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Prenatal Alcohol Exposure Increases Histamine H 3 Receptor‐Mediated Inhibition of Glutamatergic Neurotransmission in Rat Dentate Gyrus
Author(s) -
Varaschin Rafael K.,
Allen Nyika A.,
Rosenberg Martina J.,
Valenzuela C. Fernando,
Savage Daniel D.
Publication year - 2018
Publication title -
alcoholism: clinical and experimental research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.267
H-Index - 153
eISSN - 1530-0277
pISSN - 0145-6008
DOI - 10.1111/acer.13574
Subject(s) - dentate gyrus , endocrinology , medicine , histamine h3 receptor , histaminergic , long term potentiation , perforant path , hippocampus , biology , chemistry , receptor , neuroscience , histamine , agonist
Background We have reported that prenatal alcohol exposure ( PAE )‐induced deficits in dentate gyrus, long‐term potentiation ( LTP ), and memory are ameliorated by the histamine H 3 receptor inverse agonist ABT ‐239. Curiously, ABT ‐239 did not enhance LTP or memory in control offspring. Here, we initiated an investigation of how PAE alters histaminergic neurotransmission in the dentate gyrus and other brain regions employing combined radiohistochemical and electrophysiological approaches in vitro to examine histamine H 3 receptor number and function. Methods Long‐Evans rat dams voluntarily consumed either a 0% or 5% ethanol solution 4 hours each day throughout gestation. This pattern of drinking, which produces a mean peak maternal serum ethanol concentration of 60.8 ± 5.8 mg/dl, did not affect maternal weight gain, litter size, or offspring birthweight. Results Radiohistochemical studies in adult offspring revealed that specific [ 3 H]‐A349821 binding to histamine H 3 receptors was not different in PAE rats compared to controls. However, H 3 receptor‐mediated G i /G o protein–effector coupling, as measured by methimepip‐stimulated [ 35 S]‐ GTP γ S binding, was significantly increased in cerebral cortex, cerebellum, and dentate gyrus of PAE rats compared to control. A LIGAND analysis of detailed methimepip concentration–response curves in dentate gyrus indicated that PAE significantly elevates receptor–effector coupling by a lower affinity H 3 receptor population without significantly altering the affinities of H 3 receptor subpopulations. In agreement with the [ 35 S]‐ GTP γ S studies, a similar range of methimepip concentrations also inhibited electrically evoked field excitatory postsynaptic potential responses and increased paired‐pulse ratio, a measure of decreased glutamate release, to a significantly greater extent in dentate gyrus slices from PAE rats than in controls. Conclusions These results suggest that a PAE ‐induced elevation in H 3 receptor‐mediated inhibition of glutamate release from perforant path terminals as 1 mechanism contributing the LTP deficits previously observed in the dentate gyrus of PAE rats, as well as providing a mechanistic basis for the efficacy of H 3 receptor inverse agonists for ameliorating these deficits.