Facilitation of cognitive functions by a specific α2-adrenoceptor antagonist, atipamezole

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Abstract

The present experiments investigated the effects of a specific and potent α2-adrenoceptor antagonist, atipamezole (as a stimulator of the noradrenergic system) on cognitive performance in rats. Atipamezole enhanced the acquisition of a linear-arm maze test and also improved the choice accuracy of poorly performing rats in a delayed (20 min) three-choice maze test. Furthermore, atipamezole improved the achievement of a one-trial appetite-maze when injected immediately after teaching, thus having an effect on consolidation. Atipamezole clearly impaired the acquisition of the active avoidance test. The present results indicate that stimulation of noradrenergic system by atipamezole improves the performance of animals in tasks assessing relational learning and memory, possibly affecting attention, short-term memory and the speed of information processing. It has also an effect on a consolidation process unrelated to attentional or motivational mechanisms. In a stressful test, stimulation of noradrenaline release leads to impairment of performance.

Introduction

The importance of the forebrain projections of the noradrenergic nucleus, locus coeruleus, in the mediation of attention, learning and memory is supported by many investigations (Anlezark et al., 1973; Robbins et al., 1985). The neurones in the locus coeruleus are activated by novel and salient external stimuli (Aston-Jones et al., 1991; Sara et al., 1994; Simson and Weiss, 1988). In the terminal fields (e.g., cortical areas, hippocampus and amygdala), noradrenaline modulates the excitability of neurones leading to an enhanced `signal-to-noise' ratio, thought to support focusing of attention (Berridge et al., 1993; Dahl and Winson, 1985; Harley, 1987). Furthermore, noradrenaline is also known to play an important modulatory role in a form of synaptic plasticity, long term potentiation, considered to be associated with memory processes (Bliss et al., 1983; Dahl and Winson, 1985; Harley, 1987). At the behavioural level, noradrenaline can facilitate memory consolidation and retrieval. Blockade of β-adrenoceptors has been reported to impair consolidation (McGaugh, 1989; McGaugh et al., 1990), whereas the electrical stimulation of the noradrenergic neurones of the locus coeruleus has been shown to improve memory retrieval (Sara and Devauges, 1988). However, the results from several lesion studies have been conflicting (Connor et al., 1992; Selden et al., 1990; Valjakka et al., 1990).

The activity of the noradrenergic neurones in the locus coeruleus is regulated by α2-adrenergic autoreceptors (Cedarbaum and Aghajanian, 1977; Simson and Weiss, 1988). Blockade of these receptors by an α2-adrenoceptor antagonist can increase the firing rate of the neurones and increase the release of noradrenaline in the brain (Freedman and Aghajanian, 1984; Pettibone et al., 1985; Scheinin et al., 1988). It has been postulated that an appropriate level of stimulation of the central noradrenergic system can improve cognitive functions. Interestingly, some reports have shown that the α2-adrenoceptor antagonists, yohimbine and idazoxan, improve performance in some learning and memory tests (Bunsey and Strupp, 1995; Devauges and Sara, 1990; Sara and Devauges, 1989; Sara et al., 1994). Unfortunately, the specificity and selectivity of those compounds have been questioned. Yohimbine has affinity to many receptors other than noradrenergic receptors, e.g., dopaminergic, 5-hydroxytryptaminergic and benzodiazepine receptors (Lal et al., 1983; Van Oene et al., 1984; Winter and Rabin, 1992). Even though, idazoxan is a more specific α2-adrenoceptor antagonist than yohimbine (Freedman and Aghajanian, 1984), it has a high affinity for noradrenergic imidazoline binding sites (Miralles et al., 1993). Yohimbine, idazoxan and also some more novel α2-adrenoceptor antagonists such as RX821002, (2-methoxy idazoxan), BRL 44408 and ARC 239 have affinity for 5-hydroxytryptamine (5-HT) 5-HT1A receptors (Meana et al., 1996; Sanger and Schoemaker, 1992; Winter and Rabin, 1992). Furthermore, yohimbine, idazoxan and ethoxy idazoxan have been demonstrated to have 5-HT1A-receptor agonistic properties in vivo (Jordan et al., 1995; Llado et al., 1996; Pettibone et al., 1985; Sanger and Schoemaker, 1992; Winter and Rabin, 1992) and 5-HT1A-receptor agonists have been reported to clearly modulate cognitive function (Carli et al., 1992; Mendelson et al., 1993). While these possible direct effects of the α2-adrenoceptor antagonists on other receptors should not be exaggerated, they should be taken into consideration when the effects of these drugs are assessed.

