The effect of CA1 dopaminergic system in harmaline-induced amnesia

Neuroscience 285 (2015) 47–59

THE EFFECT OF CA1 DOPAMINERGIC SYSTEM IN HARMALINE-INDUCED AMNESIA M. NASEHI, a,c* M. KETABCHI, b F. KHAKPAI c AND M.-R. ZARRINDAST a,c,d,e,f*

line-induced impairment of memory acquisition. Ó 2014 Published by Elsevier Ltd. on behalf of IBRO.

a

School of Advanced Sciences in Medicine, Islamic Azad University, Tehran Medical Sciences Branch, Tehran, Iran

Key words: harmaline, dopamine, step-down, CA1, passive avoidance memory.

b Department of Biology, Faculty of Basic Sciences, Northern Branch, Islamic Azad University, Tehran, Iran c

Institute for Cognitive Science Studies (ICSS), Tehran, Iran

d

INTRODUCTION

Department of Pharmacology School of Medicine, Tehran University of Medical Sciences, Tehran, Iran

b-Carboline alkaloids can be divided into three structural groups, depending upon their degree of ring saturation (Moura et al., 2006; Nasehi et al., 2012): (a) the fully aromatic harmane derivatives, i.e. those with a fully unsaturated pyridine ring; (b) the dihydro or harmalane derivatives; and (c) the tetrahydro derivatives (RuizDurantez et al., 2001; Anderson et al., 2006; Moura et al., 2006). Harmaline (7 methoxy 3,4-dihydro-b-carboline), an alkaloid derived from the seeds of the plant Peganum harmala (Frostholm et al., 2000; Jimenez et al., 2008; Rook et al., 2010), is a monoamine oxidase inhibitor (Frostholm et al., 2000; Bonnet et al., 2008; Jimenez et al., 2008; Nenaah, 2010; Nasehi et al., 2012), and an indolaminergic compound (Frostholm et al., 2000). In the human body, the b-carbolines may be formed from the biogenic amines tryptamine and 5HT through condensation with aldehydes or a-keto acids (Talhout et al., 2007; Rook et al., 2010). Several investigations indicate a wide spectrum of therapeutic activities for the b-carbolines such as antinociceptive effect (Nenaah, 2010), neuroregulatory effect (Munoz et al., 2000; Splettstoesser et al., 2005; Moura et al., 2006), antibiotic properties (Martin et al., 1997; Hamsa and Kuttan, 2010; Yang et al., 2011), antidepressant-like effect (Herraiz and Chaparro, 2005), learning processes (Venault and Chapouthier, 2007), and excitation (Rommelspacher et al., 1980). The b-carboline alkaloids may act in biological tissues, such as the heart, kidney, liver and brain tissue (Ruiz-Durantez et al., 2001; Splettstoesser et al., 2005; Moura et al., 2006; Rook et al., 2010; Nasehi et al., 2012). The b-carbolines have a mixed pharmacology and individual compounds have been shown to bind to a variety of different targets including monoamine oxidase-A (MAO-A) or B (MAO-B), benzodiazepine, dopamine and 5-HT receptors (Herraiz and Chaparro, 2005; Moura et al., 2006; Talhout et al., 2007; Nasehi et al., 2010). These alkaloids increase the extracellular dopamine, norepinephrine and 5-HT levels in several brain areas by inhibition of monoamine reuptake systems (Venault and Chapouthier, 2007; Nasehi et al., 2010, 2012).

e Iranian National Center for Addiction Studies, Tehran University of Medical Sciences, Tehran, Iran f

School of Cognitive Sciences, Institute for Research in Fundamental Sciences (IPM), Tehran, Iran

