Neurochem Res DOI 10.1007/s11064-014-1337-8
ORIGINAL PAPER
Involvement of Neurotransmitters in the Action of the Nociceptin/ Orphanin FQ Peptide-Receptor System on Passive Avoidance Learning in Rats ´ gnes Adamik • Gyula Telegdy Miklo´s Palotai • A
Received: 25 February 2014 / Revised: 8 May 2014 / Accepted: 13 May 2014 Ó Springer Science+Business Media New York 2014
Abstract The nociceptin/orphanin FQ peptide (NOP) receptor and its endogenous ligand plays role in several physiologic functions of the central nervous system, including pain, locomotion, anxiety and depression, reward and drug addiction, learning and memory. Previous studies demonstrated that the NOP-receptor system induces impairment in memory and learning. However, we have little evidence about the underlying neuromodulation. The aim of the present study was to investigate the involvement of distinct neurotransmitters in the action of the selective NOP receptor agonist orphan G protein-coupled receptor (GPCR) SP9155 P550 on memory consolidation in a passive avoidance learning test in rats. Accordingly, rats were pretreated with a nonselective muscarinic acetylcholine receptor antagonist, atropine, a c-aminobutyric acid subunit A (GABA-A) receptor antagonist, bicuculline, a D2, D3, D4 dopamine receptor antagonist, haloperidol, a nonselective opioid receptor antagonist, naloxone, a non-specific nitric oxide synthase inhibitor, nitro-L-arginine, a nonselective a-adrenergic receptor antagonist, phenoxybenzamine and a b-adrenergic receptor antagonist, propranolol. Atropine, bicuculline, naloxone and phenoxybenzamine reversed the orphan GPCR SP9155 P550-induced memory impairment, whereas propranolol, haloperidol and nitro-L-arginine were ineffective. Our results suggest that the NOP system-induced impairment of memory consolidation is mediated through muscarinic ´ . Adamik G. Telegdy (&) M. Palotai A Department of Pathophysiology, Faculty of Medicine, University of Szeged, Semmelweis Str. 1, Szeged 6701, Hungary e-mail: [email protected] G. Telegdy MTA-SZTE Neuroscience Research Group of the Hungarian Academy of Sciences, Szeged, Hungary
cholinergic, GABA-A-ergic, opioid and a-adrenergic receptors, whereas b-adrenergic, D2, D3, D4-dopaminergic and nitrergic mechanisms are not be implicated. Keywords Nociception/orphanin FQ Orphan GPCR SP9155 P550 Passive avoidance learning Neurotransmitters Receptor antagonits
Introduction The nociceptin/orphanin FQ peptide (NOP) receptor also known as opioid receptor-like 1 receptor (ORL1) is a G protein-coupled receptor (GPCR), which consists of seven transmembrane domains [1]. Nociceptin, also called orphanin FQ (N/OFQ), a 17-amino acid opioid-like neuropeptide, has been identified as the natural and selective ligand of the NOP receptor [1]. The NOP system plays an important role in pain [2], locomotion [3], anxiety [4] and depression [5], reward and drug addiction [6, 7], learning and memory [8, 9]. The activation of the NOP receptor produces inhibition of the adenylyl cyclase enzyme, reduction of calcium channel conductance and activation of potassium channels. Through these mechanisms, NOP receptor may exert both inhibitory and disinhibitory effects, which depend on the regional and synaptic localization in the central nervous system (CNS) [10, 11]. NOP receptors and N/OFQ are highly expressed in brain sites that are involved in learning and memory, such as the hippocampus, amygdala and cerebral cortex [12–14]. Previous studies demonstrated that the nociceptin/orphanin FQ peptide-receptor system induces impairment in learning and memory [8, 15]. However, we have little evidence about the underlying neuromodulation. Therefore,
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the aim of the present study was to investigate the involvement of distinct neurotransmitters in the action of the selective NOP receptor agonist orphan GPCR SP9155 P550 [16] on memory consolidation in a passive avoidance learning test in rats. Accordingly, rats were pretreated with a nonselective muscarinic acetylcholine receptor antagonist, atropine, a c-aminobutyric acid subunit A (GABA-A) receptor antagonist, bicuculline, a D2, D3, D4 dopamine receptor antagonist, haloperidol, a nonselective opioid receptor antagonist, naloxone, a non-specific nitric oxide synthase (NOS) inhibitor, nitro-L-arginine, a nonselective a-adrenergic receptor antagonist, phenoxybenzamine and a b-adrenergic receptor antagonist, propranolol.
