Samantha L. McLean

Animal models of cognitive dysfunction and negative symptoms of schizophrenia: Focus on NMDA receptor antagonism

Cognitive deficits in schizophrenia remain an unmet clinical need. Improved understanding of the neuro- and psychopathology of these deficits depends on the availability of carefully validated animal models which will assist the development of novel therapies. There is much evidence that at least some of the pathology and symptomatology (particularly cognitive and negative symptoms) of schizophrenia results from a dysfunction of the glutamatergic system which may be modelled in animals through the use of NMDA receptor antagonists. The current review examines the validity of this model in rodents. We review the ability of acute and sub-chronic treatment with three non-competitive NMDA antagonists; phencyclidine (PCP), ketamine and MK801 (dizocilpine) to produce cognitive deficits of relevance to schizophrenia in rodents and their subsequent reversal by first- and second-generation antipsychotic drugs. Effects of NMDA receptor antagonists on the performance of rodents in behavioural tests assessing the various domains of cognition and negative symptoms are examined: novel object recognition for visual memory, reversal learning and attentional set shifting for problem solving and reasoning, 5-Choice Serial Reaction Time for attention and speed of processing; in addition to effects on social behaviour and neuropathology. The evidence strongly supports the use of NMDA receptor antagonists to model cognitive deficit and negative symptoms of schizophrenia as well as certain pathological disturbances seen in the illness. This will facilitate the evaluation of much-needed novel pharmacological agents for improved therapy of cognitive deficits and negative symptoms in schizophrenia.

A preliminary investigation into the effects of antipsychotics on sub-chronic phencyclidine-induced deficits in attentional set-shifting in female rats.

RATIONALE The NMDA receptor antagonist, phencyclidine (PCP), has been shown to induce symptoms characteristic of schizophrenia. A loss in executive function and the ability to shift attention between stimulus dimensions is impaired in schizophrenia; this can be assessed in rodents by the perceptual attentional set-shifting task. OBJECTIVE The aim of this study was to investigate whether the deficits induced by sub-chronic PCP in attentional set-shifting could be reversed by sub-chronic administration of clozapine, risperidone or haloperidol. METHODS Adult female hooded-Lister rats received sub-chronic PCP (2 mg/kg) or vehicle (1 ml/kg) i.p. twice daily for 7 days, followed by a 7-day washout period. PCP-treated rats then received clozapine, risperidone, haloperidol or vehicle once daily for 7 days and were then tested in the perceptual set-shifting task. RESULTS PCP significantly (p<0.01) increased the number of trials to reach criterion in the EDS phase when compared to vehicle and this deficit was significantly (p<0.01) attenuated by sub-chronic clozapine (2.5 mg/kg) and risperidone (0.2 mg/kg), but not by sub-chronic haloperidol treatment (0.05 mg/kg). CONCLUSIONS These data show that sub-chronic PCP produced a robust deficit within the EDS phase in the attentional set-shifting task, in female rats. Atypical antipsychotics, clozapine and risperidone, but not the classical agent, haloperidol, significantly improved the PCP-induced cognitive deficit.

Isolation rearing impairs novel object recognition and attentional set shifting performance in female rats

It has been suggested that the isolation rearing paradigm models certain aspects of schizophrenia symptomatology. This study aimed to investigate whether isolation rearing impairs rats’ performance in two models of cognition: the novel object recognition (NOR) and attentional set-shifting tasks, tests of episodic memory and executive function, respectively. Two cohorts of female Hooded-Lister rats were used in these experiments. Animals were housed in social isolation or in groups of five from weaning, post-natal day 28. The first cohort was tested in the NOR test with inter-trial intervals (ITIs) of 1 min up to 6 h. The second cohort was trained and tested in the attentional set-shifting task. In the NOR test, isolates were only able to discriminate between the novel and familiar objects up to 1-h ITI, whereas socially reared animals remembered the familiar object up to a 4-h ITI. In the attentional set-shifting task, isolates were significantly and selectively impaired in the extra-dimensional shift phase of the task (P < 0.01). Rats reared in isolation show impaired episodic memory in the NOR task and reduced ability to shift attention between stimulus dimensions in the attentional set-shifting task. Because schizophrenic patients show similar deficits in performance in these cognitive domains, these data further support isolation rearing as a putative preclinical model of the cognitive deficits associated with schizophrenia.