Abstract—In the present study, the effects of bilateral injections of dopaminergic drugs into the hippocampal CA1 regions (intra-CA1) on harmaline-induced amnesia were examined in male mice. A one-trial step-down passive avoidance task was used for the assessment of memory retention in adult male mice. Pre-training intra-peritoneal (i.p.) administration of harmaline (1 mg/kg) induced impairment of memory retention. Moreover, intra-CA1 administration of dopamine D1 receptor antagonist, SCH23390 (0.02 lg/mouse), dopamine D1 receptor agonist, SKF38393 (0.5 lg/mouse), dopamine D2 receptor antagonist, sulpiride (1 lg/mouse) and dopamine D2 receptor agonist, quinpirole (0.25 and 0.5 lg/mouse) suppressed the learning of a singletrial passive avoidance task. Also, pre-training intra-CA1 injection of subthreshold doses of SCH23390 (0.001 lg/ mouse) or sulpiride (0.25 lg/mouse) with the administration of harmaline (1 mg/kg, i.p.) reversed impairment of memory formation. However, pre-training intra-CA1 injection of SKF38393 (0.1 lg/mouse) or quinpirole (0.1 lg/mouse) increased pre-training harmaline (0.25 and 0.5 mg/kg, i.p.)induced retrieval impairment. Moreover, SKF Ca blocker (SKF) (0.01 lg/mouse) decrease the amnesia induced by harmaline (1 mg/kg), while co-administration of SKF (0.01 lg/mouse)/sulpiride (0.25 lg/mouse) or SCH23390 (0.25 lg/mouse) potentiate (0.001 lg/mouse)/sulpiride amnesia caused by harmaline. These findings implicate the involvement of CA1 dopaminergic mechanism in harma-

*Corresponding authors. Address: Department of Pharmacology School of Medicine, Tehran University of Medical Sciences, P.O. Box 13145-784, Tehran, Iran. Tel/fax: +98-21-66402569. E-mail addresses: [email protected] (M. Nasehi), [email protected]. ir (M.-R. Zarrindast). Abbreviations: ANOVA, analysis of variance; LTP, long-term potentiation; MAO-A, monoamine oxidase-A; MAO-B, monoamine oxidase-B. http://dx.doi.org/10.1016/j.neuroscience.2014.11.012 0306-4522/Ó 2014 Published by Elsevier Ltd. on behalf of IBRO. 47

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The hippocampus as a part of limbic system is a model for the physiological analysis of neural systems. The hippocampus involved in memory processes (Riedel and Micheau, 2001; Hartman et al., 2005; Khakpai et al., 2012). The hippocampus receives dopaminergic input from mesolimbic structures (Swanson-Park et al., 1999; Thierry et al., 2000), such as the ventral teg mental area (Thierry et al., 2000; Zarrindast et al., 2010). Dopaminergic receptor activation is critical for memory processes in the CA1 areas of the dorsal hippocampus (Otmakhova and Lisman, 1996; Izquierdo et al., 1998; Khakpai et al., 2013). Five different dopamine receptors have been identified, which are G proteincoupled and are categorized as belonging to one of the two classes designated as D1-like (D1 and D5) or D2-like (D2, D3, and D4) receptors (Vallone et al., 2000; Rezayof et al., 2007). These two receptors exert their biological actions through coupling to and activating diverse G-protein complexes. The D1 receptor interacts with the Gs complex to activate adenyl cyclase, but the D2 interacts with Gi to inhibit cyclic adenosine monophosphate production (Bressan and Crippa, 2005; Ferreira et al., 2011). Some evidence reported that harmaline could influence dopaminergic transmission (Kim et al., 1970; Palmery et al., 1992), which may be done by inhibition of MAO-A or MAO-B (Herraiz and Chaparro, 2005; Touiki et al., 2005; Talhout et al., 2007; Yang et al., 2011). Since harmaline and dopamine receptors have interaction (Kim et al., 1970; Palmery et al., 1992), and considering the role of dopamine receptors (Kandel and Weeks, 1995; Wise, 2004; de Lima et al., 2011), harmaline (Meignin et al., 1999), and hippocampus (Whishaw, 1998; Burgess et al., 2002; Harvey, 2003; Faerber et al., 2007) in memory process, we attempt to determine the role of harmaline and dopamine receptors in memory acquisition and locomotor activity in the step-down passive avoidance and open field test.