Methods and Materials Experimental Animals and Ethics Statement Male Wistar rats, weighing 150–250 g were used. The animals were maintained and treated during the experiments in accordance with the instructions of the Ethical Committee for the Protection of Animals in Research of the University of Szeged (Szeged, Hungary), which specifically approved this study. The rats were kept in their home cages at a constant temperature (23 °C) on a standard illumination schedule with 12-h light and 12-h dark periods (lights on from 6:00 a.m.). Commercial food and tap water were available ad libitum. To minimize the effects of nonspecific stress, the rats were handled daily. All surgery was performed under anesthesia, and all efforts were made to minimize suffering. Surgery For intracerebroventricular (i.c.v.) administration, the rats were implanted with a stainless steel Luer cannula (10 mm long) aimed at the right lateral cerebral ventricle under Nembutal (35 mg/kg, intraperitoneally, i.p.) anesthesia. The stereotaxic coordinates were 0.2 mm posterior; 1.7 mm lateral to the bregma; 3.7 mm deep from the dural surface, according to the atlas of Pellegrino et al. [17]. Cannulas were secured to the skull with dental cement and acrylate. The rats were used after a recovery period of 5 days. Chemicals Orphan GPCR SP9155 P550 was obtained from Bachem Inc. (Switzerland); atropine sulfate, from EGIS (Budapest, Hungary); bicuculline, from Sandoz (Basle, Switzerland); haloperidol, from G. Richter (Budapest, Hungary);
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naloxone hydrochloride, from Endo Labs (Wilmington, USA); nitro-L-arginine methylester hydrochloride, from Sigma-Aldrich Inc. (St. Louis, USA); phenoxybenzamine hydrochloride, from Smith Kline and French (Herts, UK) and propranolol hydrochloride, from ICI Ltd. (Macclesfield, UK). Treatments All the experiments were performed in the morning. Orphan GPCR SP9155 P550 in a quantity of 10 lg per ampoule was lyophilized and stored at -20 °C. Immediately before the experiments, orphan GPCR SP9155 P550 was dissolved in sterile pyrogen-free 0.9 % saline and administered i.c.v. in a volume of 2 ll via the cannula. First, different doses of orphan GPCR SP9155 P550 (0.5, 1.0, 2.0 lg) were used to establish a dose–response curve, then only the minimum effective dose of orphan GPCR SP9155 P550 (1.0 lg) was used in combination with the receptor antagonists (RA). The RA were dissolved in 0.9 % saline and were administered i.p., except for nitro-L-arginine, which was administered i.c.v. The effective doses of the RA were selected on the basis of previous experience where the minimal doses were effective (in other tests), but did not themselves influence the tests [18, 19]. Immediately following the learning trial and 30 min later, the control rats were treated with 0.9 % saline (on each occasion with 2 ll, i.c.v.). Immediately following the learning trial, the orphan GPCR SP9155 P550 group was treated with 0.9 % saline (2 ll, i.c.v.) which was followed 30 min later by orphan GPCR SP9155 P550 (1 lg/2 ll, i.c.v.). In the combined treatment, the animals were treated immediately with a RA and 30 min later with orphan GPCR SP9155 P550. All groups were tested at 24 h. The same protocol was followed in all treated groups. Behavioral Testing Passive Avoidance Test One-trial learning, step-through passive avoidance behavior was measured according to Ader et al. [20]. The apparatus consists of two separate chambers connected through a guillotine door. One of the chambers was illuminated, while the other was dark. Rats were placed on the illuminated platform and allowed to enter the dark compartment. Since rats prefer dark to light, they normally entered within 5 s. Two additional trials were delivered on the following day. After the second trial, unavoidable mild electric footshocks (0.75 mA, 2 s) were delivered through the grid floor. The guillotine door was closed immediately after the rat entered the dark chamber and the animals could not escape the footshock. After this single trial, the
Neurochem Res
Fig. 1 The effects of orphan GPCR SP9155 P550 (orphan) on the consolidation of passive avoidance learning. Orphan (0.5 lg/2 ll, i.c.v.), orphan (1.0 lg/2 ll, i.c.v.) *p \ 0.05 versus control, orphan (2.0 lg/2 ll, i.c.v.) *p \ 0.05 versus control. The mean and SE are shown. Numbers in brackets denote the numbers of animals used
Fig. 3 The effect of a c-aminobutyric acid subunit A (GABA-A) receptor antagonist, bicuculline on orphan GPCR SP9155 P550 (orphan)-induced consolidation of passive avoidance learning. Orphan (1.0 lg/2 ll, i.c.v.) *p \ 0.05 versus control, bicuculline (1 mg/kg, i.p.), combined (bicuculline 1 mg/kg, i.p. ? orphan 1.0 lg/ 2 ll, i.c.v.). The mean and SE are shown. Numbers in brackets denote the numbers of animals used
Tukey’s post hoc comparison test. Only the mean percentages were plotted and the standard error of the mean (SEM) is given in the figure captions. The differences between groups were examined by Tukey’s post hoc comparison test, and a probability level of 0.05 or less was accepted as indicating a statistically significant difference.
Results
Fig. 2 The effect of a nonselective muscarinic acetylcholine receptor antagonist, atropine on the orphan GPCR SP9155 P550 (orphan)induced consolidation of passive avoidance learning. Orphan (1.0 lg/ 2 ll, i.c.v.) *p \ 0.05 versus control, atropine (2 mg/kg, i.p.), combined (atropine 2 mg/kg, i.p. ? orphan 1.0 lg/2 ll, i.c.v.). The mean and SE are shown. Numbers in brackets denote the numbers of animals used
rats were immediately removed from the apparatus and were treated. The consolidation of passive avoidance behavior was tested 24 h later. In the 24-h testing, each animal was placed on the platform and the latency to enter the dark compartment was measured up to a maximum of 300 s. Statistical Analysis Statistical analysis of the behavioral testing was performed by analysis of variance (ANOVA), which was followed by
Orphan GPCR SP9155 P550 dose-dependently impaired the consolidation of passive avoidance learning. While the 0.5 lg/2 ll, i.c.v. dose was ineffective, 1 lg/2 ll and 2 lg/ 2 ll doses exerted a significant effect on learning [F(3,19) = 19.11]; p \ 0.01 (Fig. 1). In the experiments with atropine, orphan GPCR SP9155 P550 (1 lg/2 ll, i.c.v.) impaired the consolidation of passive avoidance learning [F(3,18) = 12.88]; p \ 0.01. Atropine (2 mg/kg, i.p.) itself had no action, while atropine pretreatment prevented the action of orphan GPCR SP9155 P550 on this consolidation (Fig. 2). In the series of experiments with bicuculline, orphan GPCR SP9155 P550 (1 lg/2 ll, i.c.v.) impaired the learning [F(3,20) = 75.32]; p \ 0.01. Bicuculline (1 mg/ kg, i.p.) itself had no action, but pretreatment with bicuculline fully blocked the action of orphan GPCR SP9155 P550 (Fig. 3). In the experiments with naloxone, orphan GPCR SP9155 P550 (1 lg/2 ll, i.c.v.) impaired the learning [F(3,18) = 13.08]; p \ 0.01. Naloxone (0.3 mg/kg, i.p.) itself had no action on the test, but blocked the action of orphan GPCR SP9155 P550 (Fig. 4).
