Article

JNJ-10181457, a selective non-imidazole histamine H(3) receptor antagonist, normalizes acetylcholine neurotransmission and has efficacy in translational rat models of cognition

Johnson & Johnson Pharmaceutical Research & Development, L.L.C., San Diego, CA 92121, USA.
Neuropharmacology (Impact Factor: 5.11). 05/2009; 56(8):1131-7. DOI: 10.1016/j.neuropharm.2009.03.011
Source: PubMed

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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Available from: Brian Lord, Oct 13, 2014
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    • "The ability of ciproxifan, used to try overcome impairment evoked by exposure to prolonged stress or prolonged administration of GCs and to reverse negative influence of both factors on cognitive functions in the MWM and BM, observed in this study, may be related to the H3-mediated neurotransmitter release thought to contribute to the cognitiveenhancing effects of H3 antagonists, seen also in other models. For example, H3 antagonists have been shown to increase levels of ACh and DA in the prefrontal cortex [49] [50], ACh, DA, and NA in the anterior cingulate cortex [42] [51], and ACh in the hippocampus [50]. In contrary, it is known that chronic stress induced reduction of dopaminergic transmission in the prefrontal cortex [7]. "
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    • "The ability of ciproxifan to improve performance in the passive avoidance and object recognition tasks, observed in this study, may be related to the H3-mediated neurotransmitter release which was thought to contribute to the cognitiveenhancing effects of H3 antagonists, seen also in other models. For example, H3 antagonists have been shown to increase levels of ACh and DA in the prefrontal cortex (Fox et al. 2005; Galici et al. 2009), ACh, DA, and NA in the anterior cingulate cortex (Mizoguchi et al. 2001; Medhurst et al. 2007), and ACh in the hippocampus (Fox et al. 2005). On the contrary, it is known that chronic stress induces reduction of dopaminergic transmission in the prefrontal cortex (Mizoguchi et al. 2000). "
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    • "), quinine (15 and 30 mM) and sucrose (3%, w v -1 ) were dissolved in tap water. Injected drugs including alcohol [10–20% (w v -1 )], ciproxifan hydrochloride (Sigma-Aldrich, St Louis, MO, USA), JNJ-10181457 and JNJ-39220675 (both from Johnson & Johnson Pharmaceutical Research & Development, L.L.C., La Jolla, CA, USA; Bonaventure et al., 2007; Galici et al., 2009; 2011) were diluted with sterile 0.9% saline. All drug doses correspond to free bases. "
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