apparatus (Stoelting Co, IL, USA). Then, the skin was slit and skull was cleaned. Following, 22-gauge guide cannulae (0.7 mm diameter) were placed (bilaterally) 1 mm above the intended site of injection according to the atlas of Paxinos and Franklin (2001). Stereotaxic coordinates for the CA1 areas were: AP: 2 mm from bregma, L: ±1.6 from the sagittal suture and V: 1.5 mm from the skull surface. Cannulae were protected with dental acrylic. Stainless steel stylets (27-gauge) were inserted into the guide cannulae to preserve them free of debris. All animals were allowed 5–7 days to recover from the surgery and get cleared from effects of the anesthetic agents. Memory testing and apparatus The inhibitory avoidance apparatus comprised of a wooden box (30  30  40 cm3) with a floor which consisted of parallel caliber stainless steel bars (0.3 cm in diameter, spaced 1 cm apart). A wooden platform (4  4  4 cm3) was positioned in the center of the grid floor. Electric shocks (1 Hz, 0.5 s and 50VDC) were delivered to the grid floor by an isolated stimulator (Borj Sanat Co, Tehran, Iran). For testing, animals were trained on a one-trial stepdown passive avoidance task. In the training session, each mouse was gently placed on the wooden platform. Once the animal stepped down from the platform and put all four paws on the grid floor, intermittent electric shocks were delivered continuously for 15 s. The training procedure was carried out between 8:00 a.m. and 12:00 p.m. Retention test session was carried out 24 h after training and was procedurally similar to training, except that no shock was existed. Step-down latency was recorded as memory retention. An upper cut-off time of 300 s was set. The retention test was also carried out among 8:00 a.m. and 12 p.m. Measurement of locomotor activity

EXPERIMENTAL PROCEDURES Animals Subjects were male NMRI mice weighing 25–30 g obtained from the Institute of Cognitive Science (Tehran, Iran). The animals were housed ten per cage, in a room under a 12-h light:12-h dark cycle (lights on 07:00 h) and controlled temperature (23 ± 1 °C) with free access to food and water except during the limited times of experiments. Mice were handled about 3 min each day prior to behavioral testing. Behavioral tests were performed between 8:00 and 12:00 h and each mouse was tested only once. All procedures in this study were conducted in accordance with institutional guidelines for animal care and use. Stereotaxic surgery Mice were anesthetized with intraperitoneal administration of ketamine hydrochloride (50 mg/kg) plus xylazine (5 mg/kg) and positioned in a stereotaxic

The locomotion apparatus (Borj Sanat Co, Tehran, Iran) consisted of clear perspex container box (30 cm  30 cm  40 cm high). The apparatus has a gray perspex panel (30 cm  30 cm  2.2 cm thick) with 16 photocells which divided the box to 16 equal-sized squares. Locomotion was measured as the number of crossings from one square to another during 300 s. Drugs The drugs used in the present study were harmaline (1-methyl-7-methoxy-3,4-dihydro-bcarboline) from Sigma (St. Louis, MO, USA), SKF38393 (1-phenyl-7,8-dihydroxy2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride), SCH2 3390 (R(+)-7-chloro-8-hydroxyl-3-methyl-1-phenyl-2,3,4, 5-tetrahydro-1H-3-benzazepine hydrochloride), quinpirole, sulpiride and SKF Ca blocker (SKF) (Sigma, St. Louis, CA, USA). The compounds were tested at doses: harmaline 0.25, 0.5 and 1 mg/kg; SKF38393, 0.1, 0.25 and 0.5 lg/mouse; SCH23390, 0.001, 0.01 and 0.02 lg/mouse, quinpirole, 0.01, 0.25 and 0.5 lg/mouse; sulpiride, 0.25, 0.5 and

