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Cross state-dependent memory retrieval between morphine and norharmane in the mouse dorsal hippocampus
Brain Research Bulletin 153 (2019) 24–29
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Cross state-dependent memory retrieval between morphine and norharmane in the mouse dorsal hippocampus Mohaddeseh Ebrahimi-Ghiria, Fatemeh Khakpaib, Mohammad-Reza Zarrindastc,d,e,f,
T
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a
Department of Biology, Faculty of Sciences, University of Zanjan, Zanjan, Iran Cognitive and Neuroscience Research Center (CNRC), Tehran Medical Sciences, Islamic Azad University, Tehran, Iran c Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran d Iranian National Center for Addiction Studies, Tehran University of Medical Sciences, Tehran, Iran e Institute for Cognitive Science Studies (ICSS), Tehran, Iran f Department of Neuroendocrinology, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran b
A R T I C LE I N FO
A B S T R A C T
Keywords: Morphine Norharmane State-dependent memory (SDM) Passive avoidance memory Mice
State-dependent memory (SDM) describes a phenomenon that memory is efficiently restored only when the brain state during restoration matches the state during encoding. Some psychoactive drugs such as morphine, ethanol, and cocaine evoke SDM. The scope of this study was to investigate the cross SDM between morphine and norharmane injected into the dorsal hippocampus of male NMRI mice, and the involvement of μ-opioid receptors (MORs) in the SDM of the drugs. Bilateral cannulae were implanted into the CA1 regions (intra-CA1), and memory retrieval was measured by the step-down apparatus. Results showed that pre-test microinjection of morphine (1 μg/mouse, intra-CA1) reversed amnesia induced by pre-training administration of the same dose of morphine, indicating morphine SDM. Moreover, norharmane (10 μg/mouse) also exerted a SDM. Pre-test microinjection of naloxone (0.5 μg/mouse) abolished amnesia induced by morphine or norharmane, and impaired SDM produced by each drug. The results demonstrated the contribution of MORs in the SDM induced by morphine as well as norharmane. Pre-test administration of morphine (1 μg/mouse, intra-CA1) also inhibited amnesia induced by pre-training intra-CA1 microinjection of norharmane (10 μg/mouse) and vice versa, suggesting a cross SDM between the drugs. In conclusion, it seems that there may be a cross SDM between morphine and norharmane, and MORs have a critical role in this phenomenon.
1. Introduction The memory of previous experiences and information helps us escape the danger and enables us to make a better choice in the future (Jiang et al., 2018). However, all remembered information is not equally well retrieved (Michalak et al., 2018). Aside from the external environment and context, memory recall also depends on the psychophysiological state, termed as state-dependent memory (SDM). SDM describes a phenomenon, if memory is formed when the subject is under the influence of certain mood, pain, emotion or centrally acting drug, it will be after that remembered most efficiently only when the same mental or drug condition is established again (Jiang et al., 2018). A large body of evidence has confirmed that morphine evokes SDM (Ghasemzadeh and Rezayof, 2018; Niknamfar et al., 2019; Ofogh et al., 2016). Pre-training administration of morphine induces memory impairment in animals when tested 24 h later (Niknamfar et al., 2019). Interestingly, repeated injection of the same amount of drug before the ⁎
test can restore the previously caused memory loss, triggering SDM. In recent years it has been reported that morphine can also overturn the amnestic effects of other drugs and vice versa inducing cross SDM (Ghasemzadeh and Rezayof, 2018; Michalak et al., 2018; Niknamfar et al., 2019). Previous studies have shown that memory deficit induced by pre-training and/or pre-test administrations of morphine are reversible by the μ-opioid receptor (MOR) antagonist naloxone, indicating the involvement of MORs in the phenomenon (Jafari-Sabet and Jannat-Dastjerdi, 2009; Niknamfar et al., 2019). These receptors are found almost exclusively on inhibitory interneurons in the hippocampal area CA1 (Drake and Milner, 2002), a structure that is important for the formation of long term memory (McQuiston, 2011). β-carboline norharmane is an endogenous constituent in the brain and other tissues in man and animals (Greiner and Rommelspacher, 1984; Wodarz et al., 1996). The elevated plasma levels of norharmane in chronic alcoholics (Rommelspacher et al., 1991) and heroin addicts (Stohler et al., 1993) demonstrate its contribution to drug dependence
Corresponding author at: Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, 13145-784, Tehran, Iran. E-mail address: [email protected] (M.-R. Zarrindast).
https://doi.org/10.1016/j.brainresbull.2019.08.003 Received 30 May 2019; Received in revised form 31 July 2019; Accepted 5 August 2019 Available online 07 August 2019 0361-9230/ © 2019 Published by Elsevier Inc.
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2.4. Step-down inhibitory avoidance test
processes. It has been reported that norharmane blocks the effect of morphine withdrawal. Anti-withdrawal effect of norharmane can be mediated via opioid receptors because it acts as a partial MOR agonist and competes with naloxone for binding to central opioid receptors (Cappendijk et al., 1994). There is another report that high-affinity binding of norharmane to imidazoline I2B receptors and monoamine oxidase A (MAO-A) blocks the behavioral and biochemical effects of opiate withdrawal (Miralles et al., 2005). Animal studies have shown that effect of norharmane on learning and memory is dose-dependent, so that low doses of the drug (1 and 2 mg/kg) improves learning and memory, while high doses of it (3 and 4 mg/kg) further worsen cognitive function in streptozotocin-induced rat model of Alzheimer’s disease (Esmaeili et al., 2017). Considering that norharmane plays a role in drug dependence and has psychogenic/hallucinatory properties (Cappendijk et al., 1994), one of the aims of the present study was to investigate the effects of norharmane on memory retrieval and state of memory. Further, we investigated the role of MORs in norharmane and morphine SDM via the administration of naloxone. Finally, we examined the possible interaction between norharmane and morphine in memory retrieval (cross SDM between norharmane and morphine) in a step-down inhibitory avoidance learning task in male adult mice.
