Behavioural activity of (S)-3,5-DHPG, a selective agonist of group I metabotropic glutamate receptors

Pharmacological Research, Vol. 42, No. 3, 2000 doi:10.1006/phrs.2000.0683, available online at http://www.idealibrary.com on

BEHAVIOURAL ACTIVITY OF (S)-3,5-DHPG, A SELECTIVE AGONIST OF GROUP I METABOTROPIC GLUTAMATE RECEPTORS ∗ ´ ´ ALICJA ZALEWSKA-WINSKA and KONSTANTY WISNIEWSKI

Department of Pharmacology, Medical University, Mickiewicza 2c, 15-222 Białystok, Poland Accepted 13 March 2000

The influence of intracerebroventricular (i.c.v.) injections of (S)-3,5-dihydroxyphenyl-glycine (S)3,5-DHPG, a selective agonist of group I metabotropic glutamate receptors (mGluRs), on the activity of the central nervous system was examined in male rats. (S)-3,5-DHPG at doses of 25, 50 and 100 nmol significantly attenuated crossings of squares and rearings, but not bar approaches, in an ‘open field’ test and failed to change apomorphine-induced stereotypy. (S)-3,5-DHPG at the above doses, given immediately after the learning trial, significantly facilitated the consolidation process in a passive avoidance situation, but given before the learning trial and before the retention testing did not have any influence on acquisition and retrieval processes, respectively. Moreover, (S)-3,5-DHPG did not influence recognition memory evaluated in an object recognition test. These results may suggest that activation of group I mGluRs takes part in the consolidation process in affectively-motivated memory, but is probably not necessary for processing of recognition memory, and that (S)-3,5-DHPG memory facilitation seems to be independent of glutamatergic c 2000 Academic Press and dopaminergic interaction.

K EY WORDS : (S)-3,5-DHPG, metabotropic glutamate receptors, locomotor activity, learning, memory, rats.

INTRODUCTION Glutamate is the main excitatory neurotransmitter in the mammalian central nervous system, which plays an important role in many brain functions via activation of the multiple receptor system [1–4]. Glutamate receptors have been classified into ionotropic receptors (iGluRs), which function as ion channels [1, 5], and metabotropic glutamate receptors (mGluRs) coupled to the different second messenger systems [4, 6–10]. The family of metabotropic glutamate receptors consists of at least eight mGluRs, named mGluR1–8 [11]. This family was further divided into three groups, based on their sequence similarity, signal transduction, and agonist rank order potency. Group I includes mGluR1 and mGluR5, which couple primarily to increase phosphoinositide hydrolysis, while group II (mGluR2 and mGluR3) and group III (mGluR4, 6, 7, and 8) are negatively linked to adenyl cyclase activity [11]. Splice variants, the result of alternative splicing, have been found for both mGluR1 and mGluR5 [12–14]. In situ localization of mRNA, encoding different mGluRs, shows that they are differentially distributed in the brain. A high density of mGluR1 and mGluR5 was found in the hippocampus and cerebellum, while a lower density of mGluR1 was ∗ Corresponding author.

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described in the entorhinal and cingulate cortex and throughout the neocortex [6, 15–17]. A high density of the group I mGluRs in the hippocampus and cerebellum may indicate their possible role in synaptic plasticity which takes place in these structures [6, 18]. Activation of group I mGluRs appears to increase the metabolism of phosphatydyloinositol phosphate to diacyloglycerol and inositol triphosphate, which, in turn activates protein kinase C and mobilizes calcium from intracellular stores, respectively [7, 19]. In our previous study [20] we have found that 1S,3R-ACPD, an agonist of group I and group II mGluRs, significantly improved consolidation of affectively-motivated memory, but failed to influence recognition memory. Moreover, 1S,3R-ACPD attenuated apomorphine-induced stereotypy. In an attempt to evaluate whether these effects were mediated by group I mGluRs, the influence of 3,5dihydroxyphenylglycine [(S)-3,5-DHPG], a selective agonist for group I mGluRs [21, 22] on affectivelymotivated memory and on recognition memory, was investigated in the present study. Since in our previous study 1S,3R-ACPD attenuated stereotyped behaviour, and interaction between the glutamatergic and dopaminergic system was proved [23], the influence of (S)-3,5-DHPG on dopaminergic transmission (apomorc 2000 Academic Press

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phine stereotypy) and on the spontaneous locomotor and exploratory activity was investigated.

the influence of lower doses (6.25 and 12.5 nmol) of the compound were also evaluated in this behavioural paradigm.

