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.