The experiment was performed in step down inhibitory avoidance equipment with specifications, 30 cm × 30 cm × 40 cm. The grid floor of the equipment was lined with 0.3 cm steel bars spaced 1.0 cm. A wooden platform (4 cm × 4 cm × 4 cm) was fixed on the middle of the floor. The experiment was initiated by allowing the animals on the wooden platform. The animals received 1 Hz, 0.5 s and 45 VDC foot shock during the trial session after keeping the paws down to the grid. The memory preservation was measured without giving shock during the experimental sessions with a maximum observation time of 5 min. 24 h after the training session, the retention experiment was performed to evaluate long-term memory. 2.5. Experimental design Eight animals were used in each group. Microinjection of the drugs into the hippocampal CA1 region was performed 5 min before the training or/and the testing phase. Interval between drug microinjections was 5 min. Experiment 1. In this experiment, nine groups of animals were used to evaluate whether microinjection of morphine into the CA1 region of the hippocampus induces SDM. Four groups of animals received pretraining microinjection of the different doses of morphine (0, 0.1, 0.5 and 1 μg/mouse) and the other four groups received pre-testing microinjection of the same doses of morphine. The last group received pretraining and pre-test microinjections of morphine (1 μg/mouse). Experiment 2. In this experiment, nine groups of animals were used. Four groups received pre-training, intra-CA1 microinjection of various doses of norharmane (0, 1, 5 and 10 μg/mouse) and the other four groups received pre-test, intra-CA1 microinjection of the same doses of norharmane. The last group received pre-training and pre-test microinjections of norharmane (10 μg/mouse). Experiment 3. Influence of pre-test, intra-CA1 microinjection of naloxone on morphine or norharmane SDM in the step-down task was assessed. Eight groups of animals in this experiment including: saline/ saline, saline/naloxone (0.5 μg/mouse), morphine/saline, norharmane/ saline, morphine/naloxone, norharmane/naloxone, morphine/naloxone-morphine or norharmane/naloxone-norharmane groups. Experiment 4. To detect morphine-norharmane cross SDM, five groups of animals were submitted to the step-down task. The control group received pre-training and pre-test microinjections of saline (1 μl/ mouse). Two groups received pre-training microinjection of morphine (1 μg/mouse) or norharmane (10 μg/mouse), followed by pre-test microinjection of saline. One group received pre-training microinjection of morphine, followed by pre-test infusion of norharmane. The last group received pre-training microinjection of norharmane, followed by pre-test morphine.
2. Material and methods 2.1. Animals Male albino NMRI mice (25–30 g) were used. Mice were housed in polycarbonate cages with hardwood chip bedding and ad lib access to food and water. Housing rooms were maintained on a 12/12-h light/ dark cycle (7 am–7 pm) at 22 ± 2 °C and 45–55% humidity. Each animal was used once only. Eight animals were used in each group. Training and testing were done during the light phase of the cycle. All procedures were carried out by institutional guidelines for animal care and use.
2.2. Cannula guide implantation and drug microinjection Mice (n = 248) were anesthetized with a ketamine hydrochloride (50 mg/kg) plus xylazine (5 mg/kg) at a volume of 10 ml/kg. The mice were fixed in a stereotactic frame, and the skull was exposed. Guide cannulae (22-gauge) were bilaterally implanted into the dorsal hippocampus (2 mm posterior to Bregma, ± 1.6 mm lateral to the midline, and 1.5 mm beneath the surface of the skull). Dummy cannulae were inserted into the guide cannulae to prevent clogging and reduce the risk of infection. Mice were given at least five days to recover before behavioral training. For drug infusion, the dummy cannulae were removed, and injection needles (27-gauge) were inserted into the guide cannulae. The tips of the injection needle were 1 mm lower than those of the guide cannulae, i.e., at a location 2.5 mm ventral to the skull surface. Drug solutions were bilaterally infused into the CA1 region, at the rate of 0.5 μl/min. The injection needles were left in place for an additional 60 s after infusion. Experiments were carried out in a double-blind way.
2.6. Statistical analysis Given the wide variability in the data, the retention latencies were expressed as the median and interquartile range and analyzed using the Kruskal–Wallis non-parametric one-way analysis of variance, followed by a two-tailed Mann–Whitney’s U test and Holm’s Bonferroni correction for the paired comparisons. The confidence limit of P < 0.05 was considered statistically significant. Calculations were accomplished using the SPSS statistical package (SPSS Inc., Chicago, IL, USA).
2.3. Drugs Morphine sulfate (0.1, 0.5 and 1 μg/mouse; Temad, Tehran, Iran), norharmane HCl (1, 5 and 10 μg/mouse; Sigma-Aldrich, USA) and naloxone HCl (0.5 μg/mouse; Sigma-Aldrich, USA) were dissolved in sterile 0.9% saline just before the experiments. All drugs were microinjected into the hippocampal CA1 regions (intra-CA1) at a total volume of 1 μl (0.5 μl per each CA1 region). Control groups received saline.
3. Results 3.1. Microinjection of morphine into the hippocampal CA1 region induced SDM Fig. 1 shows the effect of pre-training or/and pre-test microinjection of various doses of morphine (0, 0.1, 0.5 and 1 μg/mouse, intra-CA1) on 25
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Fig. 1. Morphine-induced SDM in mice in the step-down task. Four animal groups were microinjected with different doses of morphine (0, 0.1, 0.5 and 1 μg/mouse) into the CA1 region, 5 min before the training. Other four groups received the same doses of morphine 5 min before the test. The last group was microinjected with morphine (1 μg/mouse) 5 min before the training and test. Data represent the means ± S.E.M. and are expressed as the latency index; n = 8; ***P < 0.001 and **P < 0.01 compared to its respective control group. +P < 0.05 compared to morphine (1 μg/mouse).
3.3. Pre-test microinjection of naloxone abolished memory impairment induced by pre-training microinjection of morphine or norharmane and impaired SDM-induced by each one
memory performance in the step-down task. Kruskal-Wallis test showed a statistically significant difference between groups treated with morphine [H (8) = 26.106; P = 0.001]. The post hoc Mann-Whitney test revealed that pre-training or pre-test injection of morphine (1 μg/ mouse) decreased step-down latency compared to the saline group, suggesting a memory retrieval impairment. Meanwhile, pre-test microinjection of morphine (1 μg/mouse) restored previously caused by morphine impairment of memory retrieval, indicating morphine-induced SDM.
Fig. 3 shows the effect of naloxone on memory impairment induced by morphine or norharmane and SDM-induced by each one. Statistical analysis revealed a significant effect of treatment [Kruskal-Wallis nonparametric ANOVA, H (7) = 32.983, P = 0.000]. Post hoc analysis revealed that the pre-test administration of naloxone significantly abrogated memory impairment induced by pre-training injection of morphine or norharmane into the hippocampal CA1 region (Fig. 3, middle panel). Interestingly, the analysis demonstrated that the pre-test administration of naloxone attenuated morphine- and norharmane-induced SDM (Fig. 3, right panel).
