thiourea and Memory-Disorders

Histamine is a modulatory neurotransmitter regulating neuronal activity. Antidepressant drugs target modulatory neurotransmitters, thus ultimately regulating glutamatergic transmission and plasticity. Histamine H3 receptor (H3R) antagonists have both pro-cognitive and antidepressant effects; however, the mechanism by which they modulate glutamate transmission is not clear. We measured the effects of the H3R antagonist clobenpropit in the Flinders Sensitive Line (FSL), a rat model of depression with impaired memory and altered glutamatergic transmission.. Behavioral tests included the forced swim test, memory tasks (passive avoidance, novel object recognition tests), and anxiety-related paradigms (novelty suppressed feeding, social interaction, light/dark box tests). Hippocampal protein levels were detected by Western blot. Hippocampal plasticity was studied by in slice field recording of CA3-CA1 long-term synaptic potentiation (LTP), and glutamatergic transmission by whole-cell patch clamp recording of excitatory postsynaptic currents (EPSCs) in CA1 pyramidal neurons.. Clobenpropit, administered systemically or directly into the hippocampus, decreased immobility during the forced swim test; systemic injections reversed memory deficits and increased hippocampal GluN2A protein levels. FSL rats displayed anxiety-related behaviors not affected by clobenpropit treatment. Clobenpropit enhanced hippocampal plasticity, but did not affect EPSCs. H1R and H2R antagonists prevented the clobenpropit-induced increase in LTP and, injected locally into the hippocampus, blocked clobenpropit's effect in the forced swim test.. Clobenpropit's antidepressant effects and the enhanced synaptic plasticity require hippocampal H1R and H2R activation, suggesting that clobenpropit acts through disinhibition of histamine release. Clobenpropit reverses memory deficits and increases hippocampal GluN2A expression without modifying anxiety-related phenotypes or EPSCs in CA1 pyramidal neurons.

Topics: Animals; Antidepressive Agents; Anxiety; Behavior, Animal; Depression; Disease Models, Animal; Excitatory Postsynaptic Potentials; Glutamic Acid; Hippocampus; Histamine H3 Antagonists; Imidazoles; Long-Term Potentiation; Male; Memory Disorders; Patch-Clamp Techniques; Pyramidal Cells; Rats; Rats, Sprague-Dawley; Thiourea

Schizophrenia (SCZ) afflicts around 1% of the world's population with characteristic symptoms such as hallucinations, delusions, and cognitive disorders. Several experimental studies in the past have indicted brain histaminergic neuronal system involvement in the pathogenesis of psychotic disorders including SCZ. Present study investigates anti-schizophrenic activity using two histamine H(3)-receptor (H(3)R)-antagonists/inverse agonists, ciproxifan (3.0 mg/kg, i.p.) and clobenpropit (15 mg/kg, i.p.), on some of the established animal model of schizophrenia, for example, amphetamine (AMPH) and dizocilpine (MK-801)-induced hyperactivity, apomorphine (APO)-induced climbing behavior, scopolamine and MK-801-induced learning and memory deficits and haloperidol-induced catalepsy including determination of acetylcholinesterase (AChE) activity. Results of the present study demonstrate that ciproxifan and clobenpropitwere able to control AMPH and MK-801-induced hyperlocomotor activities demonstrated as reduced horizontal activity and reduced number of movements made by rats. Further, there was overall reduction in APO-induced climbing behavior. Learning and memory deficits, as evaluated on elevated plus maze, followed by estimation of brain AChE activity demonstrated positive results with these protypical imidazole H(3)R-antagonists/inverse agonists.