M. Nasehi et al. / Neuroscience 285 (2015) 47–59

1 lg/mouse; and SKF 0.01 lg/mouse. SCH23390 is a highly potent and selective dopamine D1-like receptor antagonist with a K(i) of 0.2 and 0.3 nM for the D1 and D5 dopamine receptor subtypes, respectively. In vitro, it also binds with high affinity to the 5-HT1C and 5-HT2C serotonin receptor subtypes (6.3 nM to 9.3 nM, respectively). Although, the doses required to induce a similar response in vivo are greater than 10-fold higher than those required to induce a D1-mediated response (Ajdary et al., 2011). In this investigation, SCH23390 used at lower doses (0.001, 0.01 and 0.02 lg/mouse) which act as D1/D5 antagonist but not a 5HT1C and 5HT2C agonist. Harmaline was dissolved in sterile 0.9% saline and the compound was stirred for 1 h previously obtaining the final solution. Other drugs were dissolved in 0.9% physiological saline, just before the experiments, except for sulpiride which was dissolved in one drop of glacial acetic acid with a Hamilton micro-syringe and made up to a volume of 5 ml with sterile 0.9% saline and was then diluted to the required volume. Dopaminergic drugs were administered into the CA1 areas (intra-CA1) and harmaline was injected intraperitoneally (i.p.). Ten animals were used in each experimental group. In experiments where animals received one infusion, control groups received either saline (1 ll/mouse) or vehicle (1 ll/mouse) administration. The time of injection and doses of drugs used in the experiments were chosen according to pilot and published work in scientific literature (Zarrindast et al., 2010; Nasehi et al., 2013). Drug treatment In memory studies, when drugs are administered before training, the drug’s effects can be attributed to influences on the acquisition of memory. Moreover, when drugs are injected after training, the drug’s effects can be attributed to influences on the consolidation of memory. On the other hand, pre-test administration of drugs may affect retrieval process (McGaugh, 1989, 2000). In this investigation, we examine the effect of drugs on memory acquisition. Thus, we administrated the drugs before training. For drug injection, the animals were gently restrained by hand; the stylets were removed from the guide cannulae and replaced by 27-gauge infusion needles (1 mm below the tip of the guide cannulae). The infusion solutions were administered manually in a total volume of 1 ll/mouse (0.5 ll in each side) over a 60-s period. Administration needles were left in place for an extra 60 s to facilitate diffusion of the drugs. Since the animals have the same body weight, we administrated drugs based on the mg/kg in i.p. injection and lg/mouse in intra-CA1 injection. Statistical analysis Since individual variations in the step-down apparatus data, we selected to analyze the data using the Kruskal–Wallis nonparametric one-way analysis of variance (ANOVA) followed by a two-tailed Mann– Whitney’s U-test. Holmes Sequential Bonferroni Correction Test was using for paired comparisons once appropriate. The median as well as interquartile ranges of step-down latencies were recorded for ten mice in each experimental group. One/two-way ANOVA

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followed by post hoc test was used for the statistical evaluation in the locomotor activity. In all evaluations p < 0.05 was reflected statistically significant. Verification of cannulae placements After the testing sessions each animal was deeply anesthetized and 0.5 ll/site of a 4% methylene-blue solution was infused into the CA1, as illustrated in the drug section, then decapitated and its brain removed and placed in formaldehyde (10%). After numerous days, the brains were sliced and the sites of infusions were verified according to Paxinos and Franklin (2001). Cannulae were implanted into the CA1 regions of the dorsal hippocampus of a total of 520 animals, but only the data from 500 animals with correct cannulae implants were included in the statistical analyses. Experiment 1: effects of pre-training D1 receptor drugs administration on memory acquisition and locomotor activity. In this experiment, eight groups of animals were used. Four groups of animals received saline (1 ll/mouse) or different doses of SCH23390 (0.001, 0.01 and 0.02 lg/mouse) 5 min before training. The other four groups received saline (1 ll/mouse) or different doses of SKF38393 (0.1, 0.25 and 0.5 lg/mouse) 5 min before training. Experiment 2: effects of pre-training D2 receptor drugs administration on memory acquisition and locomotor activity. In this experiment, eight groups of mice were used. Four groups of animals received vehicle (1 ll/mouse) or diverse doses of sulpiride (0.25, 0.5 and 1 lg/mouse) 5 min before training. Another four groups received saline (1 ll/mouse) or different doses of quinpirole (0.1, 0.25 and 0.5 lg/mouse) 5 min before training. Experiment 3: effects of pre-training D1 receptor drugs administration on memory acquisition and locomotor activity under the amnesia induced by harmaline. In this experiment, twelve groups (three arms) of mice were used. The animals received saline (1 ll/mouse) or diverse doses of harmaline (0.25, 0.5 and 1 mg/kg; i.p.) 5 min before training. These animals received intra-CA1 pre-training saline (1 ll/mouse, four groups), subthreshold dose of SCH23390 (0.001 lg/mouse, four groups) or SKF38393 (0.1 lg/mouse, four groups) 5 min before training. Experiment 4: effects of pre-training D2 receptor drugs administration on memory acquisition and locomotor activity under the amnesia induced by harmaline. In this experiment, twelve groups (three arms) of animals were used. The mice received saline (1 ll/mouse) or several doses of harmaline (0.25, 0.5 and 1 mg/kg; i.p.) 5 min before training. These animals received intra-CA1 pretraining vehicle (1 ll/mouse), subthreshold dose of sulpiride (0.25 lg/mouse) or quinpirole (0.1 lg/mouse) 5 min before training. Experiment 5: effects of pre-training D1/D2 receptor drugs and SKF administration on memory acquisition and locomo-

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tor activity under the amnesia induced by harmaline. In this experiment, ten groups (two arms) of animals were used. Five groups of animals received saline (1 ll/mouse), significant dose of harmaline (1 mg/kg; i.p.); subthreshold dose of sulpiride (0.25 lg/mouse); subthreshold dose of SCH23390 (0.001 lg/mouse); and subthreshold dose of quinpirole (0.1 lg/mouse) 5 min before training. These animals received intra-CA1 pre-training SKF (0.01 lg/mouse) 5 min before training.