MATERIALS AND METHODS

Behavioural testing

Subjects Male Wistar rats of laboratory strain, weighing 160– 180 g, were used. They were housed in plastic cages (50×40×20 cm), four animals per cage, in a temperature controlled room (22 ◦ C) under a 12 h light–dark cycle beginning at 7:00 h. Food and water were freely available. All behavioural experiments were carried out in a quiet, diffusely lit room (25 W bulb, 2 m away from an animal, light indirect) between 11:00 and 16:00 h. Each group was equally represented at the time of testing.

Surgery Under light ether anaesthesia, a round piece of skin 7 mm in diameter was cut off the rat’s head and the underlying skull surface was cleaned of soft tissue. Burr holes, 0.5 mm in diameter, were drilled in the skull 2.5 mm laterally and 1 mm caudally from the point of intersection of the bregma and the superior sagittal suture on the right and left side of the head. After 48 h of recovery, the wound was completely dry and the animal behaved normally. The intracerebroventricular (i.c.v.) injections of (S)-3,5-dihydroxyphenylglycine [(S)-3,5DHPG] were made freehand into the lateral cerebral ventricles with a 10 µl Hamilton syringe, using a removable KF 730 needle cut 4.5 mm from its base. This procedure allowed the tip of the needle to be lowered about 0.5 mm below the ceiling of the lateral cerebral ventricle. It was relatively nontraumatic as the animal, gently fixed in the left hand of the experimenter, was usually quiet and no vocalization occurred. The injection volume was 5µl administered over 3 s. Upon completion of each experiment, all rats were sacrificed and the sites of injections were verified microscopically after brain sectioning.

Locomotor and exploratory activity. Locomotor (crossings) and exploratory activity (rearings, bar approaches) was measured in an open field [24] which was a 100 cm2 white floor divided by eight lines into 25 equal squares, and it was surrounded by a 47 cm high wall. Four plastic bars, 20 cm high, were located in four line crossings in the central area of the floor. Following 1 min of adaptation, crossings, rearings, and bar approaches were counted manually for 5 min.

Stereotyped behaviour Stereotyped behaviour was recorded and scored according to the scale described by Kennedy and Zigmond [25]: −1, quiet or asleep; 0, normal activity; 1, occasional non-directed sniffing; 2, continuous sniffing; 3, continuous sniffing on a restricted area of the cage floor; 4, as 3, but with occasional licking; 5, continuous licking; 6, continuous licking with occasional biting; 7, continuous biting. Stereotyped behaviour was induced by an i.p. injection of 2 mg kg−1 of apomorphine hydrochloride (Sandoz) dissolved in 0.9% NaCl and administered at a volume of 1 ml kg−1 .

Passive avoidance performance Passive avoidance performance was studied in a stepthrough passive avoidance situation [26]. The apparatus consisted of an illuminated platform attached to a large dark compartment. The subjects were placed on the platform and were allowed to enter the naturally preferred dark compartment. Two more trials were given on the following day. At the end of the second trial, an inescapable electric footshock (0.5 mA for 3 s) was delivered through the grid floor of the dark compartment. Retention of passive avoidance was tested 24 h later by measuring the latency to re-enter the dark compartment up to a maximum of 300 s.

Drugs The following drugs were used: apomorphine hydrochloride (Sandoz, Basel, Switzerland), haloperidol (Polfa, Warsaw, Poland), and (S)-3,5-dihydroxyphenylglycine (S)-3,5-DHPG (Tocris Cookson). (S)-3,5-DHPG was dissolved in 0.9% NaCl, and was given i.c.v. at doses of 25, 50 and 100 nmol per rat in an injection volume of 5µl, 20 min before placing the animals in the open field, and simultaneously with apomorphine. The compound tested at the above i.c.v. doses was applied 30 min before the learning session, immediately after it, and 30 min before testing, when its influence on acquisition of information, consolidation, and on retrieval process was evaluated, respectively, both in a passive avoidance situation and in an object recognition test. Since (S)-3,5-DHPG at a dose of 25 nmol per rat appeared to facilitate consolidation in a passive avoidance situation,

