A single application of MK801 causes symptoms of acute psychosis, deficits in spatial memory, and impairment of synaptic plasticity in rats

Abstract

Schizophrenia is mostly a progressive psychiatric illness. Although cognitive changes in chronic schizophrenia have been investigated, little is known about the consequences of a single psychotic episode on memory mechanisms and formation. We investigated changes in hippocampal long-term potentiation (LTP) and spatial memory in a rat model of an acute psychotic episode. Application of NMDA receptor antagonists, such as MK801 (dizolcilpine) in rats, have been shown to give rise to an acute and short-lasting behavioral state, which mirrors many symptoms of schizophrenia. Furthermore, NMDA antagonist-intake in humans elicits symptoms of schizophrenia such as hallucinations, delusions, and affective blunting. We therefore treated animals with a single systemic injection of MK801 (5 mg/kg). Increased stereotypy, locomotion, and ataxia were evident immediately after MK801-treatment, with effects disappearing within 24 h. MK801-treatment caused a disruption of prepulse inhibition of the acoustic startle reflex, 1 day but not 7 or 28 days after treatment. These effects were consistent with the occurrence of an acute psychotic episode. LTP was profoundly impaired in freely moving rats 7 days after MK801 application. Four weeks after treatment, a slight recovery of LTP was seen, however marked deficits in long-term spatial memory were evident. These data suggest that treatment with MK801 to generate an acute psychotic episode in rats, gives rise to grave disturbances in synaptic plasticity and is associated with lasting impairments with the ability to form spatial memory.

Enhanced Dopamine-Dependent Hippocampal Plasticity after Single MK-801 Application

“…Lasting hippocampus-dependent deficits after a single application of NMDAR antagonists including MK-801 that persisted for up to months have been reported (Lukoyanov and Paula-Barbosa, 2000;Manahan-Vaughan et al, 2008;Wiescholleck and Manahan-Vaughan, 2013;Wozniak et al, 1996). The enhanced subicular LTP occurred 1 h after MK-801 treatment and lasted for about 1 week.…”

MK-801-induced impairments on the trial-unique, delayed nonmatching-to-location task in rats: effects of acute sodium nitroprusside

“…Similarly, non-competitive NMDA receptor antagonism in rodents produces behaviors analogous to the positive, negative, and cognitive symptoms of schizophrenia (Moghaddam and Krystal 2012). For example, locomotor hyperactivity (Manahan-Vaughan et al 2008;Howland et al 2012;Zemanova et al 2013;Mahmood et al 2016), reduced sociability (Morales and Spear 2014), and performance deficits on visual learning and working memory tasks (Brown et al 2013;Zemanova et al 2013;Kumar et al 2015b;Kumar et al 2015a;Lins and Howland 2016) are observed following MK-801 administration, mirroring the positive, negative, and cognitive symptoms respectively. Beyond its direct effect on NMDA receptors, MK-801 administration indirectly mimics other pathophysiological features of the disease (Lewis et al 2005).…”

Neural mechanisms of MK-801 induced sensitisation

“…Changes in excitatory synaptic transmission and plasticity are attributed to core features of schizophrenia pathophysiology (Grace, 2000, Yin et al, 2012. Animal models of schizophrenia using MK-801 have previously shown alterations in synaptic plasticity in the hippocampus (Buck et al, 2006, Manahan-Vaughan et al, 2008, Wohrl et al, 2007 and PFC (Blot et al, 2013, Blot et al, 2015. Thus the decrease in NAc synaptic strength shown in this thesis provides further support that the NAc brain region, the interface for limbic and motor signalling, could be involved in schizophrenia pathophysiology.…”