The H3 antagonist, ciproxifan, alleviates the memory impairment but enhances the motor effects of MK-801 (dizocilpine) in rats

Abstract

Summary Antagonists of H3-type histamine receptors exhibit cognitive-enhancing properties in various memory paradigms as well as evidence of antipsychotic activity in normal animals. The present study determined if a prototypical H3 antagonist, ciproxifan, could reverse the behavioral effects of MK-801, a drug used in animals to mimic the hypoglutamatergic state suspected to exist in schizophrenia. Four behaviors were chosen for study, locomotor activity, ataxia, prepulse inhibition (PPI), and delayed spatial alternation, since their modification by dizocilpine (MK-801) has been well characterized. Adult male Long-Evans rats were tested after receiving a subcutaneous injection of ciproxifan or vehicle followed twenty minutes later by a subcutaneous injection of MK-801 or vehicle. Three doses of MK-801 (0.05, 0.1, & 0.3 mg/kg) increased locomotor activity. Each dose of ciproxifan (1.0 & 3.0 mg/kg) enhanced the effect of the moderate dose of MK-801, but suppressed the effect of the high dose. Ciproxifan (3.0 mg/kg) enhanced the effects of MK-801 (0.1 & 0.3 mg/kg) on fine movements and ataxia. Deficits in PPI were observed after treatment with MK-801 (0.05 & 0.1 mg/kg), but ciproxifan did not alter these effects. Delayed spatial alternation was significantly impaired by MK-801 (0.1 mg/kg) at a longer delay, and ciproxifan (3.0 mg/kg) alleviated this impairment. These results indicate that some H3 antagonists can alleviate the impact of NMDA receptor hypofunction on some forms of memory, but may exacerbate its effect on other behaviors.

Differential effects of histamine H3 receptor inverse agonist thioperamide, given alone or in combination with the N-methyl-d-aspartate receptor antagonist dizocilpine, on reconsolidation and consolidation of a contextual fear memory in mice

“…If such an interaction has not been reported previ- ously for reconsolidation, it has also been demonstrated for other memory phases like acquisition, retrieval and working memory in a variety of tasks (Chen et al, 1999;Orsetti et al, 2001;Huang et al, 2003Huang et al, , 2004Nishiga and Kamei, 2003;Bardgett et al, 2009Bardgett et al, , 2010.…”

“…There is also convincing evidence for a deep participation of histamine in the mechanisms of learning and memory (Haas et al, 2008;Benarroch, 2010;Berlin et al, 2011). More precisely, an increasing number of recent animal-model studies using not only classical imidazolebased but also several newly-synthesized non-imidazole histamine H 3 inverse agonists strongly suggest a promoting action of histamine release in several processes or aspects of learning and memory, like working memory, reference memory, acquisition or retrieval/recall (Huang et al, 2004;Gemkow et al, 2009;Bardgett et al, 2010;Brioni et al, 2011).…”

Ciproxifan, an H3 receptor antagonist, alleviates hyperactivity and cognitive deficits in the APPTg2576 mouse model of Alzheimer’s disease

“…Moreover, H 3 antagonists can generate theta rhythms in the brain (Hajós, Siok, Hoffmann, Li, & Kocsis, 2008) – a form of activity that predicts the onset of new learning (Berry & Seager 2001). On a behavioral level, drugs that act as H 3 antagonists, such as the prototypical imidazole-containing compounds, ciproxifan and thioperamide, have been shown to improve memory function in several tasks – in normal rats and mice, as well as in animals treated with anti-cholinergic or anti-glutamatergic drugs (Bardgett, Points, Kleier, LaMontagne, & Griffith, 2010; Fox, Pan, Radek, Lewis, Bitner, et al, 2003; Bernaerts, Lamberty, & Tirelli, 2004; Galici, Boggs, Aluisio, Fraser, Bonaventure, et al, 2009; Ligneau et al, 1998). In addition to their effects on learning and memory, H 3 antagonists have also been shown to modulate the elevating effects of psychostimulants on locomotor activity in rats and mice (Clapham & Kilpatrick, 1994, Fox et al, 2005; Ligneau, Landais, Perrin, Piriou, Uguen, et al, 2007a; Morisset, Pilon, Tardivel-Lacombe, Weinstein, Rostene, et al, 2002).…”

“…Using a between-subjects design, approximately half of the mice of each genotype received daily intraperitoneal injections of ciproxifan (3 mg/kg) and the other half received injections of saline. The dose of ciproxifan chosen for study was based on previous research demonstrating its ability to improve attention and memory in normal rats (Bardgett et al, 2010; Fox et al, 2003; 2005; Ligneau et al, 1998) and inhibit stimulant-induced hyperactivity in mice (Morisset et al, 2002). Mice received daily injections for one week prior to testing and daily injections 30 minutes prior to testing over the subsequent three weeks.…”

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“…23 Ciproxifan increasing swim speed in the swim maze, although no such effect has been seen with another H 3 R Antagonist. 24 Ciproxifan appears to be an orally bioavailable whose vigilance-and attention-promoting effects are promising for therapeutic applications in aging disorders.…”