Object recognition test An object recognition was tested in the apparatus, which consisted of a plastic box 62 cm long, 38 cm wide, and 20 cm high, covered with a wire mesh lid. The objects to be discriminated were made of glass, metal or porcelain and existed in triplicate; apparently they had no natural significance for rats, and they have never been associated with reinforcement. Their weight was such that they could not be displaced by the rats. The procedure was similar to that described by Ennaceur and Delacour [27] and may be summarized as follows. All rats were submitted to two habituation sessions, whereby they were allowed 3 min to explore the apparatus with a 1 h interval between sessions before testing began 24 h later. The experimental session was made of two trials, each 3 min long. In the first trial (T1), the rats

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were exposed to two identical objects A (A1 and A2). In the second trial (T2) performed 60 min later, the rats were exposed to two objects, one of which was a duplicate of the familiar object A (A0 ), in order to avoid olfactory traits, and a new object B. For each rat, the role (familiar or new object) as well as the relative positions of the two objects were counterbalanced and randomly permuted during trial T2. These precautions were taken in order to reduce object and place preference effects. The basic measure was the time spent by the rat in exploring the objects during T1 and T2 trials. Exploration of an object was defined as touching it with the nose. Turning around or sitting on the object was not considered as exploratory behaviour. From this measure the following variables were defined: A = the time spent in exploring objects A1 and A2 in T1; A0 and B = the time spent in exploring, respectively, the duplicate of the familiar and the new object in T2. Object recognition was measured by the variable B − A0 and the total exploration in T2 by B + A0 . Moreover, as B − A0 may be biased by the differences in the overall levels of exploration, the variable (B − A0 )/(B + A0 ) was also computed.

Statistical analysis The results of the experiments were evaluated by analysis of variance (ANOVA) followed by Newman– Keul’s test, and the Mann–Whitney test which was used for the evaluation of passive avoidance behaviour. All ratings of stereotyped behaviour for each rat were summed up first, and the overall group means were then calculated. F-rations, degrees of freedom, and P-values were reported only for significant differences. In all comparisons between particular groups, a probability of P < 0.05, or less, was considered significant.

RESULTS

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The effect of (S)-3,5-DHPG on the apomorphine-induced stereotypy Figure 2 shows that (S)-3,5-DHPG at all the doses tested (25, 50 and 100 nmol per rat) tended to attenuate the stereotyped behaviour produced by a direct dopamine receptor agonist apomorphine. However, statistical analysis of the cumulative ratings of apomorphine stereotypy did not reveal significant differences between the particular groups of rats.

The effect of (S)-3,5-DHPG on passive avoidance behaviour The passive avoidance performance was significantly different between the groups only when (S)-3,5-DHPG was given immediately after the learning trial. ANOVA of five groups injected with (S)-3,5-DHPG and one group injected with saline yielded F5,79 = 4.79; P < 0.001. Further post hoc comparisons between these groups, made with the Mann–Whitney test, revealed a significant increase of the mean step-through latency in the groups injected with 25, 50 and 100 nmol of (S)-3,5-DHPG per rat [Fig. 3(b)]. The passive avoidance performance did not differ between the groups of rats injected with (S)-3,5-DHPG and the controls injected with saline, when the compound was applied before the learning trial [Fig. 3(a)] and before the retrieval testing [Fig. 3(c)].

Object recognition test Object recognition memory measured by the variable B − A0 did not differ between particular groups of rats (Fig. 4) when the compound was given before the first trial (T1) (a), immediately after it (b), and before the discrimination testing (T2) (c). Rats injected with all three doses of (S)-3,5-DHPG spent a similar time exploring the familiar and new objects, as did the control rats injected with saline. Moreover, the total time spent by rats on the exploration of objects A1 and A2 in T1 and objects B and A0 in T2 was similar in all the groups of rats.

The effect of (S)-3,5-DHPG on the locomotor and exploratory activity evaluated in an ‘open field’ test

DISCUSSION

For the number of crossings in the open field (Fig. 1), ANOVA revealed significant differences between the groups (F3,33 = 9.02; P < 0.001). Further post hoc comparisons made with Newman–Keul’s test revealed a significantly decreased number of crossings in all (S)-3,5-DHPG-treated groups as compared with the saline-treated control group. In addition, in the number of rearings there were significant group differences (F3,33 = 6.34; P < 0.001). As shown by Newman– Keul’s test, the rearings in all (S)-3,5-DHPG-treated groups were significantly less frequent than in the control group. Only the differences in bar approaches between the particular groups of rats were insignificant.