Even if the behavioral effects of yohimbine and idazoxan are exclusively mediated via α2-adrenoceptors, it has been speculated that their action is due to behavioural arousal rather than to any specific enhancement of the various processes involved in learning and memory (Dickinson et al., 1989a, Dickinson et al., 1989b; Huang et al., 1987). With post-training administration of an agent it is possible to influence only the memory consolidation phase; whereas with the pretraining administration paradigm which allows the drug to influence the acquisition and consolidation phase, it becomes involved with other non-cognitive influences including arousal and motivation. Idazoxan has been ineffective when administered post-training in learning tasks (Dickinson et al., 1989a, Dickinson et al., 1989b).

Atipamezole is a specific and potent α2-adrenoceptor antagonist, which has minimal effects on other receptors. It can thus be considered as a specific tool with which to evaluate the effects of α2-adrenoceptor blockade in vivo (Haapalinna et al., 1997; Scheinin et al., 1988; Virtanen et al., 1989; Winter and Rabin, 1992). Atipamezole does differ from the other commonly used α2-adrenoceptor antagonists in brain neurochemical, in vivo electrophysiological and behavioural experiments (Haapalinna et al., 1997; Jordan et al., 1995; Winter and Rabin, 1992; Yavich et al., 1994). In the evaluation of the effects of atipamezole on cognitive functions, it has been found that atipamezole stabilizes age-associated electroencephalogram changes, improves passive avoidance retention in aged rats (Riekkinen et al., 1992) and improves intermediate-term memory retention in a radial-arm maze task (Ylinen et al., 1996). Depending on the testing conditions and the dose used, atipamezole has been reported to have no effect or to improve the performance of rats in an attentional task (Jäkälä et al., 1992; Sirviö et al., 1993). It has also been reported to impair spatial learning of rats in a Morris water maze test (Sirviö et al., 1992).

The aim of the present experiment was to elucidate further the effects of atipamezole on different learning and memory processes. Previous studies had revealed that atipamezole has some beneficial effects on attentional processes and memory recall, but impaired acquisition. Therefore we studied the effects of atipamezole on short-term memory in a three-choice maze task as well as on acquisition of long-term memory using a linear-arm maze and active avoidance tasks. The linear-arm maze task assesses the spatial relational memory of rats and is thought to be analogous to human declarative memory whereas active avoidance test assesses emotionally meaningful stimulus–response learning, a form of non-declarative memory. With respect to the different phases of long-term memory (acquisition, consolidation, and retrieval) a lighted-arm maze task was used to assess the effect of atipamezole on the consolidation phase.

Section snippets

Animals

Male rats of the Sprague–Dawley strain (Bantin and Kingman, Sweden) were used in all the tests. In the linear-arm maze test, 30 approximately 7-month-old rats, weighing 466–657 g at the beginning of the study, were used. In the three-choice maze task, 40 rats and in the lighted-arm maze tests 58 rats, in the active avoidance test, 20 rats and in the conditioned avoidance response test, 15 rats, weighing 222–286 g at the beginning of the study, were used. The animals were housed in groups of

Effect of atipamezole on linear-arm maze performance

The effects of atipamezole (0.3 mg/kg s.c.) on the performance of rats in the linear-arm maze are presented in Fig. 1A–D. There was a clear decrease in the number of errors from the teaching trial to trial 1 (Fig. 1A). There was no significant overall treatment effect, but a clear repetition effect and an interaction between treatment and repetition (treatment: F(1,28)=0.0, P=1; trial: F(1,28)=35.49, P<0.001; interaction: F(1,28)=5.54, P<0.05). The change from the teaching trial to trial 1 was

Discussion

The present study elucidated the effects of the specific α2-adrenoceptor antagonist, atipamezole, as a stimulator of noradrenaline release, on cognitive functions. The particular objective of this study was to investigate the effects of atipamezole on (acquisition) relational learning and memory, conditioned stimulus learning and on consolidation processes involved in relational memory.

In the present study, atipamezole improved performance of adult rats trained on a linear-arm maze test. The

Acknowledgements

Dr. E. MacDonald is acknowledged for revising the language of the manuscript, Dr. P. Hakulinen is acknowledged for professional advice with statistical analyses and Ms. K. Svärd is acknowledged for preparing the mazes used in the tests.

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