Differential effects of the histamine H(3) receptor agonist methimepip on dentate granule cell excitability, paired-pulse plasticity and long-term potentiation in prenatal alcohol-exposed rats.

BACKGROUND: We previously reported that prenatal alcohol-induced deficits in dentate gyrus (DG) long-term potentiation (LTP) are ameliorated by the histamine H3 receptor inverse agonist ABT-239. ABT-239 did not enhance LTP in control rats, suggesting that the possibility of a heightened H3 receptor-mediated inhibition of LTP in prenatal alcohol-exposed (PAE) offspring. METHODS: To further investigate this mechanism, we examined the effect of methimepip, a selective histamine H3 receptor agonist, on DG granule cell responses and LTP in saccharin control and PAE rats. Long-Evans rat dams voluntarily consumed either a 0 or 5% ethanol solution 4 hours each day throughout gestation. Adult male offspring from these dams were anesthetized with urethane and electrodes implanted into the entorhinal cortical perforant path and the DG. RESULTS: In control offspring, methimepip reduced the coupling of fast excitatory postsynaptic field potentials to population spikes (E-S coupling), the probability of glutamate release, as measured by paired-pulse ratio (PPR) and diminished DG LTP. Similar reductions in E-S coupling and LTP were observed in saline-treated PAE offspring. In contrast to the control group, methimepip did not exacerbate PAE-induced reductions in E-S coupling or LTP. CONCLUSIONS: While the effects of methimepip in control offspring were consistent with speculation of a PAE-induced enhancement of H3 receptor-mediated inhibition of E-S coupling and LTP, the absence of an added effect of methimepip in PAE offspring could indicate either an inability to further inhibit these responses with methimepip in PAE rats or the presence of more complex regulatory neural interactions with in vivo recordings in PAE rats. Follow-up studies of H3 receptor-mediated responses in DG slice preparations are under way to provide clearer insights into the role of the H3 receptor regulation of excitatory transmission in PAE rats.