetic and environmental factors, including harmful effects of substance abuse on foetal development, may play a part,” says Dr Khemiri. “We hope that the results will contribute to the preventative efforts, as well as to the improved diagnosis of children with an intellectual disability and to timely intervention directed both to the child as well as parents in need of substance use disorder treatment.”
Alcohol is a major risk factor
Intellectual disability was observed to be much more likely in alcohol-related problems during pregnancy, where the risk was five and three times higher depending on whether it was the mother or father who had the alcohol use disorder diagnosis.
The study was financed by several bodies, primarily Region Stockholm, Systembolaget (the Swedish government alcohol retail monopoly) and the Fredrik and Ingrid Thuring Foundation. Co-author and KI researcher Henrik Larsson has received research grants from Shire/Takeda and fees from Medice, Shire/Takeda and Evolan Pharma AB, although unconnected to this present study. All other researchers report no conflicts of interest.
Publication: “Parental substance use disorder and risk of intellectual disability in offspring in Sweden: a national register study”, Lotfi Khemiri, Ralf Kuja-Halkola, Henrik Larsson, Agnieszka Butwicka, Magnus Tideman, Brian M. D’Onofrio, Antti Latvala, Paul Lichtenstein, eClinicalMedicine, online 30 August 2023, doi: 10.1016/j.eclinm.2023.102170.
JOURNAL
EClinicalMedicine
METHOD OF RESEARCH
Observational study
SUBJECT OF RESEARCH
People
ARTICLE TITLE
Parental substance use disorder and risk of intellectual disability in offspring in Sweden: a national register study
Gene discovery nets FAU researchers U.S. patent for molecular approach to treat addiction
Invention by Randy D. Blakely, Ph.D. and Maureen Hahn, Ph.D., relates to fields of pharmacology, medicine, neuroscience and psychiatry
Business AnnouncementIMAGE: RANDY D. BLAKELY, PH.D., AND MAUREEN K. HAHN, PH.D., HAVE RECEIVED A PATENT FROM THE U.S. PATENT AND TRADEMARK OFFICE FOR A NOVEL METHOD TO IDENTIFY THERAPEUTIC AGENTS TO TREAT ADDICTION. view more
CREDIT: FLORIDA ATLANTIC UNIVERSITY
According to the Substance Abuse and Mental Health Services Administration, approximately 40 million people in the United States had a substance use disorder in 2020. In addition, over the last decade, the prevalence of opioid addition has increased to epidemic levels. Unfortunately, therapeutic interventions for the treatment of addiction remain limited.
Florida Atlantic University’s Randy D. Blakely, Ph.D., and Maureen K. Hahn, Ph.D., have received a patent from the U.S. Patent and Trademark Office for a novel method to identify therapeutic agents to treat addiction. The invention, related to the fields of pharmacology, medicine, neurology and psychiatry, targets the protein MBLAC1, which the Blakely lab identified as the mammalian form of a gene the group first identified in worms as a modifier of signaling by the neurotransmitter dopamine.
“The majority of drug addiction research has focused on dopamine signaling and how changes downstream of dopamine action eventually lead to compulsive drug seeking,” said Blakely, executive director of the FAU Stiles-Nicholson Brain Institute, the David J.S. Nicholson Distinguished Professor in Neuroscience, and a professor of biomedical science in FAU’s Schmidt College of Medicine. “However, we found evidence in the worm model C. elegans that a gene expressed in glial cells supports the health and function of dopamine neurons and suspected its actions in humans might also relate to addiction.”
Glia are non-neuronal cells in the brain and peripheral nervous system well known to support neuronal metabolism and the rapid transmission of impulses.
“We now know that glial cells support brain function in many more ways, including aspects of the plasticity and drug responses of nearby neurons. Dopamine neurons are no exception,” said Blakely.
