The effects of d-cycloserine, a partial agonist at the glycine binding site, on spatial learning and working memory in scopolamine-treated rats

Abstract

The present study investigated the effect of d-cycloserine, a partial agonist at the glycine binding site on NMDA receptor complex, on the performance of scopolamine-treated adult rats in a water maze task assessing spatial learning and in a delayed non-matching to position task assessing working memory in a spatial context. In the spatial learning task, scopolamine (0.4 mg/kg, i.p.) impaired acquisition (increased escape latency and distance) and increased swimming speed of rats. D-cycloserine (1.0 mg/kg, i.p.) reversed the deficits in acquisition performance but not the increases in behavioral activity. In the working memory task, scopolamine (0.2 mg/kg, i.p.) produced deficits on nonmnemonic rather than on mnemonic performance factors; scopolamine delay-independently decreased the percent correct responses and reduced behavioral activity of rats. D-cycloserine (1.0, 3.0 and 10 mg/kg, i.p.) did not reverse these performance deficits. When administered alone, the moderate to higher doses of d-cycloserine had no effects on working memory but the lower dose produced slight deficits in mnemonic performance factors; the 1.0 mg/kg dose delay-dependently decreased the percent correct responses without affecting behavioral activity of rats. In the water maze task, d-cycloserine had no effects on acquisition performance or behavioral activity of rats. These results suggest that acute, systemic administration of d-cycloserine does not improve spatial learning or working memory. However, at appropriate doses this agent may be efficacious in disease states of central cholinergic hypofunction since 1.0 mg/kg d-cycloserine was able to reverse the scopolamine-induced deficits in acquisition.

Additive deficits in the choice accuracy of rats in the delayed non-matching to position task after cholinolytics and serotonergic lesions are non-mnemonic in nature

“…Scopolamine treatment also interfered with behavioural activity of rats which is supported by previous reports (Buxton et al 1994;Kirkby et al 1995;Pitkänen et al 1995). Scopolamine also increased food collection latencies, thus reflecting reduced motivation for food reward, which may be due to reduced palatability of food pellets resulting from dryness of mouth.…”

“…Scopolamine significantly impaired choice accuracy of rats as found previously in both delayed matching and non-matching to position task at doses of 0.1-0.5 mg / kg (Sahgal et al 1990;Andrews et al 1994;Buxton et al 1994;Kirkby et al 1995;Pitkänen et al 1995). In addition, scopolamine (0.1; 0.2; 0.3 mg/kg) impaired the accuracy of the performance in the continuous non-matching to sample working memory task (Sakurai and Wenk 1990).…”

“…For example, previous experiments using the Morris water maze have demonstrated that manipulation of the cholinergic system can interfere with spatial learning and reference memory (Riekkinen Jr et al 1990) and recently it has been shown that scopolamine also impairs the working memory in the water maze paradigm (Santucci et al 1995). However, nucleus basalis magnocellularis lesions, induced by quisqualic acid, resulted in a nonmnemonic type of deficit in the continuous delayed non-matching to position tasks which measures the working memory (Sahgal et al 1990;Sahgal and Keith 1993), and that this could be mimicked by systemic administration of scopolamine (Sahgal et al 1990;Pitkänen et al 1995). In addition, administration of scopolamine into the prefrontal area induced an impairment in choice accuracy not dependent on delay, whereas the intrahippocampal administration of scopolamine caused a reduction of choice accuracy in this task interpreted as a failure in working memory ).…”

Neonatal Phencyclidine Treatment in Mice Induces Behavioral, Histological and Neurochemical Abnormalities in Adulthood

“…The doses of clozapine were established on the basis of the reports of Ballard et al 11) and Qiao et al 12) D-Cycloserine (Sigma-Aldrich Co.) was suspended in 0.5% methylcellulose and administered orally at 0.3, 1 and 10 mg/kg 2 h before the test. Dose levels of D-cycloserine were established with reference to previous reports by Noda et al 13) and Pitkänen et al 14) Flumazenil (SigmaAldrich Co.) at 3 and 10 mg/kg was injected s.c. while SHC50911 (Wako Chemical, Tokyo, Japan) at 1 and 3 mg/kg was injected intraperitoneally (i.p.) 30 min before the test.…”

Genetic inactivation of D-amino acid oxidase enhances extinction and reversal learning in mice

“…Activation of the NMDAR glycine site has been shown to be necessary for the acquisition and memory retrieval of a single platform location (Watanabe et al 1992). However, the ability of glycine site activators to potentiate this type of spatial learning and memory beyond normal capacity remains controversial (Pitkänen et al 1995;Andersen and Pouzet 2004;Maekawa et al 2005b;Duffy et al 2008;Zhang et al 2008), and discrepancies may reflect different procedural demands, dosing regimes, or species. In the acquisition phase of our study, animals were trained to achieve asymptotic performance in order to assess reversal learning and extinction from a common baseline.…”