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Fig. 4 The effect of a nonselective opioid receptor antagonist, naloxone on orphan GPCR SP9155 P550 (orphan)-induced consolidation of passive avoidance learning. Orphan (1.0 lg/2 ll, i.c.v.) *p \ 0.05 versus control, naloxone (0.3 mg/kg, i.p.), combined (naloxone 0.3 mg/kg, i.p. ? orphan 1.0 lg/2 ll, i.c.v.). The mean and SE are shown. Numbers in brackets denote the numbers of animals used
Fig. 6 The effect of a D2, D3, D4 dopamine receptor antagonist, haloperidol on orphan GPCR SP9155 P550 (orphan)-induced consolidation of passive avoidance learning. Orphan (1.0 lg/2 ll, i.c.v.) *p \ 0.05 versus control, haloperidol (10 lg/kg, i.p.), combined (haloperidol 10 lg/kg, i.p. ? orphan 1.0 lg/2 ll, i.c.v.) *p \ 0.05 versus control. The mean and SE are shown. Numbers in brackets denote the numbers of animals used
Fig. 5 The effects of a nonselective a-adrenergic receptor antagonist, phenoxybenzamine on orphan GPCR SP9155 P550 (orphan)-induced consolidation of passive avoidance learning. Orphan (1.0 lg/2 ll, i.c.v.) *p \ 0.05 versus control, phenoxybenzamine (2 mg/kg, i.p.), combined (phenoxybenzamine 2 mg/kg i.p. ? orphan 1.0 lg/2 ll, i.c.v.). The mean and SE are shown. Numbers in brackets denote the numbers of animals used
Fig. 7 The effect of a non-specific nitric oxide synthase (NOS) inhibitor, nitro-L-arginine on orphan GPCR SP9155 P550 (orphan)induced consolidation of passive avoidance learning. Orphan (1.0 lg/ 2 ll, i.c.v.) *p \ 0.05 versus control, nitro-L-arginine (10 lg/2 ll, i.c.v.), combined (nitro-L-arginine 10 lg/2 ll, i.c.v. ? orphan 1.0 lg/ 2 ll, i.c.v.) *p \ 0.05 versus control. The mean and SE are shown. Numbers in brackets denote the numbers of animals used
In the series of experiments with phenoxybenzamine, orphan GPCR SP9155 P550 (1 lg/2 ll, i.c.v.) impaired the consolidation [F(3,18) = 13.41]; p \ 0.05. Phenoxybenzamine (2 mg/kg, i.p.) had no action on the test, but fully blocked the action of orphan GPCR SP9155 P550 (Fig. 5). In the experiments with haloperidol, orphan GPCR SP9155 P550 (1 lg/2 ll, i.c.v.) impaired the consolidation of passive avoidance learning [F(3,16) = 25.74]; p \ 0.01. Haloperidol (10 lg/kg, i.p.) itself had no action. In the combined treatment, haloperidol did not block the action of
orphan GPCR SP9155 P550 (p \ 0.05 vs. the control) (Fig. 6). Nitro-L-arginine (10 lg/2 ll, i.c.v.) itself had no action on the passive avoidance test. Orphan GPCR SP9155 P550 (1 lg/2 ll, i.c.v.) impaired the consolidation of the passive avoidance learning [F(3,19) = 38.70]; p \ 0.01. Combined treatment with OFQ/N and nitro-L-arginine did not modify the action of orphan GPCR SP9155 P550 (p \ 0.05 vs. the control) (Fig. 7).
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Fig. 8 The effects of a b-adrenergic receptor antagonist, propranolol on orphan GPCR SP9155 P550 (orphan)-induced consolidation of passive avoidance learning. Orphan (1.0 lg/2 ll, i.c.v.) *p \ 0.05 versus control, propranolol (10 mg/kg, i.p.), combined (propranolol 10 mg/kg i.p. ? orphan 1.0 lg/2 ll, i.c.v.) *p \ 0.05 versus control. The mean and SE are shown. Numbers in brackets denote the numbers of animals used
Propranolol (10 mg/kg, i.p.) alone exerted no action. Orphan GPCR SP9155 P550 (1 lg/2 ll, i.c.v.) impaired the consolidation of the passive avoidance learning [F(3,19) = 7.89]; p \ 0.01. Propranolol pretreatment did not modify the action of orphan GPCR SP9155 P550. The combined treatment had no action on the consolidation induced by orphan GPCR SP9155 P550 (p \ 0.05 vs. the control) (Fig. 8).
