Involvement of σ1 receptor in (+)-N-allylnormetazocine-stimulated hippocampal cholinergic functions in rats

BRAIN RESEARCH ELSEVIER

Brain Research 690 (1995) 200-206

Research report

Involvement of 0-1 receptor in ( +)-N-allylnormetazocine-stimulated hippocampal cholinergic functions in rats Kiyoshi Matsuno *, Toshihiko Senda, Tetsuya Kobayashi, Shiro Mita Central Research Laboratories, Santen Pharmaceutical Co., Ltd., Higashivodogawa Osaka 533, Japan

Accepted 2 May 1995

Abstract

The effects of the stereoisomers of N-allylnormetazocine (SKF-10,047) on the hippocampal cholinergic functions were compared in rats. A putative 0"1 receptor agonist, (+)-SKF-10,047, elicited an increase of hippocampal extracellular acetylcholine level and anti-amnesic effect against scopolamine-induced memory dysfunctions in rats. These phenomena were not produced by (-)-SKF-10,047, and were reversed by haloperidol, a putative 0"1 receptor antagonist. Such stereoselectivity and antagonism imply an involvement of o-l receptors in these (+)-SKF-10,047-stimulated hippocampal cholinergic functions. Keywords: o"l Receptor; Hippocampus; Acetylcholine; SKF-10,047 (N-allylnormetazocine); Haloperidol; Amnesia; Stereoselectivity; Rat

1. Introduction

Benzomorphan derivatives were firstly introduced as narcotic agonist or antagonist analgesics [11]. Subsequently, these derivatives were reported to cause hallucinations, depersonalization and drunkenness in humans [14]. In the chronic spinal dogs and other rodents, the derivatives produced autonomic stimulations, such as mydriasis, tachypnea a n d / o r tachycardia, or behavioral stimulations, such as hyperlocomotion a n d / o r stereotyped behavior [17,28,33]. Recently, benzomorphans have reported to regulate the firing rate of midbrain dopamine cells [12,18,43], and the N-methyl-D-aspartate (NMDA)-mediated responses [32]. However, the precise mechanism by which the drugs induced these responses remains unclear, because benzomorphans have been reported to interact with various receptors. For example, (+)-N-allylnormetazocine ((+)-SKF-10,047) reportedly binds to the o" receptor [26,50,52], the NMDA receptor channel complex [25,38] a n d / o r the muscarinic cholinoceptor [3,5,21,30]. The stereoselectivity of benzomorphans on their responses is an important criterion distinguishing among the

* Corresponding author. New Drug Research, Central Research Laboratories, Santen Pharmaceutical Co., Ltd., 3-9-19, Shimoshinjo, Higashiyodogawa, Osaka 533, Japan. Fax: (81) (6) 370-1651. 0006-8993/95/$09.50 © 1995 Elsevier Science B.V. All rights reserved SSDI 0 0 0 6 - 8 9 9 3 ( 9 5 ) 0 0 6 1 8 - 4

multiple classes of receptors to which the benzomorphans bind. Namely, a preference of ( - )enantiomer indicates the contribution of opioid receptors, while reverse stereoselectivity shows the interactions with o- receptors. This discrimination is based on the evidence that the inhibitory potencies of ( - )enantiomers for opioid receptors are more potent than those of (+)enantiomers [37,47,55], while a preference of ( + )enantiomer is shown in the inhibition of the bindings to o- receptors [24,26,50,52]. In addition, benzomorphans reportedly possess a modest stereoselectivity of (-)enantiomers over (+)enantiomers for muscarinic cholinoceptors [21,30]. With regard to the NMDA receptor channel complex, cyclazocine shows a preference of ( - )enantiomer [7,47,54,55]. In contrast, the stereoselectivity of SKF-10,047 is reported as not only ( + )preferring character [8,42,49], but also (-)preferring [54,55]. Since the identification of o- receptor was reported [38], intensive studies to elucidate the physiological function of the o- receptor in the central nervous system have been carried out [10,44,50]. In the central cholinergic systems, a prototype benzomorphan o" receptor ligand, (+)-SKF10,047, has been reported to potentiate the electrical stimulation- and KCl-evoked acetylcholine release in guinea pig [40] and rat cerebral slices [23]. However, the mechanisms involved in the (+)-SKF-10,047-induced increases in acetylcholine release are controversial. Namely, Siniscalchi et al. [40] have suggested that the (+)-SKF-10,047-

