Toward a Neuro-Cognitive Animal Model of the Cognitive Symptoms of Schizophrenia: Disruption of Cortical Cholinergic Neurotransmission Following Repeated Amphetamine Exposure in Attentional Task-Performing, but Not Non-Performing, Rats

Abstract

Impairments in attentional functions and capacities represent core aspects of the cognitive symptoms of schizophrenia. Attentional performance has been demonstrated to depend on the integrity and activity of cortical cholinergic inputs. The neurobiological, behavioral, and cognitive effects of repeated exposure to psychostimulants model important aspects of schizophrenia. In the present experiment, prefrontal acetylcholine (ACh) release was measured in attentional task-performing and non-performing rats pretreated with an escalating dosing regimen of amphetamine (AMPH) and following challenges with AMPH. In non-performing rats, pretreatment with AMPH did not affect the increases in ACh release produced by AMPH-challenges. In contrast, attentional task performanceassociated increases in ACh release were attenuated in AMPH-pretreated and AMPH-challenged rats. This effect of repeated AMPH exposure on ACh release was already present before task-onset, suggesting that the loss of cognitive control that characterized these animals' performance was a result of cholinergic dysregulation. The findings indicate that the demonstration of repeated AMPH-induced dysregulation of the prefrontal cholinergic input system depends on interactions between the effects of repeated AMPH exposure and cognitive performance-associated recruitment of this neuronal system. Repeated AMPH-induced disruption of prefrontal cholinergic activity and attentional performance represents a useful model to investigate the cholinergic mechanisms contributing to the cognitive impairments of schizophrenia.

Abnormal Neurotransmitter Release Underlying Behavioral and Cognitive Disorders: Toward Concepts of Dynamic and Function-Specific Dysregulation

“…In contrast, in animals with prior amphetamine exposure, the acute challenge caused a striking return of neurotransmitter release to baseline levels and, thereby, the loss of cognitive control of task performance. Importantly, in nonperforming animals, such disruption of the regulation of the neurotransmitter systems, as a result of prior amphetamine exposure, was not observed (Kozak et al, 2006b). These data indicate that, as a result of prior psychostimulant exposure, a fundamental re-regulation of the target neuronal system and associated circuitry radically alters the effects of subsequent psychostimulant exposure, and that it requires performance-induced activation of the target system and associated circuits to reveal such re-regulation.…”

Detection of the Moderately Beneficial Cognitive Effects of Low-Dose Treatment with Haloperidol or Clozapine in an Animal Model of the Attentional Impairments of Schizophrenia

“…Similar to our previous experiment , the performance of animals pretreated with AMPH recovered completely during the 10-day period between AMPH pretreatment and the test of AMPH challenges. However, the results described in Kozak et al (2007)suggest that the 'normal' attentional performance of AMPHpretreated rats was mediated via abnormally high increases in prefrontal ACh release, reaching 250-300% increase over baseline when compared with 150% in task-performing, vehicle-treated animals (see Figure 4 in Kozak et al, 2007). These augmented levels of ACh release were interpreted as indicating that AMPH-pretreated animals required more cognitive effort (defined in Sarter et al, 2006) to maintain normal levels of attentional performance.…”

Towards an animal model of an antipsychotic drug-resistant cognitive impairment in schizophrenia: scopolamine induces abnormally persistent latent inhibition, which can be reversed by cognitive enhancers but not by antipsychotic drugs

“…scopolamine, atropine) produce a schizophrenia-like syndrome (' antimuscarinic syndrome ') in humans, which includes both positive symptoms and cognitive impairments (Clarke et al, 2004 ;Fisher, 1991 ;Marchlewski, 1994 ;Minzenberg et al, 2004 ;Perry et al, 1978 ;Yeomans, 1995), as well as psychotic-like effects in animal models of schizophrenia (Jones et al, 2005 ;Mathur et al, 1997 ;Shannon and Peters, 1990 ;Sipos et al, 1999 ;Ukai et al, 2004), the cholinergic system has received less attention in schizophreniarelated research. Recent efforts to identify treatments targeting cognitive impairments in schizophrenia (see Marder and Fenton, 2004) have directed attention to the cholinergic system because of its well known role in cognition (Dean et al, 2003 ;Everitt and Robbins, 1997 ;Kozak et al, 2007 ;Raedler et al, 2007 ;Sarter et al, 2003Sarter et al, , 2005.…”