Over the past two decades, the Blakely lab has utilized the simple but powerful worm model for its ability to yield insights into the genes and proteins that regulate dopamine signaling. In 2012, the group identified a new gene they named swip-10, as the loss of this gene produces “Swimming-induced paralysis” or Swip. DNA analysis of swip-10 revealed conserved sequences that comprise a Metallo-b-lactamase Domain (MBD), an element that was also found in an uncharacterized human gene termed MBLAC1.
“Metallo-b-lactamases are well known to microbiologists for the ability of bacteria to degrade antibiotics such as penicillin and thereby contribute to antibiotic resistance,” said Blakely. “However, in more complex organisms, MBD has been repurposed to digest many other molecules. So, we suspected that drugs targeting human MBD-containing proteins would likely have non-microbial effects, perhaps even medically relevant ones.”
Indeed, prior to the Blakely lab identifying swip-10, scientists studying addiction were learning that the beta-lactam antibiotic ceftriaxone could diminish several brain changes that arise with chronic use of addictive drugs. What they didn’t know was what protein ceftriaxone bound to in the brain. In 2018, the Blakely lab reported that the protein made by the MBLAC1 gene is a major, if not exclusive, target for ceftriaxone. More recent data from mice engineered to eliminate MBLAC1 protein expression demonstrate a requirement for the protein in the ability of cocaine to establish long-term behavioral changes that reflect brain alterations scientists believe contributes to the drug’s abuse liability.
Remarkably, the Blakely lab has discovered that loss of swip-10 also causes age-dependent neurodegeneration.
“We think these findings link to recent studies implicating MBLAC1 as a contributor to risk for certain forms of Alzheimer’s disease as well as the ability of ceftriaxone to display neuroprotection in animal models,” said Hahn, co-inventor on the patent and a research associate professor of biomedical science in FAU’s Schmidt College of Medicine. “We are very excited that what began as a simple genetic screen using worms may be leading us to insights into a number of different brain disorders.”
- FAU -
About Florida Atlantic University:
Florida Atlantic University, established in 1961, officially opened its doors in 1964 as the fifth public university in Florida. Today, the University serves more than 30,000 undergraduate and graduate students across six campuses located along the southeast Florida coast. In recent years, the University has doubled its research expenditures and outpaced its peers in student achievement rates. Through the coexistence of access and excellence, FAU embodies an innovative model where traditional achievement gaps vanish. FAU is designated a Hispanic-serving institution, ranked as a top public university by U.S. News & World Report and a High Research Activity institution by the Carnegie Foundation for the Advancement of Teaching. For more information, visit www.fau.edu.
Sahmyook University researchers identify genes associated with addiction to psychostimulant drugs
Researchers discover correlation between methamphetamine-induced behavior and the expression of specific genes in mice models lacking Period 2 gene
Peer-Reviewed PublicationIMAGE: A TEAM OF RESEARCHERS FROM SAHMYOOK UNIVERSITY DISCOVERED THAT MICE LACKING PERIOD 2 (PER 2), A GENE ASSOCIATED WITH CIRCADIAN RHYTHM, SHOW GREATER ADDICTIVE RESPONSES TO THE PSYCHOSTIMULANT METHAMPHETAMINE BUT NOT COCAINE, POINTING AT THE ROLE OF PER2 EXPRESSION IN GOVERNING AN INDIVIDUAL’S VULNERABILITY TO DRUG ABUSE. view more
CREDIT: HEE JIN KIM FROM SAHMYOOK UNIVERSITY, KOREA
Psychostimulant drugs like methamphetamine (METH) and cocaine (COC) affect the brain and nervous system by boosting alertness, attention, and energy levels of the individual. However, their persistent use results in drug addiction, compromising the life of the individual and burdening the healthcare, social, and legal systems as a consequence. In order to develop effective prevention and treatment strategies for drug addiction, it is critical to explore how these drugs interact with the nervous system and understand the mechanism underlying the addictive responses of individuals towards psychostimulants.