Discussion The NOP receptor, like other opioid receptors, is a GPCR, also known as seven transmembrane receptor (7TM) [1]. N/OFQ was isolated as the natural and selective ligand of the NOP receptor, which shares sequence similarities to the opioid peptides and plays role in several important physiological functions of the CNS [1]. N/OFQ and NOP receptors are localized in brain regions which are associated with learning and memory, such as the hippocampus, amygdala and cerebral cortex [12–14]. Prior studies demonstrated that intrahippocampal or intraamygdaloid administration of NOP receptor agonists induce memory impairment in rodents [8, 15]. Additionally, N/OFQ or NOP receptor knockout mice showed memory improvement [9, 21]. In accordance with the previous studies, our results provide further evidence that NOP receptor activation impairs the consolidation of passive avoidance learning in rats. The present experiments suggest that the N/OFQ–NOP receptor system exerts this effect via mediation of muscarinic cholinergic, GABA-A-ergic, opiate and
a-adrenergic transmitters. It is interesting that b-adrenergic, D2, D3, D4-ergic and NO-ergic systems might not be involved in the impairment of memory consolidation caused by the activation of NOP receptor. The neurotransmitter acetylcholine (Ach) is prominently involved in learning and memory [22]. The cholinergic system plays role in the modulation of synaptic plasticity, including long-term potentiation (LTP) [23, 24]. Functional abnormalities of this system are associated with a number of disorders including Alzheimer’s disease and schizophrenia [25]. Prior experiments suggested that subeffective doses of N/OFQ, that alone had no significant effect, ameliorated the impairment of learning and memory induced by the muscarinic antagonist scopolamine in mice or by the nicotinic antagonist mecamylamine in rats [26, 27]. The mechanism of this action is yet unknown, but presumably not mediated by the NOP receptor [27]. Our results demonstrate for the first time that the impairment of passive avoidance learning induced by an effective dose of the selective NOP receptor agonist orphan GPCR SP9155 P550 is reversed by the non-selective muscarinic antagonist atropine in rats. This observation shows that muscarinergic neurotransmission is involved in the action of the N/OFQ–NOP receptor system on memory impairment. The neurotransmitter c-aminobutyric acid (GABA) also plays role in the mediation of physiologic memory processes [28] and in the pathogenesis of psychiatric disorders, such as schizophrenia [29]. A recently published study demonstrated that injection of the GABA-A receptor antagonist bicuculline into the basolateral amygdala (BLA) ameliorated the stress-induced memory impairment in rats [30]. Additionally, bicuculline also inhibited the N/OFQinduced anxiolytic effect in mice [31] and the N/OFQinduced food intake in cockerels [32]. Our results demonstrate for the first time that the NOP receptor mediated impairment of passive avoidance learning is attenuated by bicuculline in rats. This finding suggests that GABA-Aergic neurotransmission is also implicated in the effects of the N/OFQ–NOP receptor system on memory. The opioid system is involved in addiction as well as in memory [33]. The prefrontal cortex (PFC) and the BLA encode and retrieve the opiate reward and withdrawal aversion-related memories [34, 35]. A previous study showed that the morphine-induced impairment in memory was antagonized by the l and to a lesser extent d and j receptor antagonist naloxone [36]. In addition, naloxone also reversed the NOP receptor agonist NNC 63-0532induced anti-analgesia [37]. Our results demonstrate for the first time that the NOP receptor mediated impairment of passive avoidance learning is attenuated by naloxone in rats. This result suggests that the opioid neurotransmission is also implicated in the actions of the N/OFQ–NOP receptor system on memory.
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The adrenergic system is also important in memory functions and has been shown to modulate different forms of synaptic plasticity in the hippocampus [38]. a1-Adrenergic receptor has been proven to be a dominant mediator of hippocampal memory processes [38, 39]. Prior data showed that systemic or intra-lateral amygdala administration of the a1-adrenergic receptor antagonist terazosin facilitates fear conditioning, a major model of emotional learning and LTP [40]. Our results demonstrate for the first time that the NOP receptor mediated impairment of passive avoidance learning is reversed by the non-selective a-adrenergic receptor antagonist phenoxybenzamine in rats. On the other hand, a previous study showed that intra-BLA co-administration of the b1-adrenergic antagonist atenolol can attenuate the OFQ/N-induced memory impairment in a 48 h-inhibitory avoidance retention test in rats [15]. Our results show that pretreatment with the non-selective b-adrenergic receptor antagonist propranolol does not attenuate the orphan GPCR SP9155 P550-induced memory impairment in a 24 h-passive avoidance learning test in rats. Our findings suggest that the action of N/OFQ–NOP receptor system on memory is mediated through a-adrenergic neurotransmission, whereas b-adrenergic receptors may not be involved within 24 h of memory consolidation. The mesolimbic dopaminergic system plays role in memory, reward and drug addiction [41]. A prior study revealed that the exogenous N/OFQ suppresses the mesolimbic dopamine release and the endogenous N/OFQ has no regulatory action on the basal mesolimbic dopaminergic activity [42]. In our study, the D2, D3, D4 dopamine receptor antagonist, haloperidol has not reversed the impaired consolidation of passive avoidance learning induced by N/OFQ–NOP activation. Our results suggest that D2, D3, D4 dopaminergic receptors are not responsible for the action of N/OFQ–NOP receptor system on memory. Nitric oxide (NO) is a new type of neurotransmitter which is associated with synaptic plasticity, learning and memory [43]. A recently published study revealed that 7 day treatment with nitric oxide synthase inhibitor N(x)nitro-L-arginine methylester decreased NO content in the PFC and hippocampus resulting in impaired learning and memory performance in an electric shock-paired Y maze test in rats [44]. Previous experiments demonstrated that the NOP receptor antagonist JTC-801 alleviated neuropathic pain by inhibition of NO production of neuronal NOS [45]. Our results show that nitro-L-arginine does not reverse the NOP receptor-induced impairment in passive avoidance learning. Our finding suggest that NO might not be involved in the action of a single dose of orphan GPCR SP9155 P550 on memory. The present study demonstrates that the NOP receptor agonist orphan GPCR SP9155 P550 impairs learning and memory functions in passive avoidance learning in rats.
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Cholinergic, GABA-A-ergic, a-adrenergic and opiate transmission are all involved in this action, whereas b-adrenergic, D2, D3, D4-dopaminergic and nitrergic mechanisms may not be implicated. We believe that our results contribute to the understanding of the underlying mechanisms of NOP signaling and that the N/OFQ–NOP receptor system may serve as a pharmacological target in treatment of memory disorders and several other neurologic and psychiatric diseases, including anxiety [4], depression [5], drug addiction [6], pain [2] and Parkinson’s disease [46]. Acknowledgments This work was supported by Grants from the Neuroscience Research Group of the Hungarian Academy of Sciences and TAMOP (4.2.1.).
