Nicotinic α7 and α4β2 agonists enhance the formation and retrieval of recognition memory: Potential mechanisms for cognitive performance enhancement in neurological and psychiatric disorders

Abstract

In the current study we investigated the efficacy of donepezil, risperidone and selective nicotinic α7 and α4β2 receptor agonists to reverse a delay-induced deficit in recognition memory. Adult female hooded-Lister rats received drug treatments and were tested in the novel object recognition (NOR) task following a 6 hour inter-trial interval (ITI). In all treatment groups there was no preference for the left or right identical objects in the acquisition trial. In the retention trial vehicle, risperidone (0.16mg/kg), PNU-282987, an α7 agonist (5mg/kg) and RJR-2403, an α4β2 agonist (1mg/kg) treated rats were unable to discriminate between the novel and familiar objects following a 6 hour ITI. In contrast, donepezil (1.0mg/kg), PNU-282987 (10mg/kg) and RJR-2403 (0.1mg/kg) treated rats spent significantly more time exploring the novel compared to the familiar object following the 6 hour ITI, indicative of enhanced cognitive performance (P<0.05-P<0.01). Interestingly, these compounds were efficacious when administered either before the acquisition or the retention trial of the task, suggesting an important role for nicotinic receptor subtypes in the formation and retrieval of recognition memory.

Dopamine dysregulation in the prefrontal cortex relates to cognitive deficits in the sub-chronic PCP-model for schizophrenia: A preliminary investigation

“…The brain regions thought to be involved in object recognition memory depend on the length of the inter-trial interval (ITI). We have recently shown that normal unimpaired animals lose the ability to discriminate objects following an ITI of 6 hours (McLean et al, 2016). Rats with hippocampal lesions exhibit impairments in object recognition following long ITIs (>15 min), but not short intervals of <15 min (Clark et al, 2000).…”

Desformylflustrabromine, a positive allosteric modulator of α4β2-containing nicotinic acetylcholine receptors, enhances cognition in rats

“…5). Moreover, dFBr (1.0 or 3.0 mg/kg) reversed the impairing effects elicited by scopolamine (a two-way ANOVA interaction for exploration time: F [3,29] = 8.99, p < 0.001; Supplementary Table 1 S2, and a one-way ANOVA interaction for DI: F [3,29] = 10.76, p < 0.001; Fig. 6).…”

“…For example, the ability to discriminate between a novel object and a familiar object after a 24-h delay was improved by TC-1734 (AZD3480, ispronicline) in mice [32] and by TC-6683 (AZD1446) in rats [33]. The administration of 0.1 mg/kg TC-2403 reversed 6 h ITI-induced forgetting in rats [29]. Although the efficacy of TC-2403 was also supported in the current study (Supplement 1), the active dose was higher (i.e., 0.3 mg/kg) than that used by McLean et al [29].…”

“…There were no significant differences in the time spent exploring two identical objects in the acquisition phase in any experimental group (Supplementary Table 1 S2, a twoway ANOVA interactions for ketamine and scopolamine studies were F [3,28] = 1.82, NS and F [3,29] = 0.71, NS, Fig. 2 Dihydro-β-erythroidine inhibits the procognitive effects of desformylflustrabromine on the attentional set-shifting task.…”

“…dFBr and TC-2403 doses were based on our preliminary experiments (see Supplement 1) and previous studies demonstrating drug-evoked procognitive or behavioural effects [19,20,25,29]. Because the applied dose range was adjusted to demonstrate the minimal effective dose of the tested compounds, the dosage schedule differed between the ASST and NORT.…”