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

Abstract

Despite 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.

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

“…As a general note, systemic MK-801 and ketamine are typically associated with acute motoric effects (Gilmour et al, 2009;Smith et al, 2011). Indeed, such effects were often observed in the first 10-15 min following injections during the sub-chronic administration period.…”

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

“…At relatively low doses, MK-801 is unusual in that it has a stimulatory effect on instrumental responding (Gilmour et al 2009) and also increases head entries and premature responding in 5CSRT. At higher doses, all of these effects diminish or become significantly inhibitory, but effects on accuracy are relatively slight in terms of effect size.…”

“…All doses refer to the base weights of compounds. Doses and routes of administration were chosen on the basis of previously conducted studies (Gilmour et al 2009;Dix et al 2010) and a general assessment of existing published literature in this field.…”

“…Historically, NMDAR antagonists such as PCP, MK-801 and ketamine have been used interchangeably preclinically on the assumption that they produce essentially analogous effects on a variety of cognitive and non-cognitive behaviours. However, Gilmour et al (2009) have shown that NMDAR antagonists can have substantially different effects on motor and motivational measures, as indicated by qualitative changes in instrumental responding to variable interval schedules. Furthermore, whilst NMDA receptor-dependent mechanisms are requisite in the acquisition of, for example, a simple conditional discrimination or the consolidation of extinction, their role in working memory and reversal learning tasks appears to be less critical and potentially specific to the paradigm and NMDAR antagonist used (Dix et al 2010).…”

Effects of chronic oral treatment with aripiprazole on the expression of NMDA receptor subunits and binding sites in rat brain

“…Early treatment with NMDA-R-antagonists induced phenotypes resembling psychotic behavior in parallel to increased BDNF expression (Guo et al 2010) and reduced hippocampal parvalbumin expression (Jenkins et al 2010), and also caused long-lasting changes in the expression of excitatory and inhibitory receptors (du Bois et al 2009). In this respect, differences between phencyclidine (PCP) and MK-801 also became obvious (Baier et al 2009) (Gilmour et al 2009;Seillier and Giuffrida 2009). NR1-hypomorphic mice (Duncan et al 2009), and more specifically a cell-type-specific knockout of NR1 subunits in parvalbumin-positive GABAergic interneurons (Belforte et al 2010), show a phenotype closely reminiscent of schizophrenic pathology.…”