K. Matsuno et al. / Brain Research 690 (1995) 200-206

induced release of acetylcholine is mediated by the muscarinic cholinoceptor, because the response is antagonized by atropine. On the contrary, Junien et al. [23] have suggested that the response is mediated by the o" receptor, because it is antagonized by haloperidol, a putative oreceptor antagonist. Thus, to clarify the mechanism involved in the acetylcholine release induced by (+)-SKF10,047, we compared the effects of the stereoisomers of SKF-10,047 at the extracellular acetylcholine level in the rat hippocampus. In addition, as the hippocampal cholinergic transmission plays an important role in the complicated process of learning and memory [1], the effects of ( + ) and (-)-SKF-10,047 on the memory dysfunctions induced by scopolamine, a muscarinic cholinoceptor antagonist, were examined.

2. Materials and methods

The procedures involving animals and their care were conducted in conformity with the institutional guidelines that are in compliance with the 'Guide for the Care and Use of Laboratory Animals' (NIH Publication, No. 85-23 1985). 2.1. Animals

Male Wistar rats (Nihon SLC, Shizuoka, Japan), weighing 280 to 350 g, were used in all experiments. They were housed four per cage with free access to food and water in a controlled environment ( 2 3 _ 1°C, 5 5 _ 5% humidity), with a 12 h light-dark cycle (light on between 07.00 and 19.00 h). The rats were used following at least 7 days' adaptation to laboratory conditions. 2.2. Measurement o f extracellular acetylcholine level

Brain microdialysis was carried out as described previously [29,30]. Briefly, the rats were anesthetized with sodium pentobarbital (50 mg/kg, i.p.) and placed in a stereotaxic apparatus. A guide cannula was implanted into the right hippocampus, according to the Paxinos and Watson [36] atlas of the rat brain (coordinates measured P: + 6.0 mm and L: 5.0 mm from bregma, V: + 7.0 mm from the skull surface). The rats were allowed at least 48 h recovery time following the implantation of the guide cannula. The experiments were started at least 3 h after the setting of the concentric microdialysis probe (3 mm length; BDP-I-8-03, Eicom, Kyoto, Japan). This probe was perfused with Ringer's solution (147 mM NaCI, 1.2 mM CaCI 2, 4 mM KCI and 1.0 mM MgC12, pH6.1) containing 3 /xM physostigmine at a constant flow rate of 2 /xl/min. The dialysates were collected every 15 min in the sample loop of an automated sample injector, connected to a

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high-performance liquid chromatography (HPLC) system. Acetylcholine and choline in the dialysate were quantified by HPLC using an immobilized enzyme reactor and an electrochemical detector (ECD) (Eicom, Japan). The enzymatic reactor containing acetylcholinesterase and choline oxidase catalysed the formation of hydrogen peroxide from acetylcholine and choline. The resultant H20 2 was detected by an ECD, with the platinum electrode at 450 mV. The mobile phase, which was delivered by a pump at a rate of 1.0 ml/min, was 0.1 M sodium phosphate buffer (pH 8.0) containing 200 mg/1 sodium l-decanesulfate and 65 mg/1 tetramethylammonium chloride [13]. Each stereoisomer was injected subcutaneously once three or four consecutive, stable dialysate samples had been collected. In addition, to assess the contribution of or receptors, haloperidol was intraperitoneally injected at the same time as (+)-SKF-10,047. The location of the dialysis probe was confirmed after each experiment [29]. The in vivo recovery of acetylcholine and choline was estimated to be 23.0% and 25.0%, respectively. 2.3. Passit,e aL,oidance task