The results of the present study point to the involvement of group I mGluRs in affectively-motivated memory but not in recognition memory. (S)-3,5-DHPG, a selective agonist of group I mGluRs, given i.c.v. immediately after the learning trial significantly facilitated consolidation in a step-through passive situation, while it did not have an influence on acquisition of information and on retrieval process. Moreover, (S)-3,5-DHPG given, either before the learning trial, immediately after it, or before the retention testing failed to influence recognition memory evaluated in an object recognition test. The (S)-3,5DHPG influence on learning and memory was similar to the effect of 1S,3R-ACPD (an agonist of group I and II mGluRs) demonstrated in our earlier study [20], which

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Fig. 1. The effect of 25, 50 and 100 nmol of (S)-3,5-DHPG, administered i.c.v. 20 min before testing, on the number of crossing, rearings and bar approaches in the ‘open field’ test. Columns represent means ± SEM of the values obtained from 8–10 rats. ∗ P < 0.01 for the (S)-3,5-DHPG-treated groups as compared with the saline-treated control groups. (ANOVA and Newman–Keul’s test).

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–1 Fig. 2. The effect of 25, 50 and 100 nmol of (S)-3,5-DHPG, given i.c.v. immediately after apomorphine, on the apomorphine (2 mg kg−1 , i.p.)induced stereotypy. Points represent means ± SEM of the values obtained from 8–10 rats.

may indicate that the above effects are probably mediated by group I mGluRs. In both studies the improvement of performance in a passive avoidance situation was demonstrable when the treatment was applied after the learning trial. According to McGaugh and Dawson [28] this is an indication that the effect was memory specific; since the substance was administered after the learning experience, unspecific effects resulting from altered perception, motivation and emotion can be ruled out. Moreover, it has been shown recently that group I mGluRs are involved in nociceptive processing, but in chronic pain rather than signalling acute noxious stimuli [29]. Since in our experiments the memory-improving effect was demonstrated when (S)-

3,5-DHPG was given after the learning trial, thus as rats during footshock experienced in the dark compartment were free of the compound, its nociceptive property could not interfere with the results obtained in a passive avoidance task. The earlier studies concerning the involvement of mGluRs in cognitive processes are inconsistent. Pettit et al. [30] using subtoxic doses of 1S,3R-ACPD have demonstrated that i.c.v. injection of this compound given pre-training in a dose- dependent manner inhibited acquisition in a spatial water maze task. In contrast, Bianchin et al. [31] provided evidence that step-down avoidance learning was facilitated by intrahippocampal 1S,3R-ACPD administration and that the memory-

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0.9% NaCl 6.25 nmole (S)-3,5-DHPG 12.5 nmole (S)-3,5-DHPG 25 nmole (S)-3,5-DHPG 50 nmole (S)-3,5-DHPG 100 nmole (S)-3,5-DHPG

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) 0.9% NaCl 25 nmole (S)-3,5-DHPG 50 nmole (S)-3,5-DHPG 100 nmole (S)-3,5-DHPG

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Fig. 3. The effect of (S)-3,5-DHPG, given i.c.v. at the doses indicated in the legend, 30 min before the learning trial (a), immediately after it (b), and 30 min before the retention testing (c), on the re-entry latencies in a passive avoidance situation. Columns represent means ± SEM of the values obtained from 8–12 rats. ∗ P < 0.01 for the (S)-3,5DHPG-treated groups as compared with the saline-treated control group (ANOVA and Mann–Whitney test).

enhancing effect was only observed when the compound was administrated immediately, but not 180 min, after training. The latter studies are in agreement with our previous [20] and also present results obtained in a step-through passive avoidance task. A number of studies have been conducted in order to analyse the behavioural effects of selective mGluR antagonists. Bianchin et al. [31] have reported that the mentioned 1S,3R-ACPD effect upon memory facilitation was antagonized by co-application of MCPG—an antagonist of group I and II mGluRs. Application of 1S,3R-ACPD in conjunction with MCPG immediately after training, but not 180 min later, antagonized the amnestic effect, and higher concentrations of 1S,3RACPD even led to memory enhancement. Moreover, it has been shown [32] that intrahippocampal application of AIDA, a potent and selective antagonist of the group I mGluRs dose-dependently increased the number of errors in the working memory task with a three-panel runway set-up. However, Riedel et al. [33] have demonstrated that

(a)

(b)

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Fig. 4. The effect of 25, 50 and 100 nmol (i.c.v.) of (S)-3,5-DHPG, on discrimination between the new and familiar objects (B − A0 ) in the object recognition test, given before the first trial (T1) (a), immediately after it (b), and 30 min before the second trial (T2) (c). Columns represent means ± SEM of the values obtained from 10–12 rats.