PNU-120596, a positive allosteric modulator of α7 nicotinic acetylcholine receptors, reverses a sub-chronic phencyclidine-induced cognitive deficit in the attentional set-shifting task in female rats

The α7 nicotinic acetylcholine receptors (nAChRs) have been highlighted as a target for cognitive enhancement in schizophrenia. Adult female hooded Lister rats received sub-chronic phencyclidine (PCP) (2 mg/kg) or vehicle i.p. twice daily for 7 days, followed by 7 days’ washout. PCP-treated rats then received PNU-120596 (10 mg/kg; s.c.) or saline and were tested in the attentional set-shifting task. Sub-chronic PCP produced a significant cognitive deficit in the extra-dimensional shift (EDS) phase of the task (p < 0.001, compared with vehicle). PNU-120596 significantly improved performance of PCP-treated rats in the EDS phase of the attentional set-shifting task (p < 0.001). In conclusion, these data demonstrate that PNU-120596 improves cognitive dysfunction in our animal model of cognitive dysfunction in schizophrenia, most likely via modulation of α7 nACh receptors.

D1-like receptor activation improves PCP-induced cognitive deficits in animal models: Implications for mechanisms of improved cognitive function in schizophrenia

Phencyclidine (PCP) produces cognitive deficits of relevance to schizophrenia in animal models. The aim was to investigate the efficacy of the D(1)-like receptor agonist, SKF-38393, to improve PCP-induced deficits in the novel object recognition (NOR) and operant reversal learning (RL) tasks. Rats received either sub-chronic PCP (2 mg/kg) or vehicle for 7 days, followed by a 7-day washout. Rats were either tested in NOR or the RL tasks. In NOR, vehicle rats successfully discriminated between novel and familiar objects, an effect abolished in PCP-treated rats. SKF-38393 (6 mg/kg) significantly ameliorated the PCP-induced deficit (P<0.01) an effect significantly antagonised by SCH-23390 (0.05 mg/kg), a D(1)-like receptor antagonist (P<0.01). In the RL task sub-chronic PCP significantly reduced performance in the reversal phase (P<0.001); SKF-38393 (6.0 mg/kg) improved this PCP-induced deficit, an effect antagonised by SCH-23390 (P<0.05). These results suggest a role for D(1)-like receptors in improvement of cognitive function in paradigms of relevance to schizophrenia.

Activation of α7 nicotinic receptors improves phencyclidine-induced deficits in cognitive tasks in rats: implications for therapy of cognitive dysfunction in schizophrenia.

RATIONALE Nicotinic α7 acetylcholine receptors (nAChRs) have been highlighted as a target for cognitive enhancement in schizophrenia. AIM To investigate whether the deficits induced by sub-chronic phencyclidine (PCP) in reversal learning and novel object recognition could be attenuated by the selective α7 nAChR full agonist, PNU-282987. METHODS Adult female hooded-Lister rats received sub-chronic PCP (2mg/kg) or vehicle i.p. twice daily for 7days, followed by 7 days washout. In cohort 1, PCP-treated rats then received PNU-282987 (5, 10, 20mg/kg; s.c.) or vehicle and were tested in the reversal-learning task. In cohort 2, PCP-treated rats received PNU-282987 (10mg/kg; s.c.) or saline for 15days and were tested in the novel object recognition test on day 1 and on day 15, to test for tolerance. RESULTS Sub-chronic PCP produced significant deficits in both cognitive tasks (P<0.01-0.001). PNU-282987 attenuated the PCP-induced deficits in reversal learning at 10mg/kg (P<0.01) and 20mg/kg (P<0.001), and in novel object recognition at 10mg/kg on day 1 (P<0.01) and on day 15 (P<0.001). CONCLUSIONS These data show that PNU-282987 has efficacy to reverse PCP-induced deficits in two paradigms of relevance to schizophrenia. Results further suggest that 15-day once daily dosing of PNU-282987 (10mg/kg s.c.) does not cause tolerance in the rat. This study suggests that activation of α7 nAChRs, may represent a suitable strategy for improving cognitive deficits of relevance to schizophrenia.

