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We have investigated the effect of the local activation of histamine H3 receptors (H3Rs) in the rat prefrontal cortex (PFCx) on the impairment of pre-pulse inhibition (PPI) of the startle response induced by the systemic administration of MK-801, antagonist at glutamate N-Methyl-d-Aspartate (NMDA) receptors, and the possible functional interaction between H3Rs and MK-801 on PFCx dopaminergic transmission. Infusion of the H3R agonist RAMH (19.8 ng/1 μl) into the PFCx reduced or prevented the inhibition by MK-801 (0.15 mg/kg, ip) of PPI evoked by different auditory stimulus intensities (5, 10 and 15 dB), and the RAMH effect was blocked by the H3R antagonist/inverse agonist ciproxifan (30.6 ng/1 μl). MK-801 inhibited [3H]-dopamine uptake (-45.4 ± 2.1%) and release (-32.8 ± 2.6%) in PFCx synaptosomes or slices, respectively, and molecular modeling indicated that MK-801 binds to and blocks the rat and human dopamine transporters. However, H3R activation had no effect on the inhibitory action of MK-801 on dopamine uptake and release. In PFCx slices, MK-801 and the activation of H3Rs or dopamine D1 receptors (D1Rs) stimulated ERK-1/2 and Akt phosphorylation. The co-activation of D1Rs and H3Rs prevented ERK-1/2 and Akt phosphorylation, and H3R activation or D1R blockade prevented the effect of MK-801. In ex vivo experiments, the intracortical infusion of the D1R agonist SKF-81297 (37 ng/1 μl) or the H3R agonist RAMH increased Akt phosphorylation, prevented by D1R/H3R co-activation. These results indicate that MK-801 enhances dopaminergic transmission in the PFCx, and that H3R activation counteracts the post-synaptic actions of dopamine.

Original publication




Journal article


Prog Neuropsychopharmacol Biol Psychiatry

Publication Date





Dopamine, Histamine, Histamine H(3) receptor, MK-801, Prefrontal cortex, Schizophrenia, Animals, Benzazepines, Dizocilpine Maleate, Dopamine, Dopamine Plasma Membrane Transport Proteins, Excitatory Amino Acid Antagonists, Histamine Agonists, Imidazoles, Male, Microinjections, Mitogen-Activated Protein Kinase 1, Mitogen-Activated Protein Kinase 3, Molecular Docking Simulation, Phosphorylation, Prefrontal Cortex, Prepulse Inhibition, Proto-Oncogene Proteins c-akt, Rats, Receptors, Histamine H3, Receptors, N-Methyl-D-Aspartate, Reflex, Startle, Tritium