3.2. Microinjection of norharmane into the hippocampal CA1 region induced SDM Fig. 2 shows the effect of pre-training or/and pre-test microinjection of various doses of norharmane (0, 1, 5 and 10 μg/mouse, intra-CA1) on memory performance in the step-down task. Kruskal-Wallis test showed a statistically significant difference between groups treated with norharmane [H (8) = 23.806; P = 0.002]. The post hoc Mann-Whitney test revealed that pre-training or pre-test injection of norharmane at the dose of 10 or 5 and 10 μg/mouse impaired memory retrieval. Meanwhile, pre-test microinjection of norharmane (10 μg/mouse) restored memory impairment induced by the same dose of norharmane before the training, indicating norharmane-induced SDM.
3.4. Cross SDM between morphine and norharmane in the hippocampal CA1 region Fig. 4 indicates that pre-test, intra-CA1 microinjection of norharmane (10 μg/mouse) restored memory retrieval deficit induced by pretraining microinjection of morphine (1 μg/mouse). Also, pre-test, intraCA1 microinjection of morphine (1 μg/mouse) restored memory retrieval impairment induced by pre-training microinjection of norharmane (10 μg/mouse) [Kruskal-Wallis non-parametric ANOVA, H (4) = 15.612, P = 0.004], indicating cross SDM between morphine and norharmane.
Fig. 2. Norharmane-induced SDM in mice in the step-down task. Four animal groups were microinjected with different doses of norharmane (0, 1, 5 and 10 μg/mouse) into the CA1 region, 5 min before the training. Other four groups received the same doses of norharmane 5 min before the test. The last group was microinjected with norharmane (10 μg/mouse) 5 min before the training and test. Data represent the means ± S.E.M. and are expressed as the latency index; n = 8; **P < 0.01 compared to their respective control group. +P < 0.05 compared to norharmane (10 μg/mouse).
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Fig. 3. Effects of naloxone on memory retrieval deficit and SDM induced by morphine or norharmane. Pre-test intra-CA1 microinjection of a subthreshold dose of naloxone (0.5 μg/ mouse) abolished memory retrieval deficit induced by morphine (1 μg/mouse) or norharmane (10 μg/mouse) while impaired SDM induced by both of the drugs. Data represent the means ± S.E.M. and are expressed as the latency index; n = 8; **P < 0.01 compared to the saline group; + +P < 0.01 and + P < 0.05 compared to the morphine and norharmane in the left panel, respectively; #P < 0.05 compared to their respective groups in the middle panel.
4. Discussion
(Castellano, 1975) but facilitates memory when administered after the training/learning sessions (Staubli and Huston, 1980). Nevertheless, the mechanisms by which opioids affect hippocampus-dependent memory appear to be highly complex and poorly understood (Giannopoulos and Papatheodoropoulos, 2013). Many studies have reported the SDM in morphine-treated rodents (Michalak et al., 2018). It seems that this kind of learning and memory has been coherent with the reward effect of morphine (Zarrindast and Rezayof, 2004). It has been suggested that the different neurotransmitter systems in the different brain regions, particularly the dorsal hippocampus (Alijanpour et al., 2018), but also the amygdala (Ofogh et al., 2016), nucleus accumbens (Noorbakhshnia and Zarrinimehr, 2019) and ventral tegmental area (VTA) (Darbandi et al., 2008) modulate morphine SDM. It should be noted that these findings were obtained from systemic
We present the evidence for the involvement of μ-opioid receptors (MORs) in morphine and norharmane state-dependent memory (SDM) retrieval and cross SDM between morphine and norharmane in the hippocampal CA1 region. Our data indicate that pre-training or pre-test, intra-CA1 microinjection of morphine impaired passive avoidance memory retrieval in the step-down task. The presented results also indicate that pre-test administration of the same dose of morphine significantly improved morphine-induced memory impairment before the training phase, suggesting SDM. The diverse effects of morphine on memory formation can be attributed to the time when morphine is administered. For example, morphine impairs memory when present during encoding
Fig. 4. Cross SDM between morphine and norharmane. Three groups of animals received saline (1 μl/mouse), morphine (1 μg/mouse) and norharmane (10 μg/mouse) 5 min before to the training. One group of animals received pre-training microinjection of morphine (1 μg/mouse), and 24 h later received norharmane (10 μg/mouse) while the last group of animals was microinjected with norharmane before to the training and morphine before to the test. Data represent the means ± S.E.M. and are expressed as the latency index; n = 8; **P < 0.01 and *P < 0.05 compared to the control group; +P < 0.05 compared to the morphine group in the left panel; ##P < 0.01 compared to the norharmane group in the left panel.
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early pre-test injection of naloxone prevents morphine-produced SDM. It is well known that activation of MORs alters information coding, synaptic plasticity, and spatial memory in area CA1 of the hippocampus (Charron et al., 2008; Mansouri et al., 1999; McQuiston, 2007). Nonetheless, it is important to look for common mechanisms beyond the receptor level that could be produced by both morphine and norharmane and result in alike cellular and behavioral responses. In this context, MORs act by inhibiting GABA release onto GABA-A receptors in the CA1 regions. Furthermore, MOR activation can facilitate excitatory inputs in the CA1 dendritic layers by inhibiting synaptic activation of GABA-A receptors. In the CA1, MORs are largely concentrated in the pyramidal cell layer (Mansour et al., 1995) where they were located on the axons, terminals, dendrites, and somata of GABAergic inhibitory interneurons exclusively (Drake and Milner, 2002). In the case of norharmane, it acts as a partial MOR agonist (Airaksinen and Kari, 1981), and shows high-affinity to imidazoline I2B receptors and monoamine oxidase A (MAO-A). So, it can modulate biochemical mechanisms (Miralles et al., 2005). One intriguing results obtained in this study was that pre-test, intraCA1 microinjection of norharmane reversed the amnesia induced by pre-train injection of morphine. Also, pre-test microinjection of morphine restored the amnesia induced by pre-train injection of norharmane. These results are showing a cross SDM between morphine and norharmane. One might argue that MORs mediate the effect of morphine and norharmane on memory retention in the step-down task. Cappendijk and coworkers revealed that norharmane binds to MORs due to its properties as a partial MOR agonist (Cappendijk et al., 1994). Moreover, Miralles and his group (Miralles et al., 2005) reported that norharmane blocks some behavioral and biochemical effects induced by opiate withdrawal in morphine-dependent rats. In summary, we suggest that the MORs of the hippocampal CA1 region play an important role in SDM induced by morphine and norharmane. Also, it is proposed a cross SDM between morphine and norharmane.