Topics: Acetylcholinesterase; Animals; Behavior, Animal; Brain; Catalepsy; Female; Histamine Antagonists; Imidazoles; Learning Disabilities; Ligands; Male; Memory Disorders; Mice; Motor Activity; Rats; Rats, Wistar; Receptors, Histamine H3; Schizophrenia; Thiourea

In the present study, we investigated the effect of imetit, a selective histamine H(3) agonist, on the improvement of NMDA receptor agonists in H(1) antagonist-induced working memory deficit and the decrease of hippocampal theta activity in rats. Pyrilamine (35 mg/kg, i.p.) impaired spatial memory and decreased hippocampal theta activity during the radial maze task. In addition, intrahippocampal injection of D-cycloserine (1 microg/side) and spermidine (10 microg/side) improved the pyrilamine-induced working memory deficit and the decrease of hippocampal theta activity. The improvement effects of D-cycloserine and spermidine were antagonized by intrahippocampal injection of imetit (10 microg/side). These results indicate that, the facilitation of neurotransmitter release from the presynaptic terminals besides direct stimulation of postsynaptic NMDA receptors take part in the improvements of NMDA receptor agonists on pyrilamine-induced spatial memory deficit and the decrease of hippocampal theta activity.

Topics: Animals; Cycloserine; Excitatory Amino Acid Agonists; Hippocampus; Histamine Agonists; Histamine H1 Antagonists; Imidazoles; Male; Maze Learning; Memory; Memory Disorders; Pyrilamine; Random Allocation; Rats; Receptors, N-Methyl-D-Aspartate; Space Perception; Spermidine; Theta Rhythm; Thiourea

This study was performed to investigate whether or not the histamine H3-antagonist clobenpropit can ameliorate spatial memory deficits induced by MK-801 (0.3 microg per site) as evaluated by an eight-arm radial maze task of rats. A bilateral intrahippocampal (i.h.) injection of clobenpropit (5, 10 microg per site, dose-dependent) markedly improved the working and reference memory deficits induced by MK-801. Its ameliorating effect was potentiated by histidine, but completely antagonized by immepip (2.5 microg per site), a selective H3-agonist. alpha-Fluoromethylhistidine (FMH, 25 microg per site), a selective histidine decarboxylase inhibitor prevented the ameliorating effect of clobenpropit on the working memory deficits induced by MK-801. In addition, the H(1-antagonist pyrilamine, but not the H2-antagonist cimetidine, also inhibited the procognitive effects of clobenpropit. Both FMH and pyrilamine did not significantly modulate the effect of clobenpropit on reference memory. Therefore, the results of this study suggest that the procognitive effects of clobenpropit in MK-801-induced working memory deficits is mediated by increasing endogenous histamine release. In addition, the ameliorating effect of clobenpropit on reference memory might be due to the increased release of neurotransmitters other than histamine.

Topics: Analysis of Variance; Animals; Dizocilpine Maleate; Dose-Response Relationship, Drug; Drug Interactions; Histamine Antagonists; Imidazoles; Male; Maze Learning; Memory Disorders; Piperidines; Rats; Rats, Sprague-Dawley; Spatial Behavior; Thiourea

The effect of histamine H3-receptor antagonist, clobenpropit (VUF9153) on spatial memory deficits induced by scopolamine was investigated in rats.. Eight-Arm radial maze performance was used to measure spatial memory in rats, and the brain regions were subsequently dissected and histamine contents were determined by HPLC.. Intracerebroventricular (icv) injection of clobenpropit (50 micrograms) ameliorated memory impairment induced by scopolamine in both parameters of radial maze performance. The amelioration induced by clobenpropit was antagonized by an H3-agonist, (R)-alpha-methylhistamine (5-10 micrograms). alpha-Fluoromethylhistidine (10, 20 micrograms), a histidine decarboxylase inhibitor, also effectively reversed clobenpropit-induced ameliorating effects.. The brain histamine H3-receptor antagonists are highly related to the spatial memory, and this action may be due to cholinergic neurons.

Topics: Animals; Brain; Histamine; Histamine Antagonists; Imidazoles; Injections, Intraventricular; Male; Maze Learning; Memory Disorders; Rats; Rats, Wistar; Scopolamine; Thiourea