Janice W. Smith

A comparison of the effects of ketamine and phencyclidine with other antagonists of the NMDA receptor in rodent assays of attention and working memory

RationaleN-methyl-d-Aspartate receptor (NMDAR) antagonists such as ketamine induce cognitive symptoms in man similar to those of schizophrenia and therefore might be useful as models of the disease in animals. However, it is unclear which NMDAR antagonist(s) offer the best means to produce cognitive deficits in attention and working memory and to what extent those deficits can be measured selectively in rats.ObjectivesThe present study systematically compared the effects of eight different NMDAR antagonists—MK-801, phencyclidine, (S)-(+)-ketamine, memantine, SDZ-220,581, Ro 25-6981, CP 101-606 and NVP-AAM077—in rats using standard tests of visual attention, the five-choice serial reaction time task (5CSRT), and working memory, the delayed matching to position task (DMTP).ResultsDrug-induced responses varied qualitatively and quantitatively in both a compound- and a task-dependent manner. Effects were generally confounded by concomitant motor and motivational disruption, although individual doses of phencyclidine for example appeared to impair selectively cognitive functions. Interestingly, GluN2B selective antagonists were unique in their effects; inducing potential performance benefit in the 5CSRT.ConclusionsOverall, the opportunity to induce a selective cognitive deficit in attention (5CSRT) or working memory (DMTP) in the rat is limited by both the NMDAR antagonist and the dose range used. The importance of a preclinical focus on ketamine, which is used more frequently in clinical settings, is limited by the extent to which cognitive effects can be both detected and quantified using this exposure regimen within these two operant assays.

Diverse and often opposite behavioural effects of NMDA receptor antagonists in rats: implications for “NMDA antagonist modelling” of schizophrenia

RationaleLittle attention has been paid to the relative equivalence of behavioural effects of NMDA receptor antagonists in rodents, with different compounds often used interchangeably to “model” aspects of schizophrenia in preclinical studies.ObjectivesTo further resolve such conjecture, the present study systematically compared eight different NMDA receptor antagonists: MK-801, PCP, ketamine, memantine, SDZ 220,581, Ro 25-6981, CP 101-606 and NVP-AAM077, in a series of variable interval (VI) schedules of reinforcement. Aspects of motivation as indexed in these tasks may well be impaired in schizophrenia and undoubtedly impact on the capacity to perform more complex, explicit tasks of cognition.Methods and resultsAn initial locomotor activity assessment demonstrated that all antagonists tested, except the NR2A-subunit preferring antagonist NVP-AAM077, induced hyperactivity, albeit of greatly differing magnitudes, qualities and temporal profiles. Three distinct patterns of antagonist effect were evident from the VI assays used: a uniform decrease in responding produced by (S)-(+)-ketamine, memantine and NVP-AAM077, a uniform increase in responding caused by the NR2B-subunit preferring antagonists Ro 25-6981 and CP 101-606, and variable bidirectional effects of PCP, SDZ 220,581 and MK-801.ConclusionDespite nominally common mechanisms of action and often presumed biological equivalence, the NMDA antagonists tested produced very diverse effects on the expression of instrumental action. Other aspects of responding were left intact, including switching and matching behaviours, and the ability to respond to conditional stimuli. The implications of such findings with regard to animal modelling of schizophrenic psychotic symptoms are manifold.

A within-subject cognitive battery in the rat: differential effects of NMDA receptor antagonists

RationaleThe range of cognitive and psychotomimetic effects produced by antagonists of the N-methyl-D-aspartate (NMDA) receptor has lead to widespread usage of these molecules as pharmacological models of cognitive impairment for drug discovery. Historically, NMDA receptor antagonists have been used interchangeably on the assumption that they produce analogous effects.ObjectivesTo profile a subset of these antagonists across a novel within-subject cognitive battery in the rat.MethodsNaïve male Lister Hooded rats were subjected to a series of tests in which they were required to learn a simple visuo-auditory conditional discrimination. They then underwent testing in a delayed discrimination test followed by rule reversal and rule extinction tests.ResultsAll NMDA receptor antagonists tested impaired acquisition performance and, with the exception of ketamine and the GluN2A preferring antagonist, NVP-AAM077, impaired consolidation of extinction. GluN2B antagonism produced a singular profile with potentially enhanced delayed discrimination performance and reduced hit rates in the reversal phase. Only PCP (phencyclidine) and ketamine disrupted performance in the delay phase but did so in a delay-independent manner. MK-801, PCP and memantine all increased the hit rate in the reversal phase; whilst only MK-801 and PCP impaired extinction per se.ConclusionsNMDA receptor-dependent mechanisms are requisite in the acquisition of a simple conditional discrimination and consolidation of extinction. Their role in working memory and reversal tasks appear to be less critical and potentially specific to the paradigm and NMDA receptor antagonist used. It is clearly misleading to generalise across NMDA antagonists with respect to their preclinical cognitive profile.