morphine administration, while morphine was injected into the hippocampal CA1 regions in our study. It has been well-known that the hippocampus contains high levels of MORs (Drake and Milner, 2002). In hippocampus, activation of MORs has been demonstrated to enhance the neuronal excitability of pyramidal neurons, which has been mainly attributed to a disinhibition of pyramidal neurons via activating Gαi subunit to suppress the presynaptic release of GABA in hippocampal interneurons, because MOR is an inhibitory Gαi-protein-coupled receptor (Gi-GPCR) (Madison and Nicoll, 1988; McQuiston and Saggau, 2003; Nicoll et al., 1980; Zieglgansberger et al., 1979). Giannopoulos and Papatheodoropoulos proposed that activation of the MORs modulates the activity of sharp wave ripples, which are thought to participate in the process of memory consolidation. They also suggested that the different concentrations of MOR agonists exert a dynamic regulation on sharp wave ripples, presumably by finely tuning the balance between excitation and inhibition. This modulation may underlie the actions of MOR agonists on hippocampus-dependent memory (Giannopoulos and Papatheodoropoulos, 2013). To exclude the possibility that the observed SDM effects were compromised by the central analgesia effects of morphine, we examined this possibility using the hot plate test. Intra-hippocampal morphine (1 μg/mouse)-microinjected mice showed no significant difference in reaction latency in the hot plate compared to the saline group [t (14) = 1.665, P = 0.218]. In other words, morphine into the hippocampus had no antinociceptive activity. Therefore, it seems that the observed SDM effects were not influenced by the central analgesia effects of morphine. Our results demonstrate that pre-training or pre-test intra-CA1 microinjection of β-carboline norharmane disrupted passive avoidance memory retention. Also, pre-test microinjection of the higher dose of norharmane into the CA1 region reversed memory impairment induced by pre-training administration of the same dose of norharmane, indicating norharmane SDM. This study is the first demonstration that βcarboline norharmane induces SDM. β-carbolines demonstrate a broad spectrum of pharmacological properties due to a variety of actions on the central nervous system (Moura et al., 2006). In more recent years, a number of publications arose reporting the interaction of β-carbolines with different classes of receptors: 5-hydroxytryptamine (5-HT) (Glennon et al., 2000), dopamine (DA) (Pimpinella and Palmery, 1995), imidazoline (Squires et al., 2004), NMDA glutamate receptors (Du et al., 1997), benzodiazepine and opioid binding sites (Airaksinen and Mikkonen, 1980). We previously reported the role of dopamine (Nasehi et al., 2018) and histamine receptors in the hippocampal CA1 region in memory retention deficit induced by β-carbolines. Evidence suggests that the effect of β-carbolines on cognitive functions is dose-dependent so that they improve cognitive processes such as learning and memory at the low dose and impair these processes at the high dose. Esmaeili and his group presented that low dose of norharmane improves while its high dose impairs memory formation in a streptozotocin-induced rat model of sporadic Alzheimer’s disease (Esmaeili et al., 2017). Given the vast scope of the action of the β-carbolines, explaining the exact mechanism of their action in this study is difficult. The obtained data show that pre-test administration of an ineffective dose of naloxone abrogated amnesia induced by pre-training administration of morphine or norharmane. Also, naloxone impaired morphine- and norharmane-induced SDM. A similar effect of naloxone on norharmane response implicates that MORs mediate the effect of norharmane on memory retention in the step-down task. So, this result shows the involvement of MORs in the effects of morphine and norharmane on passive avoidance memory. In agree with our findings, previous studies have shown that memory impairment induced by pretraining and/or pre-test administrations of morphine are reversible by the MOR antagonist naloxone, indicating the involvement of MORs in the phenomenon (Jafari-Sabet and Jannat-Dastjerdi, 2009). The reversal of morphine-produced SDM through naloxone is in agreement with the researches by (Bruins Slot and Colpaert, 1999; Khavandgar et al., 2002) as well as (Mariani et al., 2011), who have reported that
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Ghasemzadeh, Z., Rezayof, A., 2018. Medial prefrontal cortical cannabinoid CB1 receptors mediate morphine-dextromethorphan cross state-dependent memory: the involvement of BDNF/cFOS signaling pathways. Neuroscience 393, 295–304. https://doi.org/10.1016/j.neuroscience.2018.10.012. Giannopoulos, P., Papatheodoropoulos, C., 2013. Effects of mu-opioid receptor modulation on the hippocampal network activity of sharp wave and ripples. Br. J. Pharmacol. 168, 1146–1164. https://doi.org/10.1111/j.1476-5381.2012.02240.x. Glennon, R.A., Dukat, M., Grella, B., Hong, S., Costantino, L., Teitler, M., Smith, C., Egan, C., Davis, K., Mattson, M.V., 2000. Binding of beta-carbolines and related agents at serotonin (5-HT(2) and 5-HT(1A)), dopamine (D(2)) and benzodiazepine receptors. Drug Alcohol Depend. 60, 121–132. Greiner, B., Rommelspacher, H., 1984. Two metabolic pathways of tetrahydronorharmane (tetrahydro-beta-carboline) in rats. Naunyn Schmiedebergs Arch. Pharmacol. 325, 349–355. Jafari-Sabet, M., Jannat-Dastjerdi, I., 2009. Muscimol state-dependent memory: involvement of dorsal hippocampal μ-opioid receptors. Behav. Brain Res. 202, 5–10. https://doi.org/10.1016/j.bbr.2009.03.010. Jiang, J., Wang, G.Y., Luo, W., Xie, H., Guan, J.S., 2018. Mammillary body regulates state-dependent fear by alternating cortical oscillations. Sci. Rep. 8, 1–12. https:// doi.org/10.1038/s41598-018-31622-z. Khavandgar, S., Homayoun, H., Torkaman-Boutorabi, A., Zarrindast, M.R., 2002. The effects of adenosine receptor agonists and antagonists on morphine state-dependent memory of passive avoidance. Neurobiol. Learn. Mem. 78, 390–405. Madison, D.V., Nicoll, R.A., 1988. Enkephalin hyperpolarizes interneurones in the rat hippocampus. J. Physiol. 398, 123–130. https://doi.org/10.1113/jphysiol.1988. sp017033. Mansour, A., Fox, C.A., Burke, S., Akil, H., Watson, S.J., 1995. Immunohistochemical localization of the cloned mu opioid receptor in the rat CNS. J. Chem. Neuroanat. 