Research report
Combined administration of alpha1-adrenoceptor antagonist prazosin and beta-blocker propranolol impairs spatial avoidance learning on a dry arena

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Abstract

Spatial learning is a widely studied type of animal behavior often considered as a model of higher human cognitive functions. Noradrenergic receptors play a modulatory role in many nerve functions, including vigilance, attention, reward, learning and memory. The present study aimed at studying the effects of separate or combined systemic administration of the alpha1-adrenergic antagonist prazosin (1 and 2 mg/kg) and beta-blocker propranolol (5 and 20 mg/kg) on the hippocampus-dependent learning in the active allothetic place avoidance (AAPA) task. Both centrally active drugs impaired spatial learning when administered together, exerting no effect in separate applications. Locomotion was impaired only in a combined application of higher doses of both drugs (2 mg/kg prazosin and 20 mg/kg propranolol). These results suggest an in vivo interaction between these two types of receptors in spatial navigation regulation.

Introduction

Noradrenaline and adrenaline exert many effects and mediate a number of functions not only in peripheral tissues but also in the central nervous system (CNS), where noradrenaline dominates. These behavioral effects include a modulation of vigilance, arousal, attention [25], [27], motivation and reward [6], learning and memory [26]. Almost all brain noradrenergic fibers arise in brainstem nuclei designated A1–A7 (including the locus coeruleus, a nucleus in which about 45% of all noradrenergic projections originate [29]). The effects of noradrenaline are mediated by two distinct super-families of receptors, named alpha- and beta-adrenoceptors [28]. Alpha-adrenoceptors are divided into two families, alpha1- and alpha2-subtypes. Originally it was assumed that alpha1-adrenergic receptors were solely post-synaptic in the CNS, whilst the alpha2-subtype was localized pre-synaptically; however, both types were later found in both pre-synaptic and post-synaptic membrane regions [29]. Both alpha1- and alpha2-adrenoceptors are further divided into subgroups, as well as beta-adrenoceptors, which are also found both in the brain and periphery.

Prazosin, an antagonist of alpha1-adrenoceptors (with no selectivity for their individual subtypes), is used to assess the role of these types of receptors in the regulation of behavioral functions and their involvement in learning and memory [9], [10], [33]. However, the blockade of alpha1-adrenoceptors was found to have only minor effects on learning and cognitive functions, as revealed by several studies (e.g. [24], [33]). Our previous paper showed that a blockade of alpha1-adrenergic receptors in the brain using prazosin resulted in learning impairments at higher doses (4 mg/kg), which concurrently disrupted motor activity, suggesting a procedural deficit and no selective effects upon cognition [33]. To the contrary, the actions of the centrally active beta-blocker propranolol are relatively well-studied, especially with respect to memory consolidation (implying application of propranolol after a conditioning session [2], [12]). The effects of propranolol administered prior to testing have been studied less frequently. Our previous study [30] assessed learning in the place avoidance task (a spatial learning test) in rats treated with various doses of propranolol and found relatively selective disruption of place avoidance learning at a dose of 25 mg/kg, which did not disrupt motor activity. Similarly, Heron et al. [13] demonstrated impairment by propranolol in the acquisition on the motor runway task, suggesting the effects of propranolol were not restricted to the domain of relational memory.

The above-mentioned place avoidance task, especially its modification named active allothetic place avoidance (AAPA), has proved to be a useful paradigm for assessing learning and cognitive functions and their alterations caused by neuropharmacological, lesion and other experimental manipulations [21], [22], [31], [35], [38]. This test is highly dependent upon the integrity of hippocampi on both sides of the brain [4] and it has been demonstrated to require cognitive coordination, which has been described as the ability to segregate the spatial stimuli from the arena and room frames (which are dissociated by the constant rotation of AAPA arena [15], [39]). Recently, we employed the task in a study aimed at elucidating interactions between the systemically applied alpha1-blocker prazosin and dopamine D2 receptor antagonist sulpiride, which were found to act synergistically and impaired both locomotor activity and avoidance efficiency in the AAPA task when co-applied [31]. It should be emphasized that studying the effects of specific receptor antagonists on learning and memory function ranks amongst the most intensively studied topics today (for review see Myhrer [20]).

Despite the effects of prazosin and propranolol pre-test application found in past years, their contribution was investigated mainly separately but not in combined administration. Therefore, the present study was aimed at elucidating the interaction of both prazosin and propranolol at the systemic level, an approach which may preliminarily suggest the nature of the in vivo interplay between corresponding types of adrenoceptors. The experimental hypothesis of the present study was that combined administration of both drugs (at doses eliciting no effect when administered separately) would impair spatial leaning in the AAPA task. We have also addressed the question whether this disruption was relatively selective to cognition or if locomotor activity and procedural aspects of the task would be also compromised.

Section snippets

Animals

Seventy-one naive male adult Long-Evans rats (3–4 months old, weighing 250–300 g) obtained from the breeding colony of the Institute of Physiology, ASCR were used in the study. The animals were housed in pairs in 30 cm × 30 cm × 40 cm plastic translucent cages in an air-conditioned animal room with a stable temperature (21 °C) and 12/12 light/dark cycle (lights on at 7.00). Conscious rats were gently implanted with a hypodermic needle, piercing the rat's skin between its shoulders, and creating a small

Effects of separate or combined application of drugs on locomotor activity

Visual inspection of rats revealed that most animals exhibited normal overt behavior including locomotion; only animals co-administered with the highest doses of drugs (2 mg/kg of prazosin and 20 mg/kg of propranolol) were hypoactive which was later confirmed by a statistical analysis. Examples of typical trajectories from selected groups are shown in Fig. 1. Note the deceased locomotion and inability to escape efficiently from the shock in animals treated with highest doses of both drugs. This

Discussion

Roles of both alpha1- and beta-adrenergic receptors in animal behavior in general and in learning and memory in particular represent a well-studied topic of behavioral pharmacology. There are numerous studies on this subject, including those done in our laboratory using the AAPA behavioral task [30], [33]. In general, our results, showing no effects on cognitive parameters in animals treated with sub-threshold doses of alpha1-adrenoceptor antagonist prazosin, are in accordance with a previous

Acknowledgements

The study was supported by GACR grants 309/07/0341 and 309/09/0286 and by AV0Z50110509. We thank Dr. Jan Bures for his critical comments on the paper and P.M. Luketic for language editing.

References (39)

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