Elsevier

Brain Research

Volume 766, Issues 1–2, 22 August 1997, Pages 101-106
Brain Research

Research report
The GABAB receptor antagonist CGP36742 attenuates the baclofen- and scopolamine-induced deficit in Morris water maze task in rats

https://doi.org/10.1016/S0006-8993(97)00529-5Get rights and content

Abstract

Effects of CGP36742 (3-aminopropyl-n-butylphosphinic acid), an orally active GABAB receptor antagonist, on the baclofen- and scopolamine-induced deficit of place learning in the Morris water maze task were examined in rats. Rats were given four training trials per day with the submerged platform at a fixed location in the maze for 4 days. On day 4, the rats were required to swim in the pool without the platform after the fourth training trial (probe test). Intraperitoneal injection of baclofen (4 mg/kg) or scopolamine (0.3 mg/kg) significantly increased the escape latency to reach the platform and decreased the duration in the quadrant where the platform had been originally located. Increased latency in the training trials and decreased duration in the probe test induced by baclofen or scopolamine were significantly attenuated by oral administration of CGP36742 at doses of 10 and 30 mg/kg. In the rotarod test, CGP36742 at a dose of 100 mg/kg but not at doses of 10 or 30 mg/kg antagonized the baclofen-induced motor incoordination. Thus, there was dissociation between the effective doses of CGP36742 in the learning task and those in the sensory motor test. These results suggest the possible involvement of cholinergic systems as well as GABAB receptor systems in the CGP36742 action.

Introduction

γ-Aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the brain. It is accepted that GABA acts on two different GABA receptors in the brain: GABAA and GABAB receptors 6, 19. GABAA receptors are coupled with benzodiazepine receptors and Cl channels 17, 31. On the other hand, GABAB receptors are coupled with G protein [18]. The activation of GABAB receptors decreases the amplitude of Ca2+ currents [15]and increases K+ conductance [28].

Both GABAA and GABAB receptors are related to learning and memory. We previously studied the effects of muscimol (GABAA receptor agonist) and baclofen (GABAB receptor agonist) on place learning in the Morris water maze task in rats 24, 25, 26. It was found that in the rats treated with muscimol on days 1–3 and with saline on day 4 there was impairment of learning performance on day 4, whereas the rats injected with muscimol on days 1–4 showed no modification of learning performance 24, 26: muscimol induced state-dependent learning [32]but not the cognitive dysfunction. In state-dependent learning it is hypothesized that acquisition of a task under a drug state may require the same or similar drug state for recall, because the drug serves as a relevant internal cue [5]. In contrast, baclofen injected on days 1–4 dose-dependently increased the latency to reach the platform in the training sessions in that task 25, 26: baclofen impaired learning and memory. We also observed that muscimol and baclofen induced state-dependent learning and cognitive dysfunction in the passive avoidance task in rats, respectively [27]. From these results, we conclude that the activation of GABAA receptors may induce state-dependent learning, whereas GABAB receptor stimulation may impair learning and memory [26]. Our conclusion may have the implication that a GABAB receptor antagonist can have an anti-dementia or anti-amnesia profile.

CGP36742 (3-aminopropyl-n-butylphosphinic acid) is orally active and has an affinity for the GABAB receptor with an IC50 of 32 μM [4]. Carletti et al. [7]and Mondadori et al. 21, 22, 23reported that CGP36742 enhanced the passive avoidance response in mice, radial arm maze learning in mice, partner-recognition learning in rats and spatial learning in rhesus monkeys. Carletti et al. [7]found that CGP36742 attenuated the baclofen-induced deficit of place learning in the radial arm maze task in mice.

Cholinergic systems in the brain play an important role in learning and memory [35]. Especially, dementia of the Alzheimer type has been shown to be closely associated with deficit in the central cholinergic systems [12]. Recently, GABAB receptor systems were also found to be abnormal in dementia of the Alzheimer type [11]. These findings led to the suggestion that GABAB receptor systems may interact with cholinergic systems in learning and memory. Indeed, it has been reported that phaclofen, a GABAB receptor antagonist, modulated acetylcholine release in rat brain slices [3]. Furthermore, oxotremorine (a muscarinic receptor agonist) attenuated the baclofen-induced deficits of passive avoidance and place learning in rodents 10, 25, 26.

In this study, therefore, we designed an experiment to examine the effects of CGP36742 on the scopolamine- as well as baclofen-induced deficit of place learning in the Morris water maze task in rats to clarify the possible involvement of cholinergic as well as GABAB receptor systems in the attenuating effect of CGP36742 on the deficits of learning and memory. A rotarod test was also conducted to see the relationship between motor incoordination and the deficit of performance in the Morris water maze task.

Section snippets

Animals

Male Wistar rats (Charles River Japan), weighing 190–240 g at the beginning of the experiment, were used. They were housed in groups in an air and light controlled room (temperature 24±2°C, light phase 08:00–20:00 h). Food and water were given ad libitum.

Apparatus and procedure

The Morris water maze task and the rotarod test were conducted according to our previous studies 24, 25, 26.

Effects of CGP36742 on the baclofen-induced deficit of place learning in the Morris water maze task

Oral administration of CGP36742 had no effect on learning performance when it was given alone (data not shown).

The upper panel of Fig. 1 shows the latency to reach the platform in the training trials. Intraperitoneal injection of baclofen (4 mg/kg) significantly increased the latency to reach the platform, and oral administration of CGP36742 dose-dependently attenuated the increased latency. ANOVA indicated significant differences (day 1: F4,45=3.11, P<0.05; day 2: F4,45=8.05, P<0.01; day 3: F

Discussion

CGP36742 is orally active and has an affinity to the GABAB receptor with an IC50 of 32 μM [4]. In this study we found that oral administration of CGP36742 at doses of 10 and 30 mg/kg attenuated the scopolamine- as well as baclofen-induced deficit of place learning in the Morris water maze task in rats. However, the baclofen-induced motor incoordination was antagonized by oral administration of CGP36742 at a dose of 100 mg/kg but not at doses of 10 or 30 mg/kg. Thus, there was dissociation

Acknowledgements

Dedicated to Yoshinori Ishibashi. We are grateful to Dr. Helmut Bittiger (Ciba-Geigy, Basel) for kindly supplying CGP36742.

References (37)

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