8, 283–305. Mansouri, F.A., Motamedi, F., Fathollahi, Y., 1999. Chronic in vivo morphine administration facilitates primed-bursts-induced long-term potentiation of Schaffer collateral-CA1 synapses in hippocampal slices in vitro. Brain Res. 815, 419–423. Mariani, R.K., Mello, C.F., Rosa, M.M., Ceretta, A.P.C., Camera, K., Rubin, M.A., 2011. Effect of naloxone and morphine on arcaine-induced state-dependent memory in rats. Psychopharmacology (Berl.) 215, 483–491. https://doi.org/10.1007/s00213-0112215-6. McQuiston, A.R., 2011. Mu opioid receptor activation normalizes temporo-ammonic pathway driven inhibition in hippocampal CA1. Neuropharmacology 60, 472–479. https://doi.org/10.1016/j.neuropharm.2010.10.029. McQuiston, A.R., 2007. Effects of mu-opioid receptor modulation on GABAB receptor synaptic function in hippocampal CA1. J. Neurophysiol. 97, 2301–2311. https://doi. org/10.1152/jn.01179.2006. McQuiston, A.R., Saggau, P., 2003. Mu-opioid receptors facilitate the propagation of excitatory activity in rat hippocampal area CA1 by disinhibition of all anatomical layers. J. Neurophysiol. 90, 1936–1948. https://doi.org/10.1152/jn.01150.2002. Michalak, A., Pekala, K., Budzynska, B., Kruk-Slomka, M., Biala, G., 2018. The role of verapamil and SL-327 in morphine- and ethanol-induced state-dependent and cross state-dependent memory. Eur. J. Pharmacol. 834, 318–326. https://doi.org/10.
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Brain Research Bulletin journal homepage: www.elsevier.com/locate/brainresbull
Cross state-dependent memory retrieval between morphine and norharmane in the mouse dorsal hippocampus Mohaddeseh Ebrahimi-Ghiria, Fatemeh Khakpaib, Mohammad-Reza Zarrindastc,d,e,f,
T
⁎
a
Department of Biology, Faculty of Sciences, University of Zanjan, Zanjan, Iran Cognitive and Neuroscience Research Center (CNRC), Tehran Medical Sciences, Islamic Azad University, Tehran, Iran c Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran d Iranian National Center for Addiction Studies, Tehran University of Medical Sciences, Tehran, Iran e Institute for Cognitive Science Studies (ICSS), Tehran, Iran f Department of Neuroendocrinology, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran b
A R T I C LE I N FO
A B S T R A C T
Keywords: Morphine Norharmane State-dependent memory (SDM) Passive avoidance memory Mice
State-dependent memory (SDM) describes a phenomenon that memory is efficiently restored only when the brain state during restoration matches the state during encoding. Some psychoactive drugs such as morphine, ethanol, and cocaine evoke SDM. The scope of this study was to investigate the cross SDM between morphine and norharmane injected into the dorsal hippocampus of male NMRI mice, and the involvement of μ-opioid receptors (MORs) in the SDM of the drugs. Bilateral cannulae were implanted into the CA1 regions (intra-CA1), and memory retrieval was measured by the step-down apparatus. Results showed that pre-test microinjection of morphine (1 μg/mouse, intra-CA1) reversed amnesia induced by pre-training administration of the same dose of morphine, indicating morphine SDM. Moreover, norharmane (10 μg/mouse) also exerted a SDM. Pre-test microinjection of naloxone (0.5 μg/mouse) abolished amnesia induced by morphine or norharmane, and impaired SDM produced by each drug. The results demonstrated the contribution of MORs in the SDM induced by morphine as well as norharmane. Pre-test administration of morphine (1 μg/mouse, intra-CA1) also inhibited amnesia induced by pre-training intra-CA1 microinjection of norharmane (10 μg/mouse) and vice versa, suggesting a cross SDM between the drugs. In conclusion, it seems that there may be a cross SDM between morphine and norharmane, and MORs have a critical role in this phenomenon.
1. Introduction The memory of previous experiences and information helps us escape the danger and enables us to make a better choice in the future (Jiang et al., 2018). However, all remembered information is not equally well retrieved (Michalak et al., 2018). Aside from the external environment and context, memory recall also depends on the psychophysiological state, termed as state-dependent memory (SDM). SDM describes a phenomenon, if memory is formed when the subject is under the influence of certain mood, pain, emotion or centrally acting drug, it will be after that remembered most efficiently only when the same mental or drug condition is established again (Jiang et al., 2018). A large body of evidence has confirmed that morphine evokes SDM (Ghasemzadeh and Rezayof, 2018; Niknamfar et al., 2019; Ofogh et al., 2016). Pre-training administration of morphine induces memory impairment in animals when tested 24 h later (Niknamfar et al., 2019). Interestingly, repeated injection of the same amount of drug before the ⁎
test can restore the previously caused memory loss, triggering SDM. In recent years it has been reported that morphine can also overturn the amnestic effects of other drugs and vice versa inducing cross SDM (Ghasemzadeh and Rezayof, 2018; Michalak et al., 2018; Niknamfar et al., 2019). Previous studies have shown that memory deficit induced by pre-training and/or pre-test administrations of morphine are reversible by the μ-opioid receptor (MOR) antagonist naloxone, indicating the involvement of MORs in the phenomenon (Jafari-Sabet and Jannat-Dastjerdi, 2009; Niknamfar et al., 2019). These receptors are found almost exclusively on inhibitory interneurons in the hippocampal area CA1 (Drake and Milner, 2002), a structure that is important for the formation of long term memory (McQuiston, 2011). β-carboline norharmane is an endogenous constituent in the brain and other tissues in man and animals (Greiner and Rommelspacher, 1984; Wodarz et al., 1996). The elevated plasma levels of norharmane in chronic alcoholics (Rommelspacher et al., 1991) and heroin addicts (Stohler et al., 1993) demonstrate its contribution to drug dependence
Corresponding author at: Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, 13145-784, Tehran, Iran. E-mail address: [email protected] (M.-R. Zarrindast).
https://doi.org/10.1016/j.brainresbull.2019.08.003 Received 30 May 2019; Received in revised form 31 July 2019; Accepted 5 August 2019 Available online 07 August 2019 0361-9230/ © 2019 Published by Elsevier Inc.
