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

Abstract

The absence of effective cognition enhancers for the treatment of patients with schizophrenia limits the validation of animal models and behavioral tests used for drug finding and characterization. However, low doses of haloperidol and clozapine were documented to produce moderately beneficial effects in patients. Therefore, this experiment was designed to determine the attentional effects of such treatments in a repeated-amphetamine (AMPH) animal model. Animals were trained in an operant-sustained attention task and underwent a 40-day pretreatment period with saline or increasing doses (1-10 mg per kg) of AMPH. After regaining baseline performance following 10 days of saline treatment, animals were treated with haloperidol (0.025 mg per kg), clozapine (2.5 mg per kg), or vehicle for 10 days. Furthermore, the effects of AMPH challenges (1.0 mg per kg) were assessed. In AMPH-pretreated animals, the administration of AMPH challenges resulted in the disruption of attentional performance. Treatment with haloperidol and clozapine attenuated the detrimental performance effects of these challenges, with clozapine exhibiting more robust attenuation. Furthermore, clozapine, but not haloperidol, impaired the performance of control animals. In contrast, the performance of AMPH-pretreated animals remained unaffected by clozapine. As this animal model detects the moderately beneficial cognitive effects of haloperidol and clozapine, it may be useful for preclinical research designed to detect and characterize treatments for the cognitive symptoms of schizophrenia.

Mouse pharmacological models of cognitive disruption relevant to schizophrenia

“…Ketamine has since been used to induce a model of psychosis in normal volunteers (Abel et al, 2003; Krystal et al, 1994; Malhotra et al, 1996; Oranje et al, 2002), and to exacerbate symptoms in patients with schizophrenia (Malhotra et al, 1997a; Malhotra et al, 1997b). While the effects of psychotomimetics described above occur following acute treatment, subchronic or sensitizing regimens of drug treatment are also used to assess behavior after a washout period while drug is not on board, avoiding putative drug by drug interaction confounds (Jentsch et al, 1998; Jentsch and Roth, 1999; Martinez and Sarter, 2008; Neill et al, 2010; Young et al, 2009). Acute, subchronic, chronic, and sensitizing regimens of psychotomimetic administration will be covered below.…”

“…Such low effect sizes may have contributed to the lack of FDA approval for these antipsychotics being indicated as procognitive. While basic science studies in animal models related to schizophrenia have assessed the effects of FGA or SGA, rarely have the authors discussed the relevance of the low to moderate effects of these drugs in patients (Martinez and Sarter, 2008). This approach becomes a problem when the animal models show full reversals of cognitive disruptions with antipsychotics – drugs that show minimal improvement in cognitive symptoms in patients.…”

Effects of the neurotensin NTS1 receptor agonist PD149163 on visual signal detection in rats

“…For example, the typical antipsychotic drug haloperidol and the atypical antipsychotic drugs clozapine and risperidone have been reported to decrease percent hits (Martinez and Sarter, 2008; Rezvani and Levin, 2004; Rezvani et al 2008). However, clozapine has been shown to reduce signal detection deficits produced by repeated-amphetamine exposure or acute MK-801 administration (Martinez and Sarter, 2008; Rezvani et al 2008). Occasional differences between the present and previous studies were observed between antipsychotic drugs for percent correct rejections.…”

“…The failure of PD149163 to improve attention in this task, and in fact disrupt attention at the highest dose tested, suggests that PD149163 may have limited or deleterious effects on attention in schizophrenia. However, to better evaluate its treatment potential for cognitive impairment in schizophrenia, studies using deficit models that better approximate the neurocognitive deficits found in schizophrenia, including attention deficits induced by NMDA receptor antagonism (Rezvani et al 2008), caused by repeated administration of amphetamine (Kondrad and Burk, 2004; Martinez and Sarter, 2008), or occurring in rats with innate cognitive deficits (e.g., Feifel et al 2007; Feifel et al 2011), are needed to better evaluate the validity of neurotensin NTS 1 receptor agonism for this purpose.…”

MAM (E17) rodent developmental model of neuropsychiatric disease: disruptions in learning and dysregulation of nucleus accumbens dopamine release, but spared executive function

“…As mentioned above, studies employing the repeated-AMPH model of schizophrenia reported alterations in task performance and changes in neurotransmitter release that become apparent following an AMPH challenge Martinez and Sarter 2008). Therefore, a theme that seems constant across different animal models of neuropsychiatric disease is that the full spectrum of neurobiological alterations becomes most apparent in the context of neural circuitry that has been engaged, be it by task performance or a pharmacological challenge.…”