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ORIGINAL PAPER
Involvement of Neurotransmitters in the Action of the Nociceptin/ Orphanin FQ Peptide-Receptor System on Passive Avoidance Learning in Rats ´ gnes Adamik • Gyula Telegdy Miklo´s Palotai • A
Received: 25 February 2014 / Revised: 8 May 2014 / Accepted: 13 May 2014 Ó Springer Science+Business Media New York 2014
Abstract The nociceptin/orphanin FQ peptide (NOP) receptor and its endogenous ligand plays role in several physiologic functions of the central nervous system, including pain, locomotion, anxiety and depression, reward and drug addiction, learning and memory. Previous studies demonstrated that the NOP-receptor system induces impairment in memory and learning. However, we have little evidence about the underlying neuromodulation. The aim of the present study was to investigate the involvement of distinct neurotransmitters in the action of the selective NOP receptor agonist orphan G protein-coupled receptor (GPCR) SP9155 P550 on memory consolidation in a passive avoidance learning test in rats. Accordingly, rats were pretreated with a nonselective muscarinic acetylcholine receptor antagonist, atropine, a c-aminobutyric acid subunit A (GABA-A) receptor antagonist, bicuculline, a D2, D3, D4 dopamine receptor antagonist, haloperidol, a nonselective opioid receptor antagonist, naloxone, a non-specific nitric oxide synthase inhibitor, nitro-L-arginine, a nonselective a-adrenergic receptor antagonist, phenoxybenzamine and a b-adrenergic receptor antagonist, propranolol. Atropine, bicuculline, naloxone and phenoxybenzamine reversed the orphan GPCR SP9155 P550-induced memory impairment, whereas propranolol, haloperidol and nitro-L-arginine were ineffective. Our results suggest that the NOP system-induced impairment of memory consolidation is mediated through muscarinic ´ . Adamik G. Telegdy (&) M. Palotai A Department of Pathophysiology, Faculty of Medicine, University of Szeged, Semmelweis Str. 1, Szeged 6701, Hungary e-mail: [email protected] G. Telegdy MTA-SZTE Neuroscience Research Group of the Hungarian Academy of Sciences, Szeged, Hungary
cholinergic, GABA-A-ergic, opioid and a-adrenergic receptors, whereas b-adrenergic, D2, D3, D4-dopaminergic and nitrergic mechanisms are not be implicated. Keywords Nociception/orphanin FQ Orphan GPCR SP9155 P550 Passive avoidance learning Neurotransmitters Receptor antagonits
Introduction The nociceptin/orphanin FQ peptide (NOP) receptor also known as opioid receptor-like 1 receptor (ORL1) is a G protein-coupled receptor (GPCR), which consists of seven transmembrane domains [1]. Nociceptin, also called orphanin FQ (N/OFQ), a 17-amino acid opioid-like neuropeptide, has been identified as the natural and selective ligand of the NOP receptor [1]. The NOP system plays an important role in pain [2], locomotion [3], anxiety [4] and depression [5], reward and drug addiction [6, 7], learning and memory [8, 9]. The activation of the NOP receptor produces inhibition of the adenylyl cyclase enzyme, reduction of calcium channel conductance and activation of potassium channels. Through these mechanisms, NOP receptor may exert both inhibitory and disinhibitory effects, which depend on the regional and synaptic localization in the central nervous system (CNS) [10, 11]. NOP receptors and N/OFQ are highly expressed in brain sites that are involved in learning and memory, such as the hippocampus, amygdala and cerebral cortex [12–14]. Previous studies demonstrated that the nociceptin/orphanin FQ peptide-receptor system induces impairment in learning and memory [8, 15]. However, we have little evidence about the underlying neuromodulation. Therefore,
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the aim of the present study was to investigate the involvement of distinct neurotransmitters in the action of the selective NOP receptor agonist orphan GPCR SP9155 P550 [16] on memory consolidation in a passive avoidance learning test in rats. Accordingly, rats were pretreated with a nonselective muscarinic acetylcholine receptor antagonist, atropine, a c-aminobutyric acid subunit A (GABA-A) receptor antagonist, bicuculline, a D2, D3, D4 dopamine receptor antagonist, haloperidol, a nonselective opioid receptor antagonist, naloxone, a non-specific nitric oxide synthase (NOS) inhibitor, nitro-L-arginine, a nonselective a-adrenergic receptor antagonist, phenoxybenzamine and a b-adrenergic receptor antagonist, propranolol.
