Prenatal Alcohol Exposure Increases Histamine H₃ Receptor-Mediated Inhibition of Glutamatergic Neurotransmission in Rat Dentate Gyrus

We have reported that prenatal alcohol exposure (PAE)-induced deficits in dentate gyrus, long-term potentiation (LTP), and memory are ameliorated by the histamine H₃ 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 H₃ receptor number and function.

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.

Radiohistochemical studies in adult offspring revealed that specific [³ H]-A349821 binding to histamine H₃ receptors was not different in PAE rats compared to controls. However, H₃ receptor-mediated G_i /G_o protein-effector coupling, as measured by methimepip-stimulated [³⁵ S]-GTPγS 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 H₃ receptor population without significantly altering the affinities of H₃ receptor subpopulations. In agreement with the [³⁵ S]-GTPγS 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.

These results suggest that a PAE-induced elevation in H₃ 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 H₃ receptor inverse agonists for ameliorating these deficits.