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2.4. Step-down inhibitory avoidance test
processes. It has been reported that norharmane blocks the effect of morphine withdrawal. Anti-withdrawal effect of norharmane can be mediated via opioid receptors because it acts as a partial MOR agonist and competes with naloxone for binding to central opioid receptors (Cappendijk et al., 1994). There is another report that high-affinity binding of norharmane to imidazoline I2B receptors and monoamine oxidase A (MAO-A) blocks the behavioral and biochemical effects of opiate withdrawal (Miralles et al., 2005). Animal studies have shown that effect of norharmane on learning and memory is dose-dependent, so that low doses of the drug (1 and 2 mg/kg) improves learning and memory, while high doses of it (3 and 4 mg/kg) further worsen cognitive function in streptozotocin-induced rat model of Alzheimer’s disease (Esmaeili et al., 2017). Considering that norharmane plays a role in drug dependence and has psychogenic/hallucinatory properties (Cappendijk et al., 1994), one of the aims of the present study was to investigate the effects of norharmane on memory retrieval and state of memory. Further, we investigated the role of MORs in norharmane and morphine SDM via the administration of naloxone. Finally, we examined the possible interaction between norharmane and morphine in memory retrieval (cross SDM between norharmane and morphine) in a step-down inhibitory avoidance learning task in male adult mice.
The experiment was performed in step down inhibitory avoidance equipment with specifications, 30 cm × 30 cm × 40 cm. The grid floor of the equipment was lined with 0.3 cm steel bars spaced 1.0 cm. A wooden platform (4 cm × 4 cm × 4 cm) was fixed on the middle of the floor. The experiment was initiated by allowing the animals on the wooden platform. The animals received 1 Hz, 0.5 s and 45 VDC foot shock during the trial session after keeping the paws down to the grid. The memory preservation was measured without giving shock during the experimental sessions with a maximum observation time of 5 min. 24 h after the training session, the retention experiment was performed to evaluate long-term memory. 2.5. Experimental design Eight animals were used in each group. Microinjection of the drugs into the hippocampal CA1 region was performed 5 min before the training or/and the testing phase. Interval between drug microinjections was 5 min. Experiment 1. In this experiment, nine groups of animals were used to evaluate whether microinjection of morphine into the CA1 region of the hippocampus induces SDM. Four groups of animals received pretraining microinjection of the different doses of morphine (0, 0.1, 0.5 and 1 μg/mouse) and the other four groups received pre-testing microinjection of the same doses of morphine. The last group received pretraining and pre-test microinjections of morphine (1 μg/mouse). Experiment 2. In this experiment, nine groups of animals were used. Four groups received pre-training, intra-CA1 microinjection of various doses of norharmane (0, 1, 5 and 10 μg/mouse) and the other four groups received pre-test, intra-CA1 microinjection of the same doses of norharmane. The last group received pre-training and pre-test microinjections of norharmane (10 μg/mouse). Experiment 3. Influence of pre-test, intra-CA1 microinjection of naloxone on morphine or norharmane SDM in the step-down task was assessed. Eight groups of animals in this experiment including: saline/ saline, saline/naloxone (0.5 μg/mouse), morphine/saline, norharmane/ saline, morphine/naloxone, norharmane/naloxone, morphine/naloxone-morphine or norharmane/naloxone-norharmane groups. Experiment 4. To detect morphine-norharmane cross SDM, five groups of animals were submitted to the step-down task. The control group received pre-training and pre-test microinjections of saline (1 μl/ mouse). Two groups received pre-training microinjection of morphine (1 μg/mouse) or norharmane (10 μg/mouse), followed by pre-test microinjection of saline. One group received pre-training microinjection of morphine, followed by pre-test infusion of norharmane. The last group received pre-training microinjection of norharmane, followed by pre-test morphine.
2. Material and methods 2.1. Animals Male albino NMRI mice (25–30 g) were used. Mice were housed in polycarbonate cages with hardwood chip bedding and ad lib access to food and water. Housing rooms were maintained on a 12/12-h light/ dark cycle (7 am–7 pm) at 22 ± 2 °C and 45–55% humidity. Each animal was used once only. Eight animals were used in each group. Training and testing were done during the light phase of the cycle. All procedures were carried out by institutional guidelines for animal care and use.
2.2. Cannula guide implantation and drug microinjection Mice (n = 248) were anesthetized with a ketamine hydrochloride (50 mg/kg) plus xylazine (5 mg/kg) at a volume of 10 ml/kg. The mice were fixed in a stereotactic frame, and the skull was exposed. Guide cannulae (22-gauge) were bilaterally implanted into the dorsal hippocampus (2 mm posterior to Bregma, ± 1.6 mm lateral to the midline, and 1.5 mm beneath the surface of the skull). Dummy cannulae were inserted into the guide cannulae to prevent clogging and reduce the risk of infection. Mice were given at least five days to recover before behavioral training. For drug infusion, the dummy cannulae were removed, and injection needles (27-gauge) were inserted into the guide cannulae. The tips of the injection needle were 1 mm lower than those of the guide cannulae, i.e., at a location 2.5 mm ventral to the skull surface. Drug solutions were bilaterally infused into the CA1 region, at the rate of 0.5 μl/min. The injection needles were left in place for an additional 60 s after infusion. Experiments were carried out in a double-blind way.
2.6. Statistical analysis Given the wide variability in the data, the retention latencies were expressed as the median and interquartile range and analyzed using the Kruskal–Wallis non-parametric one-way analysis of variance, followed by a two-tailed Mann–Whitney’s U test and Holm’s Bonferroni correction for the paired comparisons. The confidence limit of P < 0.05 was considered statistically significant. Calculations were accomplished using the SPSS statistical package (SPSS Inc., Chicago, IL, USA).
2.3. Drugs Morphine sulfate (0.1, 0.5 and 1 μg/mouse; Temad, Tehran, Iran), norharmane HCl (1, 5 and 10 μg/mouse; Sigma-Aldrich, USA) and naloxone HCl (0.5 μg/mouse; Sigma-Aldrich, USA) were dissolved in sterile 0.9% saline just before the experiments. All drugs were microinjected into the hippocampal CA1 regions (intra-CA1) at a total volume of 1 μl (0.5 μl per each CA1 region). Control groups received saline.