Methods and Materials Experimental Animals and Ethics Statement Male Wistar rats, weighing 150–250 g were used. The animals were maintained and treated during the experiments in accordance with the instructions of the Ethical Committee for the Protection of Animals in Research of the University of Szeged (Szeged, Hungary), which specifically approved this study. The rats were kept in their home cages at a constant temperature (23 °C) on a standard illumination schedule with 12-h light and 12-h dark periods (lights on from 6:00 a.m.). Commercial food and tap water were available ad libitum. To minimize the effects of nonspecific stress, the rats were handled daily. All surgery was performed under anesthesia, and all efforts were made to minimize suffering. Surgery For intracerebroventricular (i.c.v.) administration, the rats were implanted with a stainless steel Luer cannula (10 mm long) aimed at the right lateral cerebral ventricle under Nembutal (35 mg/kg, intraperitoneally, i.p.) anesthesia. The stereotaxic coordinates were 0.2 mm posterior; 1.7 mm lateral to the bregma; 3.7 mm deep from the dural surface, according to the atlas of Pellegrino et al. [17]. Cannulas were secured to the skull with dental cement and acrylate. The rats were used after a recovery period of 5 days. Chemicals Orphan GPCR SP9155 P550 was obtained from Bachem Inc. (Switzerland); atropine sulfate, from EGIS (Budapest, Hungary); bicuculline, from Sandoz (Basle, Switzerland); haloperidol, from G. Richter (Budapest, Hungary);
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naloxone hydrochloride, from Endo Labs (Wilmington, USA); nitro-L-arginine methylester hydrochloride, from Sigma-Aldrich Inc. (St. Louis, USA); phenoxybenzamine hydrochloride, from Smith Kline and French (Herts, UK) and propranolol hydrochloride, from ICI Ltd. (Macclesfield, UK). Treatments All the experiments were performed in the morning. Orphan GPCR SP9155 P550 in a quantity of 10 lg per ampoule was lyophilized and stored at -20 °C. Immediately before the experiments, orphan GPCR SP9155 P550 was dissolved in sterile pyrogen-free 0.9 % saline and administered i.c.v. in a volume of 2 ll via the cannula. First, different doses of orphan GPCR SP9155 P550 (0.5, 1.0, 2.0 lg) were used to establish a dose–response curve, then only the minimum effective dose of orphan GPCR SP9155 P550 (1.0 lg) was used in combination with the receptor antagonists (RA). The RA were dissolved in 0.9 % saline and were administered i.p., except for nitro-L-arginine, which was administered i.c.v. The effective doses of the RA were selected on the basis of previous experience where the minimal doses were effective (in other tests), but did not themselves influence the tests [18, 19]. Immediately following the learning trial and 30 min later, the control rats were treated with 0.9 % saline (on each occasion with 2 ll, i.c.v.). Immediately following the learning trial, the orphan GPCR SP9155 P550 group was treated with 0.9 % saline (2 ll, i.c.v.) which was followed 30 min later by orphan GPCR SP9155 P550 (1 lg/2 ll, i.c.v.). In the combined treatment, the animals were treated immediately with a RA and 30 min later with orphan GPCR SP9155 P550. All groups were tested at 24 h. The same protocol was followed in all treated groups. Behavioral Testing Passive Avoidance Test One-trial learning, step-through passive avoidance behavior was measured according to Ader et al. [20]. The apparatus consists of two separate chambers connected through a guillotine door. One of the chambers was illuminated, while the other was dark. Rats were placed on the illuminated platform and allowed to enter the dark compartment. Since rats prefer dark to light, they normally entered within 5 s. Two additional trials were delivered on the following day. After the second trial, unavoidable mild electric footshocks (0.75 mA, 2 s) were delivered through the grid floor. The guillotine door was closed immediately after the rat entered the dark chamber and the animals could not escape the footshock. After this single trial, the
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Fig. 1 The effects of orphan GPCR SP9155 P550 (orphan) on the consolidation of passive avoidance learning. Orphan (0.5 lg/2 ll, i.c.v.), orphan (1.0 lg/2 ll, i.c.v.) *p \ 0.05 versus control, orphan (2.0 lg/2 ll, i.c.v.) *p \ 0.05 versus control. The mean and SE are shown. Numbers in brackets denote the numbers of animals used
Fig. 3 The effect of a c-aminobutyric acid subunit A (GABA-A) receptor antagonist, bicuculline on orphan GPCR SP9155 P550 (orphan)-induced consolidation of passive avoidance learning. Orphan (1.0 lg/2 ll, i.c.v.) *p \ 0.05 versus control, bicuculline (1 mg/kg, i.p.), combined (bicuculline 1 mg/kg, i.p. ? orphan 1.0 lg/ 2 ll, i.c.v.). The mean and SE are shown. Numbers in brackets denote the numbers of animals used
Tukey’s post hoc comparison test. Only the mean percentages were plotted and the standard error of the mean (SEM) is given in the figure captions. The differences between groups were examined by Tukey’s post hoc comparison test, and a probability level of 0.05 or less was accepted as indicating a statistically significant difference.
Results
Fig. 2 The effect of a nonselective muscarinic acetylcholine receptor antagonist, atropine on the orphan GPCR SP9155 P550 (orphan)induced consolidation of passive avoidance learning. Orphan (1.0 lg/ 2 ll, i.c.v.) *p \ 0.05 versus control, atropine (2 mg/kg, i.p.), combined (atropine 2 mg/kg, i.p. ? orphan 1.0 lg/2 ll, i.c.v.). The mean and SE are shown. Numbers in brackets denote the numbers of animals used
rats were immediately removed from the apparatus and were treated. The consolidation of passive avoidance behavior was tested 24 h later. In the 24-h testing, each animal was placed on the platform and the latency to enter the dark compartment was measured up to a maximum of 300 s. Statistical Analysis Statistical analysis of the behavioral testing was performed by analysis of variance (ANOVA), which was followed by
Orphan GPCR SP9155 P550 dose-dependently impaired the consolidation of passive avoidance learning. While the 0.5 lg/2 ll, i.c.v. dose was ineffective, 1 lg/2 ll and 2 lg/ 2 ll doses exerted a significant effect on learning [F(3,19) = 19.11]; p \ 0.01 (Fig. 1). In the experiments with atropine, orphan GPCR SP9155 P550 (1 lg/2 ll, i.c.v.) impaired the consolidation of passive avoidance learning [F(3,18) = 12.88]; p \ 0.01. Atropine (2 mg/kg, i.p.) itself had no action, while atropine pretreatment prevented the action of orphan GPCR SP9155 P550 on this consolidation (Fig. 2). In the series of experiments with bicuculline, orphan GPCR SP9155 P550 (1 lg/2 ll, i.c.v.) impaired the learning [F(3,20) = 75.32]; p \ 0.01. Bicuculline (1 mg/ kg, i.p.) itself had no action, but pretreatment with bicuculline fully blocked the action of orphan GPCR SP9155 P550 (Fig. 3). In the experiments with naloxone, orphan GPCR SP9155 P550 (1 lg/2 ll, i.c.v.) impaired the learning [F(3,18) = 13.08]; p \ 0.01. Naloxone (0.3 mg/kg, i.p.) itself had no action on the test, but blocked the action of orphan GPCR SP9155 P550 (Fig. 4).