Effects of asenapine, olanzapine, and risperidone on psychotomimetic-induced reversal-learning deficits in the rat

BACKGROUND Asenapine is a new pharmacological agent for the acute treatment of schizophrenia and bipolar disorder. It has relatively higher affinity for serotonergic and alpha(2)-adrenergic than dopaminergic D(2) receptors. We evaluated the effects of asenapine, risperidone, and olanzapine on acute and subchronic psychotomimetic-induced disruption of cued reversal learning in rats. METHODS After operant training, rats were treated acutely with d-amphetamine (0.75 mg/kg intraperitoneally [i.p.]) or phencyclidine (PCP; 1.5mg/kg i.p.) or subchronically with PCP (2mg/kg i.p. for 7 days). We assessed the effects of acute coadministration of asenapine, risperidone, or olanzapine on acute d-amphetamine- and PCP-induced deficits and the effects of long-term coadministration of these agents (for 28 additional days) on the deficits induced by subchronic PCP. RESULTS Deficits in reversal learning induced by acute d-amphetamine were attenuated by risperidone (0.2mg/kg i.p.). Acute PCP-induced impairment of reversal learning was attenuated by acute asenapine (0.025 mg/kg subcutaneously [s.c.]), risperidone (0.2mg/kg i.p.), and olanzapine (1.0mg/kg i.p.). Subchronic PCP administration induced an enduring deficit that was attenuated by acute asenapine (0.075 mg/kg s.c.) and by olanzapine (1.5mg/kg i.p.). Asenapine (0.075 mg/kg s.c.), risperidone (0.2mg/kg i.p.), and olanzapine (1.0mg/kg i.p.) all showed sustained efficacy with chronic (29 days) treatment to improve subchronic PCP-induced impairments. CONCLUSION These data suggest that asenapine may have beneficial effects in the treatment of cognitive symptoms in schizophrenia. However, this remains to be validated by further clinical evaluation.

Effects of subchronic phencyclidine on behaviour of female rats on the elevated plus maze and open field

Female hooded-Lister rats received either subchronic phencyclidine (PCP) (2 mg/kg, n = 20) or vehicle (1 ml/kg, n = 20) intraperitoneally twice daily for 7 days, followed by a 7-day washout period. Rats were challenged with acute PCP or vehicle and tested for locomotor activity to ensure hyperactivity was observed in the subchronic PCP-treated rats. Rats were then tested on the elevated plus maze and in an open field for 10 min. Subchronic PCP did not significantly affect behaviour on the elevated plus maze or in the open field. In conclusion, subchronic PCP does not induce anxiety-like behaviour.

Nicotinic α7 and α4β2 agonists enhance the formation and retrieval of recognition memory: potential mechanisms for cognitive performance enhancement in neurological and psychiatric disorders

Cholinergic dysfunction has been shown to be central to the pathophysiology of Alzheimers disease and has also been postulated to contribute to cognitive dysfunction observed in various psychiatric disorders, including schizophrenia. Deficits are found across a number of cognitive domains and in spite of several attempts to develop new therapies, these remain an unmet clinical need. In the current study we investigated the efficacy of donepezil, risperidone and selective nicotinic α7 and α4β2 receptor agonists to reverse a delay-induced deficit in recognition memory. Adult female Hooded Lister rats received drug treatments and were tested in the novel object recognition (NOR) task following a 6h inter-trial interval (ITI). In all treatment groups, there was no preference for the left or right identical objects in the acquisition trial. Risperidone failed to enhance recognition memory in this paradigm whereas donepezil was effective such that rats discriminated between the novel and familiar object in the retention trial following a 6h ITI. Although a narrow dose range of PNU-282987 and RJR-2403 was tested, only one dose of each increased recognition memory, the highest dose of PNU-282987 (10mg/kg) and the lowest dose of RJR-2403 (0.1mg/kg), indicative of enhanced cognitive performance. Interestingly, these compounds were also efficacious when administered either before the acquisition or the retention trial of the task, suggesting an important role for nicotinic receptor subtypes in the formation and retrieval of recognition memory.

Using haloperidol as an antiemetic in palliative care: informing practice through evidence from cancer treatment and postoperative contexts.

ABSTRACT Nausea and vomiting are common symptoms in palliative care. Haloperidol is often used as an antiemetic in this context, although direct evidence supporting this practice is limited. To evaluate the efficacy and clinical use of haloperidol as an antiemetic in nonpalliative care contexts to inform practice, the authors conducted a rapid review of (i) published evidence to supplement existing systematic reviews, and (ii) practical aspects affecting the use of haloperidol including formulations and doses that are commonly available internationally. In nausea and vomiting related to cancer treatment, haloperidol was superior to control in two small studies. In postoperative nausea and vomiting (PONV), two randomized controlledtrials found treatment with haloperidol comparable to ondansetron. In palliative care, an observational study found a complete response rate of 24% with haloperidol (one in four patients) which would be consistent with a number needed to treat (NNT) of 3 to 5 derived from PONV. There remains insufficient direct evidence to definitively support the use of haloperidol for the management of nausea and vomiting in palliative care. However, generalizing evidence from other clinical contexts may have some validity.