Nicotine Improves Working Memory Span Capacity in Rats Following Sub-Chronic Ketamine Exposure

Abstract

Ketamine, an NMDA-receptor antagonist, produces cognitive deficits in humans in a battery of tasks involving attention and memory. Nicotine can enhance various indices of cognitive performance, including working memory span capacity measured using the odor span task (OST). This study examined the effects of a sub-chronic ketamine treatment to model cognitive deficits associated with schizophrenia, and to evaluate the effectiveness of nicotine, antipsychotic clozapine, and the novel mGlu2/3 agonist, LY404039, in restoring OST performance. Male hooded Lister rats were trained in the OST, a working memory task involving detection of a novel odor from an increasing number of presented odors until they exhibited asymptotic levels of stable performance. Sub-chronic ketamine exposure (10 and 30 mg/kg i.p. for 5 consecutive days) produced a dose-dependent impairment that was stable beyond 14 days following exposure. In one cohort, administration of graded doses of nicotine (0.025-0.1 mg/kg) acutely restored the performance in ketamine-treated animals, while significant improvements in odor span were observed in control subjects. In a second cohort of rats, acute tests with clozapine (1-10 mg/kg) and LY404039 (0.3-10 mg/kg) failed to reverse ketamine-induced deficits in doses that were observed to impair performance in the control groups. These data suggest that sub-chronic ketamine exposure in the OST presents a valuable method to examine novel treatments to restore cognitive impairments associated with neuropsychiatric disorders such as schizophrenia. Moreover, it highlights a central role for neuronal nicotinic receptors as viable targets for intervention that may be useful adjuncts to the currently prescribed anti-psychotics.

Influence of pharmacological manipulations of NMDA and cholinergic receptors on working versus reference memory in a dual component odor span task

“…We found that administration of a competitive NMDA-r antagonist (CPP) produced dosedependent impairments in our variant of the OST. These findings are consistent with and extend prior odor span studies that have reported cognitive impairments in rats produced by competitive and noncompetitive NMDA-r antagonists (MacQueen et al 2011;Rushforth et al 2011;Davies et al 2013a;Galizio et al 2013) and enhanced performance in mice overexpressing the 2B NMDA-r subunit (Cui et al 2011). Notably, CPP did not affect reference memory performance, demonstrating the selective involvement of NMDA receptors in the working memory component of the task.…”

“…Selective knockout of the a7 nicotinic acetylcholine receptor (nAChR) subunit gene in mice impaired acquisition and performance of a 12-stimuli odor span task relative to wild-type controls (Young et al 2007a). In rats, nicotine and selective nAChR agonists improved span and reversed odor span deficits produced by administration of the NMDA-r antagonist, ketamine (Rushforth et al 2011). These results indicate that manipulation of the nicotinic acetylcholine receptor can influence OST performance in rodents.…”

“…Low doses of nicotine have been shown to enhance odor span performance (Rushforth et al 2010) and to reverse NMDA-r antagonist-induced impairments (Rushforth et al 2011) in rats. We observed evidence that a moderate dose of nicotine (75 mg/kg i.p.)…”

Severe Cross-Modal Object Recognition Deficits in Rats Treated Sub-Chronically with NMDA Receptor Antagonists are Reversed by Systemic Nicotine: Implications for Abnormal Multisensory Integration in Schizophrenia

“…Indeed, studies have shown that drugs activating muscarinic or nicotinic acetylcholine receptor (nAChR) subtypes have potential for the treatment of cognitive symptoms in patients with schizophrenia (for review, see Jones et al, 2012). Specifically, nicotine, as well as agonists and positive allosteric modulators of a7 and a4b2 nAChRs, attenuate various cognitive deficits in rodent models of schizophrenia (Boess et al, 2007;Hashimoto et al, 2008;Hauser et al, 2009;Hurst et al, 2005;Pichat et al, 2007;Rushforth et al, 2011;Thomsen et al, 2009;Timmermann et al, 2007;Wallace et al, 2011;Wildeboer and Stevens, 2008;Wishka et al, 2006). Our observations that nicotine reverses the selective CMOR impairment in rats treated with subchronic NMDAR antagonists is consistent with studies using standard object recognition tasks and extends these findings by implicating nAChRs in the potential treatment of multisensory integration deficits in schizophrenia.…”

Negative Affective States and Cognitive Impairments in Nicotine Dependence

“…Nicotine also improves learning deficits induced by certain drugs or aging (Bontempi et al, 2003;Gulick and Gould, 2010;Meguro et al, 1994;Mizoguchi et al, 2011). Subtype-specific nicotinic agonists improve aversive conditioning, inhibitory avoidance, social recognition memory, object recognition and working memory, either under baseline conditions or by reversing impairments induced by other conditions or treatments (Andre et al, 2011;Azizbeigi et al, 2011;Boess et al, 2007;Bontempi et al, 2003;Decker et al, 1994;Feuerbach et al, 2009;Gatto et al, 2004;Gulick and Gould, 2008b;Obinu et al, 2002;Rueter et al, 2004;Rushforth et al, 2010;Rushforth et al, 2011). Given the variety of learning and memory tasks in which nicotine has been shown to have beneficial effects, it is not surprising that many effects of nicotine are not hippocampally mediated.…”