Amelioration of PCP-induced learning and memory deficits in the Morris’ water maze by selective α7 nAChR agonists

Presented at: British Association for Psychopharmacology annual summer conference, Oxford, 2009
Engel M, Sandager-Nielsen K, Mirza NR.
Dept In Vivo Pharmacology, NeuroSearch A/S, 93 Pederstrupvej, DK-2750 Ballerup, Denmark

Introduction
The N-methyl-D-aspartate antagonist phencyclidine (PCP) can produce schizophrenia like symptoms in healthy human subjects and exacerbate positive and negative symptoms in schizophrenic patients. Further, some studies have demonstrated that α7 nAChR agonists can improve short & long term memory in animal models. Previous studies have demonstrated that α7 agonists can reverse MK-801 or aged related impairments in rodent water maze (WM) tasks (Pichat et al., 2007, Neuropsychopharmacology, 31(1), 17-34; Boess et al., 2007, J Pharmacol Exp Ther., 321(2), 716-25).

In the present study, we determined if selective α7 agonists (SSR180711 and PNU-282987) would reverse a subchronic PCP-induced deficit in spatial learning using the WM.
Method
Saline or PCP (1.3mg/kg/day, s.c.) were administered to wistar rats for 3 consecutive days prior to the first swim trial. Forty-five min. before the start of each swim session, vehicle, SSR180711 (10mg/kg, i.p.) or PNU-282987 (10mg/kg, i.p.) were administered followed by vehicle or PCP (1.3mg/kg, s.c.) 15 min. later. There were 4 swims per day separated by 15 sec., for 4 consecutive test days.
Results
Both latency and distance parameters clearly showed that PCP treatment resulted in a shallow acquisition curve compared to control. Both α7 agonists significantly reversed this PCP induced impairment. The effect of both α7 agonists was most pronounced on days 3-4. Videotracks of rat exploration on day 3 showed that rats treated with α7 agonists clearly reversed marked thigmotaxis in PCP-treated animals. Swimming speed was not altered by any compound, indicating that motor function was unaffected.
Conclusion
These results show that subchronic PCP administration induces significant impairment of WM learning, and that this is reversed by α7 agonists. The effects seen with SSR180711 have been reproduced in two separate WM studies suggesting the subchronic PCP model is likely a reliable method for comparing various α7 agonists. Finally, nothwithstanding the limited doses of both α7 agonists assessed, in our hands PNU-282987 was the more efficacious compound in this model. The reason(s) for this are unclear, but might be important because available α7 agonists can differ considerably on parameters such as in-vitro affinity, efficacy, and additional activity at 5-HT3 receptors. More side-by-side comparisons of α7 agonists in reliable in-vivo model s of cognitive function are necessary to better ascertain the in-vitro determinants necessary for in-vivo signals.

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