1. PET Scan -Increased FDG uptake PET Scan -Decreased FDG uptake
Prenatal GABA modulation prevents metabolic derangements in drug exposed fetal brain.
Samarth Shukla MD1,2 , Sandra Scherrer3, Stergiani Agorastos3, David Orner3
Joseph Carrion3, Mohamed Ahmed M.D, Ph.D1,2,4, Stephen Dewey Ph.D3
1Cohen Children’s Medical Center of New York, New Hyde Park, NY and 2Lilling Family Neonatal Research Laboratory, 3Feinstein Institute for Medical Research, Manhasset, NY; 4Hofstra North-Shore LIJ School of Medicine, Hempstead, NY
Abstract
Introduction: Incidence of Neonatal Abstinence Syndrome (NAS) has significantly increased in past few years. Current approaches designed to treat NAS include replacement therapies that are associated with significant side effects and have addictive liability. Despite implementation of these treatments, the length of stay has not reduced.
Objective: 1) To evaluate the effect of prenatal GVG on cerebral metabolic derangements caused by prenatal exposure to narcotics.
2) To evaluate if chronic behavioral effects of prenatal narcotic exposure can be prevented by prenatal GVG.
Method: 1) Pregnant rats, starting from gestation day 2 were divided into morphine and saline groups. They continued to receive this therapy daily throughout gestation. The Morphine group either continued to receive morphine only, or received GVG for last five days of gestation in addition to morphine. Pups were allowed to grow up to 4 weeks of life when functional brain PET scans were performed using FDG marker. PET images were analyzed for increased and decreased FDG uptake. Images from saline, morphine and morphine+GVG groups were then compared.
2) For behavior analyses, same experiment was repeated replacing morphine with methadone. At 4 weeks of life, open field behavior testing was performed for 30mins. Average distance travelled for each group was calculated and averages for each group were compared with each other.
Results: On comparison to saline group, Morphine group showed increased FDG uptake in Infralimbic cortex, Nucleus Accumbens, Cingulate cortex (p<0.01). However in morphine+GVG group, the infralimbic cortex was not affected (p<0.01).
On comparison to saline group, Morphine group showed decreased FDG uptake in Superior colliculus and parts of hippocampus (p<0.01). Superior colliculus was not affected in morphine+GVG group.
On behavior analyses at adolescent age, methadone group showed increased mobility. However, this effect was not seen in methadone+GVG group.
Conclusion: Prenatal administration of GVG to morphine dependent pregnant rats prevents narcotic induced damage to areas of brain that cause visual deficits and inhibition of emotions like fear.
Narcotic exposed pups at adolescent age show increased mobility. This long term behavioral effect of narcotic exposure can be prevented by prenatal GABA modulation.
Background
Between 2000 and 2009, the incidence of NAS increased from 1.20 to 3.39 per 1000 hospital births per year (p<0.001).1
Neonatal opioid exposure has been correlated with a higher incidence of poor neurodevelopmental outcomes, cognitive delays, and behavioral concerns in adolescence2.
Replacement therapies with drugs like methadone and morphine are associated with sedation, feeding difficulties, nausea, vomiting and respiratory depression3 , and have not reduced length of stay.4,5
In recent years, GABAergic drugs have shown promise in treatment of drug withdrawal.6,7
Vigabatrin/Gamma-vinyl-GABA (GVG) is an irreversible inhibitor of GABA transaminase and increases the level of GABA in brain.
In prior studies, we showed that prenatal administration of GVG to morphine dependent pregnant rats attenuated neonatal withdrawal behavior.
Methods
At 4 weeks of life (adolescent age), functional brain PET scans were performed using FDG marker.
PET images were analyzed for increased and decreased FDG uptake using PMOD.
Images from saline, morphine and morphine+GVG groups compared using SPM programs.
For behavior analyses, same experiment was repeated replacing morphine with methadone at 7mg/kg.
At 4 weeks of life, open field behavior testing was performed for 30mins.
Each video was analyzed by Noldus Ethovision Video Tracking software.
Average distance travelled for each group was calculated.
Averages of each group compared with each other by Student’s t-test.
Results
Infralimbic cortex and superior colliculus that are affected in Morphine group are not affected in the MGVG group.
Infralimbic cortex inhibits emotions like fear.
Superior colliculus is involved in visual pathway and attention drifts.
Nucleus accumbens, Cingulate cortex and parts of hippocampus are affected in morphine group and they continue to be affected in morphine+GVG group.
Behavior Analyses
Results
PET Scan -Increased FDG uptake
Saline Vs. Morphine Morphine group showed increased FDG uptake in Infralimbic cortex (p<0.01)
Morphine Vs. MGVG The infralimbic cortex was not affected (p<0.01)
Objective
To evaluate the effect of prenatal GVG on cerebral metabolic derangements caused by prenatal exposure to narcotics.
To evaluate if chronic behavioral effects of prenatal narcotic exposure can be prevented by prenatal GVG.
Conclusions
GVG prevents narcotic induced damage to areas of brain that cause visual deficits and inhibition of emotions like fear.
Narcotic exposed pups at adolescent age show increased mobility.
This long term behavioral effect of narcotic exposure can be prevented by prenatal GABA modulation.
Methods
Pregnant rats (GD2)
Control Group (n=3, pups=15)
-Saline, s.c, daily
Morphine only (n=3, pups=15)
-Morphine, increasing dose from mg/kg
-s.c, daily
Morphine+GVG (n=3, pups=16)
-GVG at 50mg/kg
-s.c, daily, last 5 days of gestation
PET Scan -Decreased FDG uptake
Saline Vs. Morphine
Morphine group showed decreased FDG uptake in Superior colliculus (p<0.01)
Morphine Vs. MGVG
The superior colliculus was not affected (p<0.01).
References
Patrick et al; JAMA, 2012.
Irner; Child Neuropsychology, 2012.
Neofax; 2013
Hudak et al; Pediatrics, 2012
Lainwala et al; Advances in Neonatal Care, 2005
Salehi et al; Journal of Clinical Psychopharmacology, 2011
Zullino et al; Drugs Today, 2004