Research reportThe GABAB receptor antagonist CGP36742 attenuates the baclofen- and scopolamine-induced deficit in Morris water maze task in rats
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)
- et al.
GABAergic synaptic current in dissociated nucleus basalis of Meynert neurons of the rat
Brain Res.
(1992) - et al.
Increased acetylcholine and quisqualate responsiveness after blockade of GABAB receptors
Eur. J. Pharmacol.
(1992) - et al.
GABAA and GABAB antagonists prevent the opioid inhibition of endogenous acetylcholine release evoked by glutamate from rat neostriatal slices
Neurosci. Lett.
(1990) - et al.
Post-training systemic and intra-amygdala administration of the GABAB agonist baclofen impairs retention
Behav. Neural Biol.
(1989) - et al.
Oxotremorine attenuates retrograde amnesia induced by post-training administration of the GABAergic agonists muscimol and baclofen
Behav. Neural Biol.
(1991) Cholinergic function and intellectual decline in Alzheimer's disease
Neuroscience
(1986)- et al.
Stimulation of GABAB receptors in the basal forebrain selectively impairs working memory of rats in the double Y-maze
Brain Res.
(1994) - et al.
GABAergic synapses: supramolecular organization and biochemical regulation
Neuropharmacology
(1983) GABA receptors: are cellular differences reflected in function?
Brain Res. Rev.
(1989)- et al.
Baclofen, a selective GABAB receptor agonist, dose-dependently impairs spatial learning in rats
Pharmacol. Biochem. Behav.
(1996)
CGP36742: the first orally active GABAB blocker improves the cognitive performance of mice, rats, and rhesus monkeys
Behav. Neural Biol.
The GABAB receptor antagonist CGP36742 and the nootropic oxiracetam facilitate the formation of long-term memory
Behav. Brain Res.
CGP36742, an orally active GABAB receptor antagonist, facilitates memory in a social recognition test in rats
Behav. Brain Res.
Muscimol induces state-dependent learning in Morris water maze task in rats
Brain Res.
Involvement of cholinergic systems in the deficit of place learning in Morris water maze task induced by baclofen in rats
Brain Res.
Interaction between benzodiazepine and GABAA receptors in state-dependent learning
Life Sci.
A possible postsynaptic inhibitory action for GABAB receptors on hippocampal pyramidal cells
Neuropharmacology
CGP35348: a centrally active blocker of GABAB receptors
Eur. J. Pharmacol.
Cited by (64)
How do stupendous cannabinoids modulate memory processing via affecting neurotransmitter systems?
2021, Neuroscience and Biobehavioral ReviewsNeuroprotective role of GABA<inf>B</inf> receptor modulation against streptozotocin-induced behavioral and biochemical abnormalities in rats
2017, NeuroscienceCitation Excerpt :In line with our observed results, the improvement of cognitive functions has been shown in mice using active and passive avoidance, radial maze, MWM and in social learning paradigms in various experimental animals following GABABR antagonism (Froestl et al., 2004). Moreover, GABAB receptor blockade has also been reported to enhance memory function in Ts65Dn mice model of Down syndrome (Kleschevnikov et al., 2012), whereas, impaired learning and memory has been reported following baclofen treatment in MWM paradigm (Nakagawa and Takashima, 1997). It has also been demonstrated that the direct infusion of baclofen in septal nuclei’s and nucleus basalis magnocellularis containing larger distribution of cholinergic neurons, produce cognitive impairments in rats (Stackman and Walsh, 1994; DeSousa et al., 1994).
Possible involvement of the CA1 GABAergic system on harmaline induced memory consolidation deficit
2017, Brain Research BulletinSerotonergic modulation of septo-hippocampal and septo-mammillary theta activity during spatial learning, in the rat
2017, Behavioural Brain ResearchRole of GABA<inf>B</inf> receptors in learning and memory and neurological disorders
2016, Neuroscience and Biobehavioral ReviewsCitation Excerpt :As with passive avoidance, there are differential effects to a single ligand based on the strain of mouse utilized. For instance, CGP 36742 has no effect on task acquisition in BALB/c and CF1 mice (Sunyer et al., 2007) or Wistar rats (Nakagawa and Takashima, 1997); C57BL/6J and OF1 mice perform better than controls when treated with the antagonist (Sunyer et al., 2007, 2009b), and CD1 and DBA/2 mice demonstrate impaired task performance (Sunyer et al., 2007). While there are differences in basal receptor levels in the hippocampus, there are also differences in how well these strains acquire the task without any drug manipulations.
Comparison of the effects of the GABA<inf>B</inf> receptor positive modulator BHF177 and the GABA<inf>B</inf> receptor agonist baclofen on anxiety-like behavior, learning, and memory in mice
2013, NeuropharmacologyCitation Excerpt :Because the Vogel conflict test is a conflict-based anxiety test that involves aversive learning to a painful stimulus (Millan and Brocco, 2003), the flinch–jump test was conducted to determine whether analgesic effects of the compound are involved in the effects obtained in this conflict test. Furthermore, activation of the GABAB receptor by baclofen has been reported to disrupt learning and memory (Castellano et al., 1989; McNamara and Skelton, 1996; Nakagawa and Takashima, 1997; Pitsikas et al., 2003; Stackman and Walsh, 1994; Zarrindast et al., 2004). Therefore, the effects of BHF177 and baclofen on fear-related learning and memory, evaluated in the contextual and cued fear conditioning tests, and spatial learning and memory, evaluated in the Barnes maze, were investigated to characterize any potential cognitive deficits induced by these compounds.