Interestingly, the gene Period 2 (Per2) has been linked with an increased tendency towards drug abuse. Per2 is associated with our circadian rhythms, our internal clock which regulates our sleep-wake cycle. Previous studies have reported that Per2 knockout (KO) mice, i.e., mice lacking the Per2 gene, show greater addictive responses and withdrawal symptoms towards METH compared to mice with normally functioning or overactive Per2. Accordingly, Per2 KO mice have been suggested as a potential animal model for understanding the molecular mechanisms underlying susceptibility towards drug abuse. However, its addictive responses to METH and other psychostimulant drugs like cocaine have not been examined as yet.
In order to bridge this gap, a group of researchers from Korea and Germany, led by Assistant Professor Hee Jin Kim from Sahmyook University compared how Per2 KO mice and wild-type (WT) mice, i.e., mice with Per2, responded to repeated self-administered doses of METH and COC. Their findings, made available online on 2 May 2023, were published in Volume 126 of the Journal Progress in Neuropsychopharmacology & Biological Psychiatry on 30 August 2023.
The researchers first investigated the motivational effect of these drugs and their impact on the locomotor activity of the mice using specialized tests. They noted that Per2 KO mice showed a stronger addictive response to METH when compared to the WT mice. However, when it came to drugs like COC, both groups of mice responded in a similar manner. Highlighting the importance of this observation, Dr. Kim exclaims, “The higher sensitivity of Per2 KO mice to METH rather than COC helped us deduce that different genetic factors were at play behind vulnerability to different drugs.”
Probing further, the researchers used a technique that identifies the coding sequence of an RNA–RNA sequencing–to pin down the genes involved in these addictive responses. They identified 19 genes that were only activated in response to repeated doses of METH but not COC. Using existing data, the researchers could correlate these genes with those that are activated in the region of the brain that responds to drug addiction.
Finally, to identify if any of the genes expressed due to METH exposure corresponded with METH-induced behavior, the researchers correlated the mRNA expression levels with the locomotor activity tests in Per2 KO and WT mice. They found that two specific genes, Arc and Junb, were expressed only in Per2 KO mice on METH exposure.
Highlighting their study’s findings, Dr. Kim says, “Our findings indicate that Arc and Junb, along with Per2, could be used as markers for susceptibility to METH abuse. If we are able to confirm the role of Arc and Junb expression in vulnerability to drug abuse, they could even be considered as potential targets for treating or preventing drug abuse.”
In summary, by unraveling the genetic factors that influence how our brains respond to psychostimulant drugs like METH and COC, researchers can pave the way for more targeted and personalized approaches to tackling drug abuse. In this regard, this study could open doors to the development of more effective diagnostic, preventive and treatment strategies, and potentially save countless lives.
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Reference
DOI: https://doi.org/10.1016/j.pnpbp.2023.110782
About Sahmyook University
Sahmyook University is situated at Seoul, Republic of Korea. It has a long history rooted in educational philosophy of cultivating intellectually, spiritually, and physically holistic beings. It hinges on a balance between innovation, global outreach and community service. SU’s ultimate goal is to transform students into agents of love and truth that make the world a better place. It has chalked out a detailed road map to effectively achieve this goal: first, become a leading university in the Seoul Metropolitan Area by 2020 and, second, becoming an internationally leading university in our own specialty areas.
Website: https://www.syu.ac.kr/eng/
About the author
Prof. Hee Jin Kim is an Associate Professor of Uimyung Research Institute for Neuroscience, School of Pharmacy at Sahmyook University, Korea. She received her PhD in Pharmacology from Sahmyook University in 2010. Her research group at Sahmyook University is participating in developing evaluation methods for drug dependency along with diagnostics for neurodegenerative diseases, including autism spectrum disorder.
JOURNAL
Progress in Neuro-Psychopharmacology and Biological Psychiatry
METHOD OF RESEARCH
Experimental study
SUBJECT OF RESEARCH
Animals
ARTICLE TITLE
The differential vulnerabilities of Per2 knockout mice to the addictive properties of methamphetamine and cocaine