The apparatus for testing step-through type passive avoidance learning tasks consisted of two compartments, one light compartment (25 cm long, 18 cm wide and 20 cm high) and one dark compartment (15 cm long, 20 cm wide and 20 cm high), equipped with a grid floor, and connected via a guillotine door. Each rat was gently placed in the light compartment. After 10 s, the guillotine door was opened. When the rat entered the dark compartment, the guillotine door was closed. After 5 s, an electric shock (50 V for 3 s) was delivered to the animal via the grid floor. The time taken to do so was recorded in seconds. The retention test was carried out 24 h after the training session. The rat was put in the light compartment and the time taken to enter the dark compartment was recorded (step-through latency). The step-through latency was recorded up to a maximum cut-off time of 300 s. The training session and retention test were performed between 11.00 h and 18.00 h. Scopolamine (0.75 mg/kg) was administered 30 min prior to the training session. ( + ) - or (-)-SKF-10,047 were administered subcutaneously 30 min before the retention test. To examine the antagonistic effect of haloperidol, it was intraperitoneally injected at the same time as (+)-SKF10,047. 2.4. Statistical analysis

In the microdialysis studies, the results were expressed as the means_+ S.E.M.. Comparisons between the treatment groups and control were performed by analysis of variance (ANOVA) followed by Dunnett's multiple range comparison test and the differences between the two groups

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were analyzed using Student's unpaired t-test. In the behavioral studies, the results were expressed as the medians and interquartile ranges. All data were analyzed using the Kruskal-Wallis non-parametric one-way analysis of variance, then the two-tailed Mann-Whitney U-test. Differences of P values of less than 0.05 were considered to be statistically significant.

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3. Results

3.1. Comparison of stereoisomers of SKF-10,047 Extracellular acetylcholine level in rat hippocampus The average basal extracellular acetylcholine and choline levels in the rat hippocampus were 1.78 __+0.15 pmol/30 /zl (n = 42) and 16.54__+ 1.10 pmol/ 30 /xl (n = 42) per 15 min, respectively. The increase elicited by subcutaneous injection of ( + )SKF-10,047 at a dose of 5.0 m g / k g was significant, compared with those in the saline-treated group (Fig. 1). By contrast, the increase elicited by (-)-SKF-10,047 at a dose of 5.0 m g / k g was less than that produced by ( + ) SKF-10,047 at the same dose (Fig. 1). In addition, this increase by (-)-SKF-10,047 was the same as that pro-

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Fig. 2. Comparison of stereoisomers of SKF-10,047 on scopolamine (SCOP)-induced amnesia in the passive avoidance task in rats. SCOP was administered 30 min prior to the training session. Both stereoisomers were administered 30 min before the retention test. The retention test was performed 24 h after the training session, The results are expressed as the medians and interquartile ranges. The number of rats in each group is indicated in parentheses. * * P < 0.01 as compared with the saline + saline group. # P < 0.05 compared with the SCOP + saline group.

duced by (+)-SKF-10,047 at a dose of 2.5 mg/kg. No marked changes in the extracellular choline level were observed in these drug treatments (data not shown).

Scopolamine-induced amnesia The vehicle-treated rats that received an electric shock during the training session showed a prolonged stepthrough latency in the retention test. The step-through latency in more than 75% of control rats were 300 s (Fig. 2). Scopolamine administered 30 min before the training session significantly shortened the step-through latency in the retention test, which indicated the disruption of the retention performance in the passive avoidance response (Fig. 2). The disruption of retention performance elicited by scopolamine was alleviated by (+)-SKF-10,047 at doses of 2.5 and 5.0 mg/kg. The significant anti-amnesic effect was shown at a dose of 5.0 m g / k g (Fig. 2). On the other hand, (-)-SKF-10,047 did not reduce the scopolamine-induced amnesia (Fig. 2). Each step-through latency in the training session was not changed by these drug treatments (data not shown). 3.2. Antagonism with haloperidol

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Fig. 1. Comparison of stereoisomers of SKF-10,047 on the extracellular acetylcholine (ACh) level in the hippocampus of conscious, freely-moving rats. Saline (O), (+)-SKF-10,047 at doses of 2.5 (O), 5.0 ( O ) or (-)-SKF-10,047 at a dose of 5.0 m g / k g (A), were injected subcutaneously at time zero (as shown by arrow). The results are expressed as the means_+ S.E.M. of percentages of the preinjection basal levels observed from 5 to 14 rats. * * P < 0.01 as compared with the saline-treated group at corresponding times.