RESULTS Effects of pre-training D1 receptor drugs administration on memory acquisition and locomotor activity Fig. 1 showed the effects of pre-training intra-CA1 administration of SCH23390 and SKF38393 on stepdown latency and locomotor activity. Kruskal–Wallis ANOVA revealed that pre-training administration of SCH23390 (H (3) = 11.260, P < 0.001, Fig. 1A; left panel) and SKF38393 (H (3) = 16.573, P < 0.001, Fig. 1A; right panel) decreased the step-down latency in the one-trial passive avoidance task. Post hoc analysis by Mann–Whitney’s U-test indicated that SCH23390 (0.02 lg/mouse) and SKF38393 (0.5 lg/mouse) impaired memory acquisition, thus revealed an amnesic effect. In addition, one-way ANOVA indicated that SCH23390 [F (3, 28) = 1.44, P > 0.05, Fig. 1B; left panel] and SKF38393 [F (3, 28) = 2.484, P > 0.05, Fig. 1B; right panel] did not alter locomotor activity. Effects of pre-training D2 receptor drugs administration on memory acquisition and locomotor activity The effects of pre-training intra-CA1 administration of sulpiride and quinpirole on step-down latency and locomotor activity are illustrated in Fig. 2. Kruskal–Wallis ANOVA exhibited that pre-training administration of sulpiride (H (3) = 14.972, P < 0.001, Fig. 2A; left panel) and quinpirole (H (3) = 15.592, P < 0.001, Fig. 2A; right panel) decreased the step-down latency in the one-trial passive avoidance task. Post hoc analysis by Mann– Whitney’s U-test revealed that sulpiride (1 lg/mouse) and quinpirole (0.25 and 0.5 lg/mouse) impaired memory acquisition, consequently displayed an amnesic effect. Furthermore, one-way ANOVA shown that sulpiride [F (3, 28) = 1.316, P > 0.05, Fig. 2B; left panel] and quinpirole [F (3, 28) = 0.580, P > 0.05, Fig. 2B; right panel] had no effect on locomotor activity. Effects of pre-training D1 receptor drugs administration on memory acquisition and locomotor activity under the amnesia induced by harmaline The data of Fig. 3A left panel indicated that harmaline at a doses of 0.5 and 1 mg/kg impaired memory acquisition [Kruskal–Wallis ANOVA analysis (H (3) = 17.525, P < 0.001) followed by Mann–Whitney’s U-test]. Moreover, one way ANOVA indicated that harmaline did not change locomotor activity [F (3, 28) = 1.462, P > 0.05, Fig. 3B; left panel].

Furthermore, Kruskal–Wallis analysis revealed that a sub-threshold dose of SCH23390 (0.001 lg/mouse) reversed memory impairment caused by harmaline (1 mg/kg, i.p.) [Kruskal–Wallis ANOVA, H (3) = 18.140, P < 0.001, Fig. 3A; middle panel]. Also, two-way ANOVA showed that these interventions did not modify locomotor activity [F (7, 56) = 1.542, P > 0.05, Fig. 3B; middle panel]. In Fig. 3A right panel are seen the effects of SKF38393 on memory impairment induced by harmaline [Kruskal–Wallis ANOVA, H (3) = 28.016, P < 0.001]. Mann–Whitney’s U-test analysis indicated that a subthreshold dose of SKF38393 (0.5 lg/mouse) increased amnesia induced by harmaline (0.5 mg/kg, i.p.). Moreover, two-way ANOVA revealed that these interventions had no effect on locomotor activity [F (7, 56) = 1.491, P > 0.05, Fig. 3B; right panel].