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Fig. 4 The effect of a nonselective opioid receptor antagonist, naloxone on orphan GPCR SP9155 P550 (orphan)-induced consolidation of passive avoidance learning. Orphan (1.0 lg/2 ll, i.c.v.) *p \ 0.05 versus control, naloxone (0.3 mg/kg, i.p.), combined (naloxone 0.3 mg/kg, i.p. ? orphan 1.0 lg/2 ll, i.c.v.). The mean and SE are shown. Numbers in brackets denote the numbers of animals used
Fig. 6 The effect of a D2, D3, D4 dopamine receptor antagonist, haloperidol on orphan GPCR SP9155 P550 (orphan)-induced consolidation of passive avoidance learning. Orphan (1.0 lg/2 ll, i.c.v.) *p \ 0.05 versus control, haloperidol (10 lg/kg, i.p.), combined (haloperidol 10 lg/kg, i.p. ? orphan 1.0 lg/2 ll, i.c.v.) *p \ 0.05 versus control. The mean and SE are shown. Numbers in brackets denote the numbers of animals used
Fig. 5 The effects of a nonselective a-adrenergic receptor antagonist, phenoxybenzamine on orphan GPCR SP9155 P550 (orphan)-induced consolidation of passive avoidance learning. Orphan (1.0 lg/2 ll, i.c.v.) *p \ 0.05 versus control, phenoxybenzamine (2 mg/kg, i.p.), combined (phenoxybenzamine 2 mg/kg i.p. ? orphan 1.0 lg/2 ll, i.c.v.). The mean and SE are shown. Numbers in brackets denote the numbers of animals used
Fig. 7 The effect of a non-specific nitric oxide synthase (NOS) inhibitor, nitro-L-arginine on orphan GPCR SP9155 P550 (orphan)induced consolidation of passive avoidance learning. Orphan (1.0 lg/ 2 ll, i.c.v.) *p \ 0.05 versus control, nitro-L-arginine (10 lg/2 ll, i.c.v.), combined (nitro-L-arginine 10 lg/2 ll, i.c.v. ? orphan 1.0 lg/ 2 ll, i.c.v.) *p \ 0.05 versus control. The mean and SE are shown. Numbers in brackets denote the numbers of animals used
In the series of experiments with phenoxybenzamine, orphan GPCR SP9155 P550 (1 lg/2 ll, i.c.v.) impaired the consolidation [F(3,18) = 13.41]; p \ 0.05. Phenoxybenzamine (2 mg/kg, i.p.) had no action on the test, but fully blocked the action of orphan GPCR SP9155 P550 (Fig. 5). In the experiments with haloperidol, orphan GPCR SP9155 P550 (1 lg/2 ll, i.c.v.) impaired the consolidation of passive avoidance learning [F(3,16) = 25.74]; p \ 0.01. Haloperidol (10 lg/kg, i.p.) itself had no action. In the combined treatment, haloperidol did not block the action of
orphan GPCR SP9155 P550 (p \ 0.05 vs. the control) (Fig. 6). Nitro-L-arginine (10 lg/2 ll, i.c.v.) itself had no action on the passive avoidance test. Orphan GPCR SP9155 P550 (1 lg/2 ll, i.c.v.) impaired the consolidation of the passive avoidance learning [F(3,19) = 38.70]; p \ 0.01. Combined treatment with OFQ/N and nitro-L-arginine did not modify the action of orphan GPCR SP9155 P550 (p \ 0.05 vs. the control) (Fig. 7).
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Fig. 8 The effects of a b-adrenergic receptor antagonist, propranolol on orphan GPCR SP9155 P550 (orphan)-induced consolidation of passive avoidance learning. Orphan (1.0 lg/2 ll, i.c.v.) *p \ 0.05 versus control, propranolol (10 mg/kg, i.p.), combined (propranolol 10 mg/kg i.p. ? orphan 1.0 lg/2 ll, i.c.v.) *p \ 0.05 versus control. The mean and SE are shown. Numbers in brackets denote the numbers of animals used
Propranolol (10 mg/kg, i.p.) alone exerted no action. Orphan GPCR SP9155 P550 (1 lg/2 ll, i.c.v.) impaired the consolidation of the passive avoidance learning [F(3,19) = 7.89]; p \ 0.01. Propranolol pretreatment did not modify the action of orphan GPCR SP9155 P550. The combined treatment had no action on the consolidation induced by orphan GPCR SP9155 P550 (p \ 0.05 vs. the control) (Fig. 8).
