Research reportA dose–response study of the effects of pre-test administration of beta-adrenergic receptor antagonist propranolol on the learning of active place avoidance, a spatial cognition task, in rats
Introduction
Noradrenaline and adrenaline receptors (adrenoceptors) are abundantly present throughout the central nervous system of vertebrates [3]. The vast majority of central noradrenergic projections originate in the locus coeruleus, a brainstem nucleus, from which neurons releasing noradrenaline, and to lesser extent adrenaline, project to various areas of the brain [3]. The synaptic effects of noradrenaline are mediated by two classes of receptors (alpha- and beta-), both coupled with G-proteins [28]. These families are further divided into subtypes, differing in ligand specificity, kinetics, and effects. Alpha1- and beta-adrenoceptors were found to be mainly postsynaptic, whilst alpha2-adrenoceptors are localized both presynpatically and postsynaptically [3]. The role of alpha-adrenoceptors is less studied and usually not considered as crucial for cognitive functions as that of beta-subtype; e.g. [33]. However, evidence from literature [13], [19] supports the view that both alpha1- and alpha2-adrenoceptors may modulate learning and cognitive processes. Beta-adrenergic receptors are expressed in the brain to a substantially lesser extent than alpha-adrenoceptors [33], however, they have been demonstrated to exhibit important modulatory roles in the regulation of vigilance and learning [2], [26] as well as memory consolidation [6] and reconsolidation [24].
Noradrenergic neurons originating in the locus coeruleus innervate many target brain regions to include the septum, amygdala, prefrontal, parietal and other associative cortices [3]. A substantial amount of noradrenergic bundles also reaches hippocampus. This structure is crucial for spatial cognition processes in animals and for certain forms of declarative memory in humans. Lesions or transient inactivations of the hippocampus were found to impair the animal's performance in various spatial tasks [7], [8], [21]. An intact hippocampus is also required for successful performance of the active allothetic place avoidance (AAPA) task [7], [8], which was used in the present study for behavioral screening.
Research in the regulatory roles of various receptors in the spatial behavior and place navigation represents an intensively studied field of behavioral and cognitive neuroscience; for review see [22]. Approximately 10 years ago, a dry-arena spatial task, called active allothetic place avoidance, was designed in our laboratory [5], [7]. This cognitive task allows the simultaneous assessments of locomotion and spatial orientation [31], [33] and was used in several previous studies as a tool for the investigation of the neurotransmitter role in behavior [30], [31], [32], [33]. In this task, animals are trained to actively move over a slowly rotating arena and avoid a sector, entering which is punished by a mild footshock [7], [8]. The shock sector is defined in a stable position with respect to experimental room. Animals must thus recognize the position of the shock sector and walk in the safe part of the arena in a direction opposite to arena rotation; otherwise they would be repeatedly passively transported into the sector. It was demonstrated that when avoiding specific places, rats use both the intramaze cues (urine, droppings, and scent markings) as well as distal visual landmarks located in the room [11]. However, both these classes of information are brought into a conflict by arena rotation in the active place avoidance. Therefore the animals must segregate spatial stimuli (both proximal and distal) into coherent representations of the arena and room [17] and to select the room frame as the only relevant coordinate system for efficient performance in the task. This ability was described as hippocampal-dependent “cognitive coordination” in the important paper of Wesierska et al. [37]. The requirement to segregate spatial information into coherent representations of the arena and room and requirement of the selection of one of those frames [17], [37] makes the task useful for studying animal models of cognitive deficits in schizophrenia [4], [32], involvement of various brain receptors in the performance of the place avoidance [32], [33], and selective brain lesions [34], [36].
One of our previous studies demonstrated that alpha1- and alpha2-adrenergic receptors exert a rather limited role in the spatial behavior in the AAPA task [33]. The application of specific antagonists of these receptors affected spatial performance at relatively higher doses, which also depressed the locomotor activity of animals. Taking into account the fact that the impact of beta-adrenoceptors on cognitive functions is considered to be more pronounced than that of the alpha-subtype, the present study aimed at evaluating the role of central beta-adrenoceptors in spatial behavior measured in the active place avoidance task. Using systemic administration of the beta subtype-specific antagonist propranolol, the present study attempted to test the hypothesis that a certain degree of blockage of brain beta-adrenergic receptors would result in selective impairments of spatial cognition in the place avoidance task while having no effect on the locomotor activity. Based on the previous results of other studies [15], [16], [23] and our pilot data, we chose four doses of propranolol, which were most likely to represent the threshold (the minimal effective) doses for affecting place avoidance behavior.
Section snippets
Animals
Thirty-nine experimentally naive male adult rats of the Long-Evans strain (3–5 months old, weighing 250–450 g) were used in the study. The animals were obtained from the accredited breeding colony of the Institute of Physiology AS CR, v.v.i. The animals were housed in pairs in 30 cm × 30 cm × 40 cm plastic transparent cages in an air-conditioned animal room with a stable temperature (21 °C) and 12/12 light/dark cycle (lights on at 7:00). All rats were subcutaneously implanted with a hypodermic needle,
Results
Animals did not exhibit any signs of stress or excessive discomfort during or after injections of drugs. Basic behaviors were retained after injections and in the active place avoidance apparatus. Only animals treated with highest dose (30 mg/kg) of propranolol prior to testing showed decreased motor activity and impaired escape reactions, which was confirmed by measuring total distance walked (see ANOVA reports below). The highest dose of propranolol also markedly decreased defecation in the
Discussion
The results of the present study demonstrate that propranolol injected 30 min prior to behavioral testing in the AAPA task dose-dependently impaired spatial performance, with overt disruption of behavior including locomotor activity after highest dose of 30 mg/kg. Doses 5 and 20 mg/kg were without apparent effect, whereas a dose of 25 mg/kg impaired selectively spatial avoidance measured as number of entrances into shock sector. These results are rather different from those obtained in our previous
Acknowledgements
This study was supported by GACR grants 309/07/0341 and 309/09/0286 and by AV0Z50110509. Our thanks go to Dr. Jan Bures for valuable comments and ideas on the early draft versions. We are grateful to him for very positive influence on our thinking and we are delighted to dedicate this paper to him. We appreciate substantial technical assistance of Michaela Fialova. We also thank Peter M. Luketic for language review.
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