Extracellular acetylcholine level in rat hippocampus To clarify whether the (+)-SKF-10,047-induced increase of the hippocampal acetylcholine level was mediated through o" receptor, the antagonistic effect of haloperidol, a putative o" receptor antagonist, was studied. Simultaneous administration of haloperidol (0.25 mg/kg) significantly reduced the (+)-SKF-10,047-induced increase of the extracellular acetylcholine level in the rat

K. Matsuno et al. / Brain Research 690 (1995) 200-206

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induced disruption of retention performance was not affected by haloperidol alone at the same dose (Fig. 4).

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Fig. 3. Antagonism by haloperidol of the (+)-SKF-10,047-induced increases in the extracellular acetylcholine (ACh) level in the hippocampus of conscious, freely-moving rats. Saline (O), (+)-SKF-10,047 (5.0 mg/kg, s.c.; O), haloperidol (0.25 mg/kg, i.p.; D) or (+)-SKF-10,047 + haloperidol ( zx) were injected at time zero (as shown by arrow). The results are expressed as the means _+S.E.M. of percentages of the preinjection basal levels observed from 4 to 14 rats. * P < 0.05 and * * P < 0.01 as compared with the saline-treated group at corresponding times. # P < 0.05 and # # P < 0.01 as compared with the (+)-SKF-10,047 alone at corresponding times.

hippocampus (Fig. 3). Haloperidol alone at the same dose did not affect the extracellular acetylcholine level in this area (Fig. 3). Scopolamine-induced amnesia

Similar to the effect on the hippocampal acetylcholine level, simultaneous administration of haloperidol (0.25 m g / k g ) totally reduced the ( + ) - S K F - 1 0 , 0 4 7 - i n d u c e d anti-amnesic actions in the rats (Fig. 4). The scopolamine-

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Fig. 4. Antagonism by haloperidol (HAL) of the (+)-SKF-10,047-induced anti-amnesic effect on scopolamine (SCOP)-induced amnesia in the passive avoidance task in rats. SCOP was administered 30 min prior to the training session. (+)-SKF-10,047 and/or haloperidol were administered 30 min before the retention test. The retention test was performed 24 h after the training session. The results are expressed as the medians and interquatile ranges. The number of rats in each group is indicated in parentheses. * *P < 0.01 as compared with the saline+saline group. # P < 0.05 as compared with the SCOP + saline group.

The present study clearly demonstrated that ( + ) - S K F 10,047 elicited the increase of hippocampal extracellular acetylcholine level and the anti-amnesic effect against scopolamine-induced memory dysfunctions in the rats. In addition, these effects were mediated by the tr receptor (particularly o'] receptor), because these changes were not shown by ( - )-SKF-10,047 and were reversed by haloperidol. As described in Introduction, a preference of ( + )enantiomer on their responses indicates the contribution of the o" receptor [26,50,52] a n d / o r the N M D A receptor channel complex [25,38]. On the contrary, the contribution of the opioid receptor a n d / o r the muscarinic cholinoceptor to the responses can be proved by a preference of ( - )enantiomer [3,5,21,30,37,47,55]. In the present study, we found that the stimulative potencies of ( + ) - S K F - 1 0 , 0 4 7 on the hippocampal cholinergic function are more potent than those of ( - ) - S K F - 1 0 , 0 4 7 . Thus, we consider that our present finding is mediated by the o- receptor a n d / o r the N M D A receptor channel complex. Similar to the binding studies [25,38,41], behavioral and neurochemical studies have also demonstrated that a preference of ( + ) - S K F - 1 0 , 0 4 7 is shown in the NMDA-related responses which are the induction of stereotyped behavior [7] and increase in the circulating adrenocorticotropic hormone and the metabolites of dopamine in rats [18,19]. Thus, it is possible that the present findings are mediated through the N M D A receptor channel complex. However, phencyclidine, a non-competitive N M D A antagonist, has been reported to have no effect on hippocampal acetylcholine release [23,27]. In addition, haloperidol has no affinity for the N M D A receptor channel complex [25], and this compound has been reported not to reverse the NMDA-related phenomena [2]. Moreover, although the present study showed that ( + ) - S K F - 1 0 , 0 4 7 reduced the scopolamine-induced amnesia when administered before the retention test, both the competitive N M D A antagonist, ( + ) - 3 - ( 2 - c a r b o x y p i perazin-4-yl)-propyl-l-phosphonic acid (( + )-CPP) and the non-competitive N M D A antagonist, ( + ) - 5 - m e t h y l - 1 0 , 1 1 dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine ((+)MK-801) have been reported not to affect the retention performance when administered before the retention test [35,48]. Therefore, we conclude that the ( + ) - S K F 10,047-elicited increments of hippocampal cholinergic activities are mediated through the o" receptors, but not the N M D A receptor channel complex. This conclusion is similar to our previous observation that the increase in the cortical extracellular acetylcholine level elicited by ( + ) SKF-10,047 is not associated with the N M D A receptor channel complex [30]. Similarly, the potentiation of the