MCPG, given before training, dose-dependently caused amnesia in spatial alternation learning in the Y-maze, but had virtually no effect when injected post-training and prior to the retention test. There is disagreement concerning the involvement of mGluRs in mechanisms of synaptic plasticity, such as long-term potentiation (LTP) and long-term depression (LTD). Riedel and Reymann [see 34 for a review], based on their own and others investigations, have demonstrated that activation of mGluRs is essential for induction and maintenance of LTP in the hippocampus. However, the underlying mechanism by which this involvement is mediated was not fully established. In contrast, Selig et al. [35] presented experimental evidence favouring the conclusion that MCPG-sensitive mGluRs are not necessary for the induction of LTP, even when synaptic strength has been maximally depressed. Nevertheless, it remains possible that MCPG-sensitive mGluRs are capable of modulating the threshold for the induction of LTP and LTD, perhaps by influencing NMDA receptor function, or by affecting transmitter release [36]. Moreover, it has been demonstrated in the CA1 region of the hippocampus in vitro and in the

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dentate gyrus and CA1 region in vivo that application of 1S,3R-ACPD triggers a slow-onset potentiation of synaptic transmission in the hippocampus [37]. Further investigations have shown that this effect was also dosedependently evoked by group I mGluR agonists, ADA and 3,5-DHPG at i.c.v. doses of 20–100 nmol (similar to those which facilitated memory in our studies) and completely inhibited by MCPG. These results suggest that in the CA1 region in vivo, slow-onset potentiation may be mediated by group I mGluRs. The latter findings are in agreement with results obtained by Riedel et al. [33] indicating that application of class I mGluR agonists after training may selectively increase the signal-to-noise ratio and thus cause the memory facilitation. This study was the first behavioural implication that mGluRs may function in vivo as regulators setting the signal-to-noise ratio. It confirms physiological data on mGluRs obtained in the dentate gyrus and CA1 region indicating that mGluR activation may serve to increase/decrease the signal-to-noise ratio in these brain regions. Thus, weak stimuli that reach dentate or CA1 under conditions in which mGluRs are activated would be filtered out causing amnesia, while stronger stimuli which involve mGluR activation would be amplified and results in an even stronger output to targeted areas, leading in turn to memory facilitation. It remains to be determined whether this fine tuning is mediated by different mGluR subtypes. There is a lot of data supporting an interaction between glutamatergic and dopaminergic systems at different levels of the CNS [see 23 for a review]. 1S,3R-ACPD has been reported to increase the firing rate of A9 and A10 dopaminergic neurones and led to enhanced dopamine release [38]. Moreover, Scaan et al. [39] have demonstrated that a unilateral intrastriatal injection of 1S,3R-ACPD into the rat striatum leads to contralateral turning behaviour, which appears to be mediated by the enhanced release of neuronal dopamine. However, very recently, it was reported that 1S,3R-ACPD and 3,5-DHPG significantly decreased the affinity of the high-affinity state of D2 receptors for dopamine in the striatum and that this effect was specific for group I mGluRs because it was counteracted by the selective group I mGluR antagonist AIDA [40]. In an attempt to evaluate whether activation of group I mGluRs changes dopaminergic transmission, its influence on apomorphine-induced stereotypy was tested. While in our previous study 1S,3R-ACPD significantly attenuated stereotyped behaviour [20], when tested in the present study (S)3,5-DHPG did not have any effect on apomorphine stereotypy. From the inhibitory action of (S)3,5-DHPG on spontaneous locomotor activity of rats evaluated in an open field and the lack of influence on apomorphine stereotypy, one could presume that (S)3,5-DHPG exerted an inhibitory effect on the mesolimbic dopaminergic system (which is known to be primarily involved in the increase of locomotion produced by dopamine agonists) [41] rather than nigros-

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triatal neurones which are more involved in stereotyped behaviour [42]. Results of the present study indicate that activation of group I mGluRs takes part in the consolidation process in affectively-motivated memory, and perhaps is not necessary for the processing of recognition memory. Moreover, (S)-3,5-DHPG memory facilitation seems to be independent of glutamatergic and dopaminergic interaction.

ACKNOWLEDGEMENT This work was supported by AMB project NR 3-10687.

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