Dimebon enhances hippocampus-dependent learning in both appetitive and inhibitory memory tasks in mice

Abstract

a b s t r a c t a r t i c l e i n f oPre-clinical and clinical studies on dimebon (dimebolin or latrepirdine) have demonstrated its use as a cognitive enhancer. Here, we show that dimebon administered to 3-month-old C57BL6N mice 15 min prior to training in both appetitive and inhibitory learning tasks via repeated (0.1 mg/kg) and acute (0.5 mg/kg) i.p. injections, respectively, increases memory scores. Acute treatment with dimebon was found to enhance inhibitory learning, as also shown in the step-down avoidance paradigm in 7-month-old mice. Bolus administration of dimebon did not affect the animals' locomotion, exploration or anxiety-like behaviour, with the exception of exploratory behaviour in older mice in the novel cage test. In a model of appetitive learning, a spatial version of the Y-maze, dimebon increased the rate of correct choices and decreased the latency of accessing a water reward after water deprivation, and increased the duration of drinking behaviour during training/testing procedures. Repeated treatment with dimebon did not alter the behaviours in other tests or water consumption. Acute treatment of water-deprived and non-water-deprived mice with dimebon also did not affect their water intake. Our data suggest that dimebon enhances hippocampus-dependent learning in both appetitive and inhibitory tasks in mice.

Anhedonic-like traits and lack of affective deficits in 18-month-old C57BL/6 mice: Implications for modeling elderly depression

“…5A-C). Interestingly, dimebon exhibited anti-anxiety effects in mice and rats (Vignisse et al, 2011;Magrani et al, 2006), which similarly to the situation with many other drugs, overlap with its antidepressant action (Porsolt and Papp, 1998;Willner, 2005).…”

“…In contrast to imipramine, dimebontreated mice showed a significant increase in the total intake of liquid (Fig. 5D) that may suggest the emergence of the characteristic antihistamine effect of increasing water intake, reported in patients after a four-week course of dimebon, and in mice after five-day treatment, at comparable doses (Vignisse et al, 2011;Bachurin and Grigoriev, 2008;Magrani et al, 2006). Imipramine reduced water intake that was obviously owed to the compensation of increased consumption of a sucrose solution (Fig.…”

“…The apparatus was placed on a dark surface in order to reduce reflection and maintain control over lighting conditions during testing. Anxiety-like behavior was assessed using previously validated parameters (Strekalova et al, 2005;Vignisse et al, 2011). Mice were placed in one of the closedarm compartments of the apparatus.…”

“…Anxietylike behavior was assessed by earlier validated measures (Strekalova et al, 2005;Vignisse et al, 2011). Mice were placed into the dark compartment, from where they could visit the lit box, illuminated by light of 25 lx intensity.…”

“…Dimebon, a tetrahydro-g-carboline with anti-histamine effects, was reported to block the apoptosis of cortical neurons (Bachurin et al, 2001), protect the mitochondrial membrane potential Pieper et al, 2010), promote neurite outgrowth in cultured hippocampal and cortical neurons Bernales et al, 2009), dose-dependently increase neurogenesis in the rat dentate gyrus (Pieper et al, 2010), act in vitro as a low-affinity NMDA receptor blocker via the NR2B subunit (Perlovich et al, 2009) and enhance memory properties in middle-aged mice (Vignisse et al, 2011). The role of these factors in the neurobiology of depression was generally documented (Skolnick et al, 2009;Pittenger and Duman, 2008;Marcocci et al, 2002), however, it remains to be studied whether dimebon may exert any systemic effects via these mechanisms (Bachurin, 2003).…”