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

Abstract

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 PCP (2 mg/kg) or vehicle i.p. twice daily for seven 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.

Multiple Modes of α7 nAChR Noncompetitive Antagonism of Control Agonist-Evoked and Allosterically Enhanced Currents

“…PAMs of a7 are being tested in numerous preclinical models related to a range of therapeutic indications from cognitive function (McLean et al, 2012) to neuropathic pain and inflammation (Bencherif et al, 2011). The conventional interpretation of the data in all of these disparate areas is that the effects of PAMs are due to the increased ion channel activity alone.…”

The subchronic phencyclidine rat model: relevance for the assessment of novel therapeutics for cognitive impairment associated with schizophrenia

“…# P=0.055, *P<0.05, **P<0.01, ***P<0.001 vs scVEH group at ED shift; ¤P<0.05 vs scPCP group at ED shift. These data were previously published Broberg et al 2009;Goetghebeur and Dias 2009;Goetghebeur et al 2010;Dawson et al 2012;McLean et al 2012;Maeda et al 2014), reproduced with permissions from Springer, SAGE Publications, ASPET and Oxford University Press Pharmacological validation of scPCP impaired attentional set-shifting task Second-generation antipsychotics such as clozapine and sertindole, but not olanzapine or aripiprazole or the typical antipsychotic haloperidol, have been reported to reverse the scPCP-induced impairment at ED shift (McLean et al 2008;Rodefer et al 2008;Broberg et al 2009;Goetghebeur and Dias 2009;Maeda et al 2014). Risperidone alleviated the scPCP-induced impairment at ED shift in female rats (McLean et al 2008) but not in male rats (Goetghebeur and Dias 2009).…”

“…Female rats appear more sensitive to PCP, and subchronic treatment with a lower dose of PCP (2 mg/kg i.p., twice a day for 7 days, followed by 7-day washout) produced a selective impairment of the ED shift in adult female Lister Hooded rats (Fig. 2) (McLean et al 2012). Lower dosing and shorter withdrawal from PCP (2.6 mg/kg, once daily for 5 days, followed by 72-h washout) impaired ED shift in adult male Long-Evans rats ( Fig.…”

Are positive allosteric modulators of α7 nAChRs clinically safe?

“…This increase in cell viability is consistent with our own studies that demonstrated < 1 lM PNU120596 significantly reduced brain injury and neurological deficits after focal ischemia in a transient 90 min middle cerebral artery occlusion model of ischemic stroke in young adult rats Sun et al 2013), as well as significantly reduced brain cell damage and reactive gliosis after brain injury in a control cortical impact model of traumatic brain injury (Gatson et al 2015). A concentration of < 1 lM PNU120596 can be achieved in rodents shortly after intravenous 1 mg/kg (Hurst et al 2005) or subcutaneous 10-30 mg/kg (McLean et al 2012; administration. In these in vivo studies, there was no indication of PNU120596 toxicity.…”

“…Judging by the existing information, the study by Guerra-Alvarez et al 2015 attempts to predict clinical limitations of PAMIIs from in vitro modeling of strictly overdose conditions. My skepticism about the value of this approach stems from the following illustrative comparisons of concentrations and exposure durations used in Guerra-Alvarez et al 2015 versus previous in vivo studies: 3-10 lM PNU120596 versus estimated 0.5-1.5 lM found therapeutic in vivo (Hurst et al 2005;McLean et al 2012;; 100 lM nicotine versus a maximum < 1 lM found in vivo (Russell et al 1980;Gourlay and Benowitz 1997;Rose et al 2010); and 10 lM PNU282987, a selective a7 agonist versus a realistic < 1 lM expected in vivo (Walker et al 2006). The drug exposure duration was set to 24 h for a7 agonists and 48 h for PNU120596 versus~8 h, the half-life time of PNU120596 in vivo (McLean et al 2012) or~2 h, the halflife time of nicotine in vivo (Russell et al 1980;Gourlay and Benowitz 1997;Rose et al 2010).…”