GABA a receptor density alterations revealed in a mouse model of early moderate prenatal ethanol exposure using [ 18 F]AH114726

• Published in: Nuclear medicine and biology 2020-09, Vol.88-89, p.44
• Main Authors: Nguyen, Van T, Bhalla, Rajiv, Cowin, Gary, Stimson, Damion H R, Song, Xin, Chong, Suyinn, Jackson, Alexander, Trigg, William J, Tieng, Quang M, Mardon, Karine, Galloway, Graham J, Kurniawan, Nyoman D
• Format: Article
• Language: English
• Subjects: Animals; Benzodiazepines - chemistry; Brain - metabolism; Central Nervous System Depressants - toxicity; Disease Models, Animal; Ethanol - toxicity; Female; Flumazenil - chemistry; Flumazenil - metabolism; Fluorine Radioisotopes - metabolism; Male; Mice; Mice, Inbred C57BL; Positron-Emission Tomography - methods; Pregnancy; Prenatal Exposure Delayed Effects - chemically induced; Prenatal Exposure Delayed Effects - diagnostic imaging; Prenatal Exposure Delayed Effects - metabolism; Prenatal Exposure Delayed Effects - pathology; Radiopharmaceuticals - metabolism; Receptors, GABA-A - metabolism; Tissue Distribution
• ISSN: 1872-9614

Prenatal ethanol exposure (PEE) has been shown to alter the level and function of receptors in the brain, one of which is GABA receptors (GABA R), the major inhibitory ligand gated ion channels that mediate neuronal inhibition. High dose PEE in animals resulted in the upregulation of GABA R, but the effects of low and moderate dose PEE at early gestation have not been investigated. This study aimed at examining GABA R density in the adult mouse brain following PEE during a period equivalent to the first 3 to 4 weeks in human gestation. It was hypothesized that early moderate PEE would cause alterations in brain GABA R levels in the adult offspring. C57BL/6J mice were given 10% v/v ethanol during the first 8 gestational days. Male offspring were studied using in-vivo Positron Emission Tomography (PET)/Magnetic Resonance Imaging (MRI), biodistribution, in-vitro autoradiography using [ F]AH114726, a novel flumazenil analogue with a high affinity for the benzodiazepine-binding site, and validated using immunohistochemistry. In vivo PET and biodistribution did not detect alteration in brain tracer uptake. In vitro radiotracer studies detected significantly reduced GABA R in the olfactory bulbs. Immunohistochemistry detected reduced GABA R in the cerebral cortex, cerebellum and hippocampus, while Nissl staining showed that cell density was significantly higher in the striatum following PEE. Early moderate PEE may induce long-term alterations in the GABA R system that persisted into adulthood.