3. Results 3.1. Microinjection of morphine into the hippocampal CA1 region induced SDM Fig. 1 shows the effect of pre-training or/and pre-test microinjection of various doses of morphine (0, 0.1, 0.5 and 1 μg/mouse, intra-CA1) on 25
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Fig. 1. Morphine-induced SDM in mice in the step-down task. Four animal groups were microinjected with different doses of morphine (0, 0.1, 0.5 and 1 μg/mouse) into the CA1 region, 5 min before the training. Other four groups received the same doses of morphine 5 min before the test. The last group was microinjected with morphine (1 μg/mouse) 5 min before the training and test. Data represent the means ± S.E.M. and are expressed as the latency index; n = 8; ***P < 0.001 and **P < 0.01 compared to its respective control group. +P < 0.05 compared to morphine (1 μg/mouse).
3.3. Pre-test microinjection of naloxone abolished memory impairment induced by pre-training microinjection of morphine or norharmane and impaired SDM-induced by each one
memory performance in the step-down task. Kruskal-Wallis test showed a statistically significant difference between groups treated with morphine [H (8) = 26.106; P = 0.001]. The post hoc Mann-Whitney test revealed that pre-training or pre-test injection of morphine (1 μg/ mouse) decreased step-down latency compared to the saline group, suggesting a memory retrieval impairment. Meanwhile, pre-test microinjection of morphine (1 μg/mouse) restored previously caused by morphine impairment of memory retrieval, indicating morphine-induced SDM.
Fig. 3 shows the effect of naloxone on memory impairment induced by morphine or norharmane and SDM-induced by each one. Statistical analysis revealed a significant effect of treatment [Kruskal-Wallis nonparametric ANOVA, H (7) = 32.983, P = 0.000]. Post hoc analysis revealed that the pre-test administration of naloxone significantly abrogated memory impairment induced by pre-training injection of morphine or norharmane into the hippocampal CA1 region (Fig. 3, middle panel). Interestingly, the analysis demonstrated that the pre-test administration of naloxone attenuated morphine- and norharmane-induced SDM (Fig. 3, right panel).
3.2. Microinjection of norharmane into the hippocampal CA1 region induced SDM Fig. 2 shows the effect of pre-training or/and pre-test microinjection of various doses of norharmane (0, 1, 5 and 10 μg/mouse, intra-CA1) on memory performance in the step-down task. Kruskal-Wallis test showed a statistically significant difference between groups treated with norharmane [H (8) = 23.806; P = 0.002]. The post hoc Mann-Whitney test revealed that pre-training or pre-test injection of norharmane at the dose of 10 or 5 and 10 μg/mouse impaired memory retrieval. Meanwhile, pre-test microinjection of norharmane (10 μg/mouse) restored memory impairment induced by the same dose of norharmane before the training, indicating norharmane-induced SDM.
3.4. Cross SDM between morphine and norharmane in the hippocampal CA1 region Fig. 4 indicates that pre-test, intra-CA1 microinjection of norharmane (10 μg/mouse) restored memory retrieval deficit induced by pretraining microinjection of morphine (1 μg/mouse). Also, pre-test, intraCA1 microinjection of morphine (1 μg/mouse) restored memory retrieval impairment induced by pre-training microinjection of norharmane (10 μg/mouse) [Kruskal-Wallis non-parametric ANOVA, H (4) = 15.612, P = 0.004], indicating cross SDM between morphine and norharmane.
Fig. 2. Norharmane-induced SDM in mice in the step-down task. Four animal groups were microinjected with different doses of norharmane (0, 1, 5 and 10 μg/mouse) into the CA1 region, 5 min before the training. Other four groups received the same doses of norharmane 5 min before the test. The last group was microinjected with norharmane (10 μg/mouse) 5 min before the training and test. Data represent the means ± S.E.M. and are expressed as the latency index; n = 8; **P < 0.01 compared to their respective control group. +P < 0.05 compared to norharmane (10 μg/mouse).
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Fig. 3. Effects of naloxone on memory retrieval deficit and SDM induced by morphine or norharmane. Pre-test intra-CA1 microinjection of a subthreshold dose of naloxone (0.5 μg/ mouse) abolished memory retrieval deficit induced by morphine (1 μg/mouse) or norharmane (10 μg/mouse) while impaired SDM induced by both of the drugs. Data represent the means ± S.E.M. and are expressed as the latency index; n = 8; **P < 0.01 compared to the saline group; + +P < 0.01 and + P < 0.05 compared to the morphine and norharmane in the left panel, respectively; #P < 0.05 compared to their respective groups in the middle panel.
4. Discussion
(Castellano, 1975) but facilitates memory when administered after the training/learning sessions (Staubli and Huston, 1980). Nevertheless, the mechanisms by which opioids affect hippocampus-dependent memory appear to be highly complex and poorly understood (Giannopoulos and Papatheodoropoulos, 2013). Many studies have reported the SDM in morphine-treated rodents (Michalak et al., 2018). It seems that this kind of learning and memory has been coherent with the reward effect of morphine (Zarrindast and Rezayof, 2004). It has been suggested that the different neurotransmitter systems in the different brain regions, particularly the dorsal hippocampus (Alijanpour et al., 2018), but also the amygdala (Ofogh et al., 2016), nucleus accumbens (Noorbakhshnia and Zarrinimehr, 2019) and ventral tegmental area (VTA) (Darbandi et al., 2008) modulate morphine SDM. It should be noted that these findings were obtained from systemic
We present the evidence for the involvement of μ-opioid receptors (MORs) in morphine and norharmane state-dependent memory (SDM) retrieval and cross SDM between morphine and norharmane in the hippocampal CA1 region. Our data indicate that pre-training or pre-test, intra-CA1 microinjection of morphine impaired passive avoidance memory retrieval in the step-down task. The presented results also indicate that pre-test administration of the same dose of morphine significantly improved morphine-induced memory impairment before the training phase, suggesting SDM. The diverse effects of morphine on memory formation can be attributed to the time when morphine is administered. For example, morphine impairs memory when present during encoding
Fig. 4. Cross SDM between morphine and norharmane. Three groups of animals received saline (1 μl/mouse), morphine (1 μg/mouse) and norharmane (10 μg/mouse) 5 min before to the training. One group of animals received pre-training microinjection of morphine (1 μg/mouse), and 24 h later received norharmane (10 μg/mouse) while the last group of animals was microinjected with norharmane before to the training and morphine before to the test. Data represent the means ± S.E.M. and are expressed as the latency index; n = 8; **P < 0.01 and *P < 0.05 compared to the control group; +P < 0.05 compared to the morphine group in the left panel; ##P < 0.01 compared to the norharmane group in the left panel.