Discussion The NOP receptor, like other opioid receptors, is a GPCR, also known as seven transmembrane receptor (7TM) [1]. N/OFQ was isolated as the natural and selective ligand of the NOP receptor, which shares sequence similarities to the opioid peptides and plays role in several important physiological functions of the CNS [1]. N/OFQ and NOP receptors are localized in brain regions which are associated with learning and memory, such as the hippocampus, amygdala and cerebral cortex [12–14]. Prior studies demonstrated that intrahippocampal or intraamygdaloid administration of NOP receptor agonists induce memory impairment in rodents [8, 15]. Additionally, N/OFQ or NOP receptor knockout mice showed memory improvement [9, 21]. In accordance with the previous studies, our results provide further evidence that NOP receptor activation impairs the consolidation of passive avoidance learning in rats. The present experiments suggest that the N/OFQ–NOP receptor system exerts this effect via mediation of muscarinic cholinergic, GABA-A-ergic, opiate and
a-adrenergic transmitters. It is interesting that b-adrenergic, D2, D3, D4-ergic and NO-ergic systems might not be involved in the impairment of memory consolidation caused by the activation of NOP receptor. The neurotransmitter acetylcholine (Ach) is prominently involved in learning and memory [22]. The cholinergic system plays role in the modulation of synaptic plasticity, including long-term potentiation (LTP) [23, 24]. Functional abnormalities of this system are associated with a number of disorders including Alzheimer’s disease and schizophrenia [25]. Prior experiments suggested that subeffective doses of N/OFQ, that alone had no significant effect, ameliorated the impairment of learning and memory induced by the muscarinic antagonist scopolamine in mice or by the nicotinic antagonist mecamylamine in rats [26, 27]. The mechanism of this action is yet unknown, but presumably not mediated by the NOP receptor [27]. Our results demonstrate for the first time that the impairment of passive avoidance learning induced by an effective dose of the selective NOP receptor agonist orphan GPCR SP9155 P550 is reversed by the non-selective muscarinic antagonist atropine in rats. This observation shows that muscarinergic neurotransmission is involved in the action of the N/OFQ–NOP receptor system on memory impairment. The neurotransmitter c-aminobutyric acid (GABA) also plays role in the mediation of physiologic memory processes [28] and in the pathogenesis of psychiatric disorders, such as schizophrenia [29]. A recently published study demonstrated that injection of the GABA-A receptor antagonist bicuculline into the basolateral amygdala (BLA) ameliorated the stress-induced memory impairment in rats [30]. Additionally, bicuculline also inhibited the N/OFQinduced anxiolytic effect in mice [31] and the N/OFQinduced food intake in cockerels [32]. Our results demonstrate for the first time that the NOP receptor mediated impairment of passive avoidance learning is attenuated by bicuculline in rats. This finding suggests that GABA-Aergic neurotransmission is also implicated in the effects of the N/OFQ–NOP receptor system on memory. The opioid system is involved in addiction as well as in memory [33]. The prefrontal cortex (PFC) and the BLA encode and retrieve the opiate reward and withdrawal aversion-related memories [34, 35]. A previous study showed that the morphine-induced impairment in memory was antagonized by the l and to a lesser extent d and j receptor antagonist naloxone [36]. In addition, naloxone also reversed the NOP receptor agonist NNC 63-0532induced anti-analgesia [37]. Our results demonstrate for the first time that the NOP receptor mediated impairment of passive avoidance learning is attenuated by naloxone in rats. This result suggests that the opioid neurotransmission is also implicated in the actions of the N/OFQ–NOP receptor system on memory.
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The adrenergic system is also important in memory functions and has been shown to modulate different forms of synaptic plasticity in the hippocampus [38]. a1-Adrenergic receptor has been proven to be a dominant mediator of hippocampal memory processes [38, 39]. Prior data showed that systemic or intra-lateral amygdala administration of the a1-adrenergic receptor antagonist terazosin facilitates fear conditioning, a major model of emotional learning and LTP [40]. Our results demonstrate for the first time that the NOP receptor mediated impairment of passive avoidance learning is reversed by the non-selective a-adrenergic receptor antagonist phenoxybenzamine in rats. On the other hand, a previous study showed that intra-BLA co-administration of the b1-adrenergic antagonist atenolol can attenuate the OFQ/N-induced memory impairment in a 48 h-inhibitory avoidance retention test in rats [15]. Our results show that pretreatment with the non-selective b-adrenergic receptor antagonist propranolol does not attenuate the orphan GPCR SP9155 P550-induced memory impairment in a 24 h-passive avoidance learning test in rats. Our findings suggest that the action of N/OFQ–NOP receptor system on memory is mediated through a-adrenergic neurotransmission, whereas b-adrenergic receptors may not be involved within 24 h of memory consolidation. The mesolimbic dopaminergic system plays role in memory, reward and drug addiction [41]. A prior study revealed that the exogenous N/OFQ suppresses the mesolimbic dopamine release and the endogenous N/OFQ has no regulatory action on the basal mesolimbic dopaminergic activity [42]. In our study, the D2, D3, D4 dopamine receptor antagonist, haloperidol has not reversed the impaired consolidation of passive avoidance learning induced by N/OFQ–NOP activation. Our results suggest that D2, D3, D4 dopaminergic receptors are not responsible for the action of N/OFQ–NOP receptor system on memory. Nitric oxide (NO) is a new type of neurotransmitter which is associated with synaptic plasticity, learning and memory [43]. A recently published study revealed that 7 day treatment with nitric oxide synthase inhibitor N(x)nitro-L-arginine methylester decreased NO content in the PFC and hippocampus resulting in impaired learning and memory performance in an electric shock-paired Y maze test in rats [44]. Previous experiments demonstrated that the NOP receptor antagonist JTC-801 alleviated neuropathic pain by inhibition of NO production of neuronal NOS [45]. Our results show that nitro-L-arginine does not reverse the NOP receptor-induced impairment in passive avoidance learning. Our finding suggest that NO might not be involved in the action of a single dose of orphan GPCR SP9155 P550 on memory. The present study demonstrates that the NOP receptor agonist orphan GPCR SP9155 P550 impairs learning and memory functions in passive avoidance learning in rats.
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Cholinergic, GABA-A-ergic, a-adrenergic and opiate transmission are all involved in this action, whereas b-adrenergic, D2, D3, D4-dopaminergic and nitrergic mechanisms may not be implicated. We believe that our results contribute to the understanding of the underlying mechanisms of NOP signaling and that the N/OFQ–NOP receptor system may serve as a pharmacological target in treatment of memory disorders and several other neurologic and psychiatric diseases, including anxiety [4], depression [5], drug addiction [6], pain [2] and Parkinson’s disease [46]. Acknowledgments This work was supported by Grants from the Neuroscience Research Group of the Hungarian Academy of Sciences and TAMOP (4.2.1.).
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