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KCl-evoked acetylcholine release elicited by JO-1784, a novel 0- receptor ligand, in rat hippocampal slices is reportedly mediated by o- receptor, because this response was blocked by haloperidol [23]. On the other hand, (+)-SKF-10,047 has been reported not to reduce the scopolamine-induced amnesia when administered before the training session [9]. This finding differed from our present result. However, we consider that the discrepancy between both findings may be due to the difference of drug administration timing. Namely, the effect of ( + ) SKF-10,047 when administered before the training session is due to not only 0. receptor-mediated responses, but also the NMDA-mediated responses, whereas the effect of ( + )SKF-10,047 when administered before the retention test is due to the only 0. receptor-mediated response. This speculation is supported by the others' findings that (+)-CPP and (+)-MK-801 impaired memory retention when administered before the training session, but not the retention test [35,48]. Moreover, although (+)-SKF-10,047 produced a memory impairment in the rats when administered before the training session, this amnestic action was reportedly interacted with the NMDA receptor channel complex [22]. Therefore, the difference of administration timing may control the contribution of the NMDA-releated response on the (+)-SKF-10,047-induced pharmacological actions for learning and memory. In addition, augmentations of hippocampal cholinergic functions elicited by (+)-SKF-10,047 were completely blocked by the simultaneous injection of haloperidol. As this antagonist has been reported to interact with not only the o- receptor, but also dopamine D 2 receptor [4,53], the present findings may be mediated through the dopamine D 2 receptor. However, (+)-SKF-10,047 has no affinity for the dopamine D 2 receptors [18,46]. In addition, the dopamine D 2 agonist quinpirole has been reported to decrease the extracellular acetylcholine level in rat hippocampus [8]. Therefore, we consider that the stimulations of hippocampal cholinergic functions elicited by ( + ) SKF-10,047 are mediated through the 0- receptors, but not dopamine D 2 receptors. In addition, it is possible that the antagonistic activity of haloperidol is due to the trans-synaptic changes, because the blocking of dopamine receptor may lead to changes of monoaminergic transmission [6]. As the monoaminergic systems were reported to regulate the hippocampal acetylcholine release [31,34], this possibility was also considered. Recently, the classification of o- receptor subtypes has been proposed. There appear to exist at least two subtypes of the 0- receptor termed 0.1 and o"2. The o"1 receptors are characterized by stereoselectivity to benzomorphan (+)enantiomer, while the 0"2 receptors are more sensitive to benzomorphan ( - )enantiomer [15,39,45]. Therefore, we conclude that the (+)-SKF-10,047-stimulated cholinergic activities are mediated by 0-a receptor, because the present study showed that (+)-SKF-10,047 was more effective than (-)-SKF-10,047 in these actions. In addition, our

conclusion was also supported by the recent report that (+)-SKF-10,047 and haloperidol were the selective 0.1 receptor ligands [16]. To date, although the 0.~ receptor has been reported to interact with the motor function [51] and K ÷ channel [20], the biological function of the 0-1 receptor is not well established. Therefore, our present findings indicate a novel physiological function of the 0-1 receptor in the brain. In addition, these systems provide a behavioral a n d / o r neurochemical approach for the assessment of the agonist/antagonist activity of 0-1 receptors.

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