Age-related declines in delayed non-match-to-sample performance (DNMS) are reversed by the novel 5HT6 receptor antagonist SB742457

Abstract

Alterations in synaptic plasticity and neurocognitive function with age have been well documented in the literature. These changes are accompanied by modifications of neurotransmitter systems in the central nervous system (CNS). The serotonergic system in particular plays an important role in attention, alertness and cognition. Disturbances in serotonergic function have been implicated in differing neurological and neuropsychiatric disorders including depression, psychosis aggression and dementia. The serotonin receptor subtype 5HT6 is distributed within CNS regions relevant to learning and memory, including the striatum, cortex and hippocampus. We examined here the effects of acute and chronic administration of the 5HT6 receptor antagonist SB742457 on performance in a delayed non-matching-to-sample task (DNMS), which was used to identify neurocognitive differences between middle-aged (MA, 13 months) and young adult (YG, 3 months) rats. We found that MA rats have significantly lower performance in the DNMS task compared to YG rats. Acute administration of SB742457 (3 mg/kg/po) significantly improved performance of the MA rats. Chronic administration of SB742457 (3 mg/kg) reversed the age-related deficit of the MA to match their performance to that of YG rats. Furthermore, these improvements were observed for 1 week post-SB742457 treatment cessation. The acute and chronic effects of this treatment suggest that there is both an immediate effect on neurotransmitter action and potentially a longer-term modification of synaptic plasticity. Together these data indicate a role for modulation of the serotonergic system in the development of cognition-enhancing agents.

Introduction

Age-related decline in cognitive function may result from numerous and widespread changes in the brain. Neurocognitive deficits related to aging also involve concomitant alterations of neurotransmitter systems (Stemmelin et al., 2000) that might be prevented or slowed by pharmacological intervention (Frolich and Forstl, 2011; Burchinsky, 1984). Delayed-response tasks have proven reliable at identifying age-related deficits in humans (Li Hegner et al., 2010), non-human primates (Bartus et al., 1978) and rodents (Dunnett et al., 1988). We focus here on the use of the delayed non-match-to-sample (DNMS) task, where the rule requires flexibly modulating behavior through time, where the animal must choose the reverse to the previous occasion (see Methods). The DNMS task was chosen over the delayed match-to-sample (DMS) task as DNMS does not inhibit the animal's natural alternation tendency (Deacon and Rawlins, 2006). Furthermore, the DNMS task is sensitive to subtle changes in hippocampal neurophysiological dynamics that may not be visible in behavior until later in life (Hok et al., 2012), specifically, between young adult (YG) and middle-aged (MA) populations. Lesions of the hippocampus, prefrontal cortex and/or subiculum all impair performance on the DNMS task (Porter et al., 2000; Hampson et al., 1999a). Insult to any of these regions can cause deficits in performance (Dunnett et al., 1988). Furthermore, performance in the DNMS task has previously been reported to be supported by the interplay of the hippocampus and subiculum (Hampson et al., 1999b, 2003). The DNMS task is functionally partitioned between neurons within subiculum and hippocampus to uniquely identify trial-specific information accounting for both spatial and temporal constraints on performance within and between trials (Deadwyler and Hampson, 2004). At a systems level, oscillatory activity at the population level (specifically at theta frequency) between prefrontal cortex and hippocampus is highly correlated with correct trial performance (Hyman et al., 2010).

Alterations in the serotonergic system have been observed with age and with age-related impairments in spatial memory (Stemmelin et al., 2000). The 5HT6 serotonergic receptor is found almost exclusively in the CNS, with the highest concentrations found in the hippocampal formation, frontal cortex, striatum and olfactory tubercle (Gerard et al., 1996; Hamon et al., 1999). Reduced density of 5HT6 receptors were found in both the frontal and temporal cortex from post-mortem AD patients and correlated with aggression and the Present Behavioral Examination in these same patients (Garcia-Alloza et al., 2004). Critically, the 5HT6 receptor is particularly distributed in structures supporting memory formation and hence, performance in a delayed non-matching-to-sample (DNMS) task. The serotonergic system also modulates multiple neurotransmitter pathways, including central cholinergic neurotransmission (Bentley et al., 1999; Riemer et al., 2003) which has been extensively implicated in age-related cognitive decline. Modifications of the serotonergic system may affect other neurotransmitter systems, resulting in beneficial effects on cognition (Shirazi-Southall et al., 2002). Direct intracerebroventricular administration of antisense oligonucleotides in rats induced receptor knock-down and improved spatial learning and memory in the water maze (Bentley et al., 1997; Woolley et al., 2001), identifying a role for 5HT6 receptor knock-down in learning and memory. However, another study demonstrated increased 5HT6 expression, through targeted gene delivery, had no effect on spatial learning in the water maze, but decreased ability of rats to learn a reward-based instrumental learning operant task, as compared to sham surgery or GFP (green fluorescent protein)-expressing control rats. This 5HT6 receptor-associated deficit was reversed by administration of a 5HT6 antagonist, SB-258585 (Mitchell et al., 2007). Other studies have used pharmacological interventions: the select 5HT6 antagonist, SB742457, reverses scopolamine-induced deficits in object recognition and in a passive avoidance (Chuang et al., 2006). Other 5HT6 antagonists including Ro-04-6790 and SB271046 (King et al., 2004) and SB399885 (Hirst et al., 2006) reverse age-related deficits in spatial and recognition memory tasks. SB271046 improves spatial recognition memory in adult mice and reverses age-related consolidation deficits of episodic-like memory in aged mice (Da Silva Costa et al., 2009; Da Silva Costa-Aze et al., 2011). High doses of SB271046 reverses scopolamine-induced deficits in working memory and those of acquisition and retrieval of aversive learning; whereas scopolamine-induced deficits in episodic-like memory were only partially counteracted by SB271046 (Da Silva Costa-Aze et al., 2012). In a separate study sub-chronic treatment with SB271046 improved acquisition in the water maze in rats, while acute treatment only improved retention but SB271046 (acute or sub-chronic) treatment failed to reversed scopolamine-induced learning deficits (Marcos et al., 2008). The selective 5-HT6 receptor antagonist Ro4368554 restores memory performance in cholinergic and serotonergic models of memory deficiency in the rat (Lieben et al., 2005). GSK-742457 ameliorated scopolamine-induced deficits in object recognition task and high doses GSK-742457 also reduced scopolamine-induced deficits in the object location task in 3-months-old male Wistar rats (de Bruin et al., 2011). SB742457 is currently in phase II clinical trials and has proven to be generally safe and well tolerated and may be a potential treatment of Alzheimer's disease (Maher-Edwards et al., 2010). The DNMS task was utilized to induced delay deficits in normal rats and naturally occurring deficits in aged rats of short-term working memory, to provide confirmation of cognitive enhancement with SB742457. The current study aimed to examine the cognitive enhancing potential of the 5HT6 antagonist, SB742457, on delay induced cognitive deficits in normal rats and naturally occurring deficits in ageing rats. Together with its presumed role in cognitive enhancement (Upton et al., 2008), these data have lead us to test the hypothesis that the 5HT6 receptor antagonist SB742457 may modulate normal age-related deficits in short-term spatial-temporal memory as measured in the DNMS task in middle-aged animals.