A neurocognitive animal model dissociating between acute illness and remission periods of schizophrenia

Abstract

Rationale-The development and validation of animal models of the cognitive impairments of schizophrenia have remained challenging subjects.Objective-We review evidence from a series of experiments concerning an animal model that dissociates between the disruption of attentional capacities during acute illness periods and the cognitive load-dependent impairments that characterize periods of remission. The model focuses on the long-term attentional consequences of an escalating-dosing pretreatment regimen with amphetamine (AMPH).Results-Acute illness periods are modeled by the administration of AMPH challenges. Such challenges result in extensive impairments in attentional performance and the "freezing" of performance-associated cortical acetylcholine (ACh) release at pretask levels. During periods of remission (in the absence of AMPH challenges), AMPH-pretreated animals' attentional performance is associated with abnormally high levels of performance-associated cortical ACh release, indicative of the elevated attentional effort required to maintain performance. Furthermore, and corresponding with clinical evidence, attentional performance during remission periods is exquisitely vulnerable to distractors, reflecting impaired top-down control and abnormalities in fronto-mesolimbic-basal forebrain circuitry. Finally, this animal model detects the moderately beneficial cognitive effects of low-dose treatment with haloperidol and clozapine that were observed in clinical studies.Conclusions-The usefulness and limitations of this model for research on the neuronal mechanisms underlying the cognitive impairments in schizophrenia and for drug-finding efforts are discussed.

Selective Blockade of Dopamine D3 Receptors Enhances while D2 Receptor Antagonism Impairs Social Novelty Discrimination and Novel Object Recognition in Rats: A Key Role for the Prefrontal Cortex

“…Collectively, these studies in mice, rats and primates support the importance of PFC dopamine D 3 receptor activation in the control of cognitive processes involving attentional mechanisms. In a repeated amphetamineinduced model of psychosis and cognitive impairment, sustained attention in an operant task was accompanied by decreased PFC acetylcholine release (Sarter et al, 2009). It is well established that the PFC dopamine D 3 receptors modulate cholinergic neurotransmission (Lacroix et al, 2003;Millan et al, 2007) consistent with this being a potential mechanism for the observed cognitive effects seen in this study.…”

“…This is the first systematic evaluation of the comparative role of dopamine D 2 and D 3 receptors in these behavioral tasks performed by altering the delay between trials such that rats are able (with short) or unable (with long delay) to discriminate; allowing characterization of drugs exerting both positive and detrimental effects on cognitive performance. Furthermore, we previously showed that social recognition is modulated, by dopamine D 3 receptors in the PFC (Loiseau and Millan, 2009) probably reflecting its important role in the top-down control of cognitive processing, which is disrupted in schizophrenia (Baluch and Itti, 2011;Klinkenberg et al, 2011;Noudoost et al, 2010;Rossi et al, 2009;Sarter et al, 2009) and its wellestablish role on working memory. Finally, amphetamineinduced improvement in NOR in an Fmr1 knockout mouse model of Fragile X syndrome correlated with the increase in PFC but not striatal dopamine release measured by microdialysis (Ventura et al, 2004).…”

Dissociating scopolamine-induced disrupted and persistent latent inhibition: stage-dependent effects of glycine and physostigmine

“…Given the continuing debate on the capacity of typical APDs to enhance cognition on the one hand (Buchanan et al 2007;Miyamoto et al 2005;Sarter et al 2008) and the search for cognition enhancing agents for schizophrenia (Buchanan et al 2007;Marder 2006;Marder and Fenton 2004;Stip et al 2005) on the other hand, a model that can distinguish between atypical APDs and cognitive enhancers may have great utility. Our data suggest that at least with regard to some psychotic and cognitive deficits, namely, those that are muscarinic-dependent, cognitive enhancers may offer a better treatment alternative or a useful addition to APDs.…”

Current pharmacological models of social withdrawal in rats

“…Interestingly, several studies have reported the depressive effects of withdrawal, after chronic treatment with escalating doses of amphetamine, on nocturnal locomotor activity and these were accompanied by changes in monoamine concentrations in several brain regions (Robinson and Camp, 1987;Paulson et al, 1991;Paulson and Robinson, 1996). More recently, Sarter et al (2009) have reviewed a series of studies, which reported that amphetamine pretreated rats exhibited impaired attentional capacity during withdrawal periods and when given amphetamine challenges. These impairments were normalized by treatment with haloperidol and clozapine.…”