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early pre-test injection of naloxone prevents morphine-produced SDM. It is well known that activation of MORs alters information coding, synaptic plasticity, and spatial memory in area CA1 of the hippocampus (Charron et al., 2008; Mansouri et al., 1999; McQuiston, 2007). Nonetheless, it is important to look for common mechanisms beyond the receptor level that could be produced by both morphine and norharmane and result in alike cellular and behavioral responses. In this context, MORs act by inhibiting GABA release onto GABA-A receptors in the CA1 regions. Furthermore, MOR activation can facilitate excitatory inputs in the CA1 dendritic layers by inhibiting synaptic activation of GABA-A receptors. In the CA1, MORs are largely concentrated in the pyramidal cell layer (Mansour et al., 1995) where they were located on the axons, terminals, dendrites, and somata of GABAergic inhibitory interneurons exclusively (Drake and Milner, 2002). In the case of norharmane, it acts as a partial MOR agonist (Airaksinen and Kari, 1981), and shows high-affinity to imidazoline I2B receptors and monoamine oxidase A (MAO-A). So, it can modulate biochemical mechanisms (Miralles et al., 2005). One intriguing results obtained in this study was that pre-test, intraCA1 microinjection of norharmane reversed the amnesia induced by pre-train injection of morphine. Also, pre-test microinjection of morphine restored the amnesia induced by pre-train injection of norharmane. These results are showing a cross SDM between morphine and norharmane. One might argue that MORs mediate the effect of morphine and norharmane on memory retention in the step-down task. Cappendijk and coworkers revealed that norharmane binds to MORs due to its properties as a partial MOR agonist (Cappendijk et al., 1994). Moreover, Miralles and his group (Miralles et al., 2005) reported that norharmane blocks some behavioral and biochemical effects induced by opiate withdrawal in morphine-dependent rats. In summary, we suggest that the MORs of the hippocampal CA1 region play an important role in SDM induced by morphine and norharmane. Also, it is proposed a cross SDM between morphine and norharmane.
morphine administration, while morphine was injected into the hippocampal CA1 regions in our study. It has been well-known that the hippocampus contains high levels of MORs (Drake and Milner, 2002). In hippocampus, activation of MORs has been demonstrated to enhance the neuronal excitability of pyramidal neurons, which has been mainly attributed to a disinhibition of pyramidal neurons via activating Gαi subunit to suppress the presynaptic release of GABA in hippocampal interneurons, because MOR is an inhibitory Gαi-protein-coupled receptor (Gi-GPCR) (Madison and Nicoll, 1988; McQuiston and Saggau, 2003; Nicoll et al., 1980; Zieglgansberger et al., 1979). Giannopoulos and Papatheodoropoulos proposed that activation of the MORs modulates the activity of sharp wave ripples, which are thought to participate in the process of memory consolidation. They also suggested that the different concentrations of MOR agonists exert a dynamic regulation on sharp wave ripples, presumably by finely tuning the balance between excitation and inhibition. This modulation may underlie the actions of MOR agonists on hippocampus-dependent memory (Giannopoulos and Papatheodoropoulos, 2013). To exclude the possibility that the observed SDM effects were compromised by the central analgesia effects of morphine, we examined this possibility using the hot plate test. Intra-hippocampal morphine (1 μg/mouse)-microinjected mice showed no significant difference in reaction latency in the hot plate compared to the saline group [t (14) = 1.665, P = 0.218]. In other words, morphine into the hippocampus had no antinociceptive activity. Therefore, it seems that the observed SDM effects were not influenced by the central analgesia effects of morphine. Our results demonstrate that pre-training or pre-test intra-CA1 microinjection of β-carboline norharmane disrupted passive avoidance memory retention. Also, pre-test microinjection of the higher dose of norharmane into the CA1 region reversed memory impairment induced by pre-training administration of the same dose of norharmane, indicating norharmane SDM. This study is the first demonstration that βcarboline norharmane induces SDM. β-carbolines demonstrate a broad spectrum of pharmacological properties due to a variety of actions on the central nervous system (Moura et al., 2006). In more recent years, a number of publications arose reporting the interaction of β-carbolines with different classes of receptors: 5-hydroxytryptamine (5-HT) (Glennon et al., 2000), dopamine (DA) (Pimpinella and Palmery, 1995), imidazoline (Squires et al., 2004), NMDA glutamate receptors (Du et al., 1997), benzodiazepine and opioid binding sites (Airaksinen and Mikkonen, 1980). We previously reported the role of dopamine (Nasehi et al., 2018) and histamine receptors in the hippocampal CA1 region in memory retention deficit induced by β-carbolines. Evidence suggests that the effect of β-carbolines on cognitive functions is dose-dependent so that they improve cognitive processes such as learning and memory at the low dose and impair these processes at the high dose. Esmaeili and his group presented that low dose of norharmane improves while its high dose impairs memory formation in a streptozotocin-induced rat model of sporadic Alzheimer’s disease (Esmaeili et al., 2017). Given the vast scope of the action of the β-carbolines, explaining the exact mechanism of their action in this study is difficult. The obtained data show that pre-test administration of an ineffective dose of naloxone abrogated amnesia induced by pre-training administration of morphine or norharmane. Also, naloxone impaired morphine- and norharmane-induced SDM. A similar effect of naloxone on norharmane response implicates that MORs mediate the effect of norharmane on memory retention in the step-down task. So, this result shows the involvement of MORs in the effects of morphine and norharmane on passive avoidance memory. In agree with our findings, previous studies have shown that memory impairment induced by pretraining and/or pre-test administrations of morphine are reversible by the MOR antagonist naloxone, indicating the involvement of MORs in the phenomenon (Jafari-Sabet and Jannat-Dastjerdi, 2009). The reversal of morphine-produced SDM through naloxone is in agreement with the researches by (Bruins Slot and Colpaert, 1999; Khavandgar et al., 2002) as well as (Mariani et al., 2011), who have reported that
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