Preclinical findings predicting efficacy and side‐effect profile of LY2940094, an antagonist of nociceptin receptors

Nociceptin/Orphanin FQ (N/OFQ) is a 17 amino acid peptide whose receptor is designated ORL1 or nociceptin receptor (NOP). We utilized a potent, selective, and orally bioavailable antagonist with documented engagement with NOP receptors in vivo to assess antidepressant‐ and anxiolytic‐related pharmacological effects of NOP receptor blockade along with measures of cognitive and motor impingement. LY2940094 ([2‐[4‐[(2‐chloro‐4,4‐difluoro‐spiro[5H‐thieno[2,3‐c]pyran‐7,4′‐piperidine]‐1′‐yl)methyl]‐3‐methyl‐pyrazol‐1‐yl]‐3‐pyridyl]methanol) displayed antidepressant‐like behavioral effects in the forced‐swim test in mice, an effect absent in NOP−/− mice. LY2940094 also augmented the behavioral effect of fluoxetine without changing target occupancies (NOP and serotonin reuptake transporter [SERT]). LY2940094 did not have effects under a differential‐reinforcement of low rate schedule. Although anxiolytic‐like effects were not observed in some animal models (conditioned suppression, 4‐plate test, novelty‐suppressed feeding), LY2940094 had effects like that of anxiolytic drugs in three assays: fear‐conditioned freezing in mice, stress‐induced increases in cerebellar cGMP in mice, and stress‐induced hyperthermia in rats. These are the first reports of anxiolytic‐like activity with a systemically viable NOP receptor antagonist. LY2940094 did not disrupt performance in either a 5‐choice serial reaction time or delayed matching‐to‐position assay. LY2940094 was also not an activator or suppressor of locomotion in rodents nor did it induce failures of rotarod performance. These data suggest that LY2940094 has unique antidepressant‐ and anxiolytic‐related pharmacological effects in rodents. Clinical proof of concept data on this molecule in depressed patients have been reported elsewhere.

WO03/062224 is an in vivo selective agonist at nicotinic β4 receptors

Pharmacological agents that increase cholinergic transmission have considerable use in cognitive disorders and evidence from both human and animal studies suggests that nicotinic acetylcholine receptors (nAChRs) represent an attractive target for treating certain neurological disorders. This investigation aimed to provide an in vivo verification of the in vitro data on WO03/062224, an agonist selective at beta4 subunit-containing nicotinic receptors. The effects of WO03/062224 were tested on wildtype and beta4 nAChR null mice on two behavioural paradigms; locomotor behaviour and instrumental responding for food on a second order schedule. Separate groups of wildtype and beta4 nAChR subunit knockout mice were tested in each paradigm with instrumental responding and forward locomotion being measured. WO03/062224 had a greater effect in the wildtype mice than the beta4 knockout mice in both locomotor activity (unconditioned behaviour) and instrumental responding (conditioned behaviour). In wildtype mice WO03/062224 caused a significant initial depression in locomotor activity followed by a significant increase in activity. The beta4 knockout mice displayed no significant drug-induced alterations in locomotor activity at any time point. In wildtype mice WO03/062224 caused a significant depression in instrumental responding throughout the session at both 3 mg/kg and 10 mg/kg. The beta4 knockout mice only displayed a reduction in initial responding at 10 mg/kg. The present study demonstrated that the effects of WO03/062224 at 3 mg/kg on locomotor activity and instrumental responding are likely occurring through a beta4 nicotinic mechanism. This investigation has shown that at an appropriate dose WO03/062224 is a suitable in vivo probe for the contribution of beta4-containing nAChRs to behaviour and suggests that their involvement is greater than previously recognised.