Low dose citalopram reverses memory impairment and electroconvulsive shock-induced immobilization

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Abstract

Citalopram, a selective serotonin reuptake inhibitor (SSRI), is one of the most widely used antidepressants. Recently, citalopram has been reported to improve working memory in patients with depression, and psychotic symptoms and behavioral disturbances in patients with dementia. However, the possibility of using citalopram in the treatment of cognitive disorders has not received much attention. The present study investigated the effects of citalopram on scopolamine- and Δ9-tetrahydrocannabinol (THC)-induced impairment of spatial memory using an eight-arm radial maze and electroconvulsive shock (ECS)-induced immobilization (a behavioral model for the disturbance of consciousness). Low dose citalopram reversed both scopolamine- and THC-induced impairment of spatial memory, suppressed ECS-induced immobilization reversed the THC-induced decrease of acetylcholine (ACh) release in the dorsal hippocampus in vivo microdialysis, and enhanced tremors induced by oxotremorine, a muscarinic M1 receptor agonist. Taken together these findings suggest that low dose citalopram is useful for the treatment of memory deficits and consciousness disturbance.

Introduction

Citalopram, a selective serotonin reuptake inhibitor (SSRI), has been widely used in several disorders related to serotonergic dysfunction, including depression, anxiety, panic disorders, obsessive–compulsive disorder and premenstrual dysphoria (Masand and Gupta, 1999, Pollock, 2001). Citalopram exerts its clinical effects by inhibiting the uptake of serotonin (5-HT) from the synaptic cleft. It has been demonstrated by microdialysis that acute administration of citalopram raises the extracellular concentration of 5-HT in the rat dorsal and ventral hippocampus (Hjorth, 1993, Hjorth et al., 1997, Invernizzi et al., 1995). Also, local perfusion of citalopram increases acetylcholine (ACh) release in the rat frontal cortex and dorsal hippocampus (Consolo et al., 1994, Yamaguchi et al., 1997). Recently, citalopram has been reported to improve working memory in patients with depression (Zobel et al., 2004) and psychotic symptoms and behavioral disturbances in patients with dementia (Pollock et al., 2002). Furthermore, acute administration of citalopram facilitates memory consolidation in healthy volunteers (Harmer et al., 2002). Notwithstanding these results, the possibility of using citalopram in the treatment of cognitive disorders has not received much attention.

Memory impairment is a cardinal symptom of Alzheimer's disease (AD), and thought to be secondary, at least to some degree, to central cholinergic neuropathology (Bartus et al., 1982, Coyle et al., 1983). The cholinesterase inhibitors donepezil and tetrahydroaminoacridine have been shown to improve memory disorders in AD patients (Rogers et al., 1998, Summers et al., 1986). Scopolamine, a non-selective muscarinic receptor antagonist, has been used to induce memory disturbance in experimental animal models (Egashira et al., 2001, Hatip-Al-Khatib et al., 2004, Smith, 1988).

Delta9-tetrahydrocannabinol (THC), a principal psychoactive component of marijuana, is known to impair learning and memory in humans (Ameri, 1999, D'Souza et al., 2004, Heishman et al., 1997, Hollister, 1986, Miller and Branconnier, 1983). THC also impairs spatial memory in rats (Lichtman and Martin, 1996, Mallet and Beninger, 1998). We previously reported that THC-induced impairment of spatial memory is likely to be associated with dysfunction of the cholinergic and serotonergic systems (Egashira et al., 2002b, Mishima et al., 2002).

Disturbance of consciousness is an important symptom of cerebrovascular disorders and brain injury. We previously reported that electroconvulsive shock (ECS)-induced immobilization is suppressed by amantadine (Egashira et al., 2001), which has been used clinically to treat disturbance of consciousness (Zafonte et al., 1998). The immobilized state is induced by light ECS-treatment. Such ECS-induced immobilization is easily inhibited by air blowing, sound and tactile stimuli. Thus, ECS-induced immobilization is markedly different from catalepsy, which is induced by large doses of major tranquilizers. This immobilized state may be thought to represent a decreased level of consciousness. Therefore, ECS-induced immobilization is considered to be a model of consciousness disturbance.

In a recent study, we found that a very low dose of 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), a 5-HT1A receptor agonist, reversed impairment of spatial memory induced by THC in an eight-arm radial maze (Inui et al., 2004). 8-OH-DPAT at the same dose also reversed the THC-induced decrease of ACh release in the dorsal hippocampus in vivo microdialysis. Therefore, low dose 8-OH-DPAT is thought to reverse THC-induced impairment of spatial memory by enhancing ACh release in the dorsal hippocampus. Moreover, low doses of 8-OH-DPAT have been reported to prevent the impairment of spatial learning caused by intrahippocampal scopolamine through 5-HT1A receptors in the dorsal raphe (Carli et al., 2000). However, the effect of citalopram on impairment of spatial memory remains unexplored. Accordingly, the present study was conducted to investigate the effects of citalopram on scopolamine- and THC-induced impairment of spatial memory in the eight-arm radial maze in rats. We also examined the effect of citalopram on ECS-induced immobilization in rats. Furthermore, we examined the effect of citalopram on THC-induced decrease of ACh release in the dorsal hippocampus in rats. In addition, we examined the effect of citalopram on oxotremorine-induced tremors in mice, to investigate the involvement of cholinergic neurons.

Section snippets

Animals

Male Wistar rats, aged 7 weeks and weighing 200–250 g, and male ddY mice, aged 4 weeks and weighing 20–25 g, were obtained from Kyudo (Saga, Japan). They were housed in groups of four to five per cage for rats, and eight to 10 per cage for mice, in a room with a controlled temperature of 23 ± 2 °C, relative humidity of 60 ± 10% and the lights on from 07.00 to 19.00 h. The animals scheduled to undergo the eight-arm radial maze task were placed under a restricted food intake (10–12 g daily, CE-2; Clea

Effect of citalopram on scopolamine-induced impairment of spatial memory

Fig. 1 shows the effect of citalopram on scopolamine-induced impairment of spatial memory in the eight-arm radial maze. Scopolamine (0.5 mg/kg, i.p.) significantly reduced the number of correct choices and also increased the number of errors (P < 0.01 by the Bonferroni test), indicating impairment of spatial memory. Citalopram at low doses significantly reversed scopolamine-induced impairment of spatial memory (correct choices: (F(4,62) = 22.413, P < 0.001 and errors: (F(4,62) = 18.230, P < 0.001 by

Discussion

In the present study, low dose citalopram reversed scopolamine-induced impairment of spatial memory in the eight-arm radial maze. The cholinesterase inhibitors donepezil and THA have been shown to improve memory disorders in AD patients (Rogers et al., 1998, Summers et al., 1986). These drugs also have beneficial effects on scopolamine-induced memory deficits in rats (Higgins et al., 2002, Murray et al., 1991). We also reported that THA reversed the scopolamine-induced impairment of spatial

Acknowledgments

Part of this study was supported by a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan (No. 16591174). The authors are grateful to Zeria Pharmaceutical Co., Ltd. (Tokyo, Japan) for generously supplying citalopram.

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