JNJ-10181457, a selective non-imidazole histamine H(3) receptor antagonist, normalizes acetylcholine neurotransmission and has efficacy in translational rat models of cognition.
ABSTRACT Histamine 3 (H(3)) receptors are distributed throughout the brain and regulate histamine as well as the activity of other neurotransmitters including acetylcholine (ACh). Impaired ACh neurotransmission is associated with deficits of cognitive-related functioning in many species including humans. The goal of these studies was to evaluate the behavioral and neurochemical effects of JNJ-10181457, a selective non-imidazole histamine H(3) receptor antagonist, in rats. The pharmacokinetic profile and receptor occupancy of JNJ-10181457 were tested. The efficacy of JNJ-10181457 was evaluated, acutely, in the imetit-induced water licking model, delayed non-matching to position (DNMTP) task and microdialysis studies. In addition, the effects of repeated administration of JNJ-10181457 were evaluated in the reversal learning task. A single administration of JNJ-10181457 (10 mg/kg, i.p.) resulted in significant plasma and brain exposure and maximal H(3) receptor occupancy. In addition, JNJ-10181457 reversed imetit-induced water licking, similarly to thioperamide (10 mg/kg, i.p.). In the DNMTP task, scopolamine (0.06 mg/kg, i.p.) significantly decreased percentage correct responding. These effects were significantly reversed by JNJ-10181457 (10 mg/kg, i.p.) and also by donepezil (1 mg/kg, i.p.), an acetylcholinesterase inhibitor, and were associated with normalization of ACh neurotransmission in the cortex. Repeated administration of JNJ-10181457 (10 mg/kg, i.p.) significantly increased percentage correct responding in the reversal learning task. Treatment discontinuation was not associated with rebound effects on cognition. These results indicate that selective blockade of histamine H(3) receptors might have therapeutic utility for the treatment of working memory deficits and learning disorders, especially those in which ACh neurotransmission is compromised.
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ABSTRACT: The role of histamine neurons in stress evoked cognitive impairments remains unclear. Previous research has indicated that the blockade of H(3)-type histamine receptors may improve attention and memory in naïve rodents. The purpose of this study was to determine if ciproxifan, (cyclopropyl-(4-(3-1H-imidazol-4-yl) propyloxy) phenyl) ketone, an H(3) receptor antagonist, could alleviate cognitive deficits observed in chronically stressed rats. Specifically, we attempted to characterize the preventive action of single dose of ciproxifan (3 mg/kg, i.p.) against an impairment caused by chronic restraint stress (2 h daily for 21 days) on recognition memory tested in an object recognition task and on the long-term memory tested in a passive avoidance test. We found that administration of ciproxifan potently prevented deleterious effects of chronic restraint stress, when administered prior to learning, or immediately after learning, or before retrieval on both the recognition (p<0.001) and the passive avoidance behavior (p<0.001). These data support the idea that modulation of H(3) receptors represents a novel and viable therapeutic strategy in the treatment of stress evoked cognitive impairments.Psychopharmacology 08/2013; · 4.06 Impact Factor
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ABSTRACT: 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.ResultsIn 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.Alcoholism Clinical and Experimental Research 05/2014; · 3.42 Impact Factor
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ABSTRACT: Histaminergic neurons are activated by histamine H3 receptor (H3R) antagonists, increasing histamine and other neurotransmitters in the brain. The prototype H3R antagonist thioperamide increases locomotor activity and anxiety-like behaviours; however, the mechanisms underlying these effects have not been fully elucidated. This study aimed to determine the mechanism underlying H3R-mediated behavioural changes using a specific H3R antagonist, JNJ-10181457 (JNJ). First, we examined the effect of JNJ injection to mice on the concentrations of brain monoamines and their metabolites. JNJ exclusively increased N(τ)-methylhistamine, the metabolite of brain histamine used as an indicator of histamine release, suggesting that JNJ dominantly stimulates the release of histamine release but not of other monoamines. Next, we examined the mechanism underlying JNJ-induced behavioural changes using open-field tests and elevated zero maze tests. JNJ-induced increase in locomotor activity was inhibited by α-fluoromethyl histidine, an inhibitor of histamine synthesis, supporting that H3R exerted its effect through histamine neurotransmission. The JNJ-induced increase in locomotor activity in wild-type mice was preserved in H1R gene knockout mice but not in histamine H2 receptor (H2R) gene knockout mice. JNJ-induced anxiety-like behaviours were partially reduced by diphenhydramine, an H1R antagonist, and dominantly by zolantidine, an H2R antagonist. These results suggest that H3R blockade induces histamine release, activates H2R and elicits exploratory locomotor activity and anxiety-like behaviours.Neuropharmacology 02/2014; · 4.11 Impact Factor