Effects of pre-training D2 receptor drugs administration on memory acquisition and locomotor activity under the amnesia induced by harmaline The data of Fig. 4A left panel indicated that harmaline at a doses of and 1 mg/kg impaired memory acquisition [Kruskal–Wallis ANOVA analysis (H (3) = 19.005, P < 0.001) followed by Mann–Whitney’s U-test]. Moreover, one way ANOVA exhibited that harmaline did not alter locomotor activity [F (3, 28) = 1.845, P > 0.05, Fig. 4B; left panel]. Moreover, Kruskal–Wallis analysis shown that a subthreshold dose of sulpiride (0.25 lg/mouse) improved memory impairment caused by harmaline (1 mg/kg, i.p.) [Kruskal–Wallis ANOVA, H (3) = 15.601, P < 0.01, Fig. 4A; middle panel]. Furthermore, two-way ANOVA displayed that these interventions had no effect on locomotor activity [F (7, 56) = 0.965, P > 0.05, Fig. 4B; middle panel]. In Fig. 4A right panel are seen the effects of quinpirole on memory impairment induced by harmaline [Kruskal– Wallis ANOVA, H (3) = 22.472, P < 0.001]. Mann– Whitney’s U-test analysis indicated that a sub-threshold dose of quinpirole (0.1 lg/mouse) potentiated amnesia induced by harmaline (0.25 and 0.5 mg/kg, i.p.). In addition, two-way ANOVA revealed that these interventions did not change locomotor activity [F (7, 56) = 0.675, P > 0.05, Fig. 4B; right panel].

Effects of pre-training D1/D2 receptor drugs and SKF administration on memory acquisition and locomotor activity under the amnesia induced by harmaline This experiment was designed to evaluate whether dopamine D1/D2 receptor drugs via calcium channel prevented the impairing effect of harmaline on memory acquisition. The result of experiment 5 displayed that pre-training administration of harmaline changed memory acquisition [Kruskal–Wallis ANOVA, H (3) = 20.14, P < 0.001, Fig. 5A; left panel]. Mann–Whitney’s U-test analysis showed that harmaline (1 mg/kg, i.p.) impaired memory acquisition. Furthermore, one-way ANOVA exhibited that these interventions did not modify

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Fig. 1. The effects of pre-training intra-CA1 administration of saline, SCH23390 and SKF39393 on memory acquisition and locomotor activity. The animals received pre-training intra-CA1 injections of saline (1 ll/mouse), SCH23390 (0.001, 0.01 and 0.02 lg/mouse, left panel) and SKF39393 (0.1, 0.25 and 0.5 lg/mouse, right panel) 5 min before training. The memory was measured 24 h after infusion of drugs. The memory was measured 24 h after infusion of drugs. Test session step-down latencies are expressed as median and quartile for 10 animals. Moreover, locomotor activity was examined 5 min after memory testing. The step-down latency bars are expressed as median and quartile while locomotion bars are in mean ± S.E.M. (n = 8, all groups; ⁄⁄⁄P < 0.001 when compared to saline/saline group).

locomotor activity [F (7, 56) = 0.698, P > 0.05, Fig. 5B; left panel]. Moreover, Kruskal–Wallis analysis indicated that co-administration of harmaline (1 mg/kg)/SKF (0.01 lg/mouse) decreased amnesia, while co-administration of harmaline (1 mg/kg)/sulpiride (0.25 lg/mouse)/SKF (0.01 lg/mouse) and harmaline (1 mg/kg)/SCH23390 (0.01 lg/mouse)/sulpiride (0.25 lg/mouse) increased amnesia [Kruskal–Wallis ANOVA, H (3) = 27.745, P < 0.01, Fig. 5A; right panel]. In addition, two-way ANOVA revealed that these interventions had no effect on locomotor activity [F (7, 56) = 1.733, P > 0.05, Fig. 5B; right panel]. Also, Fig. 6 displayed the interaction between dopamine receptors and harmaline in the hippocampus on memory process.

DISCUSSION Our results showed that pre-training intra-CA1 administration of dopamine D1 and D2 receptors drugs impaired memory acquisition, however did not alter locomotor activity. The amnesic response of pre-training intra-CA1 injection of dopamine D1 antagonist, SCH23390 may be due to drug intrinsic activity or mediated by inhibition of postsynaptic D1 receptor mechanism. It has been demonstrated that SCH23390sensitive D1/D5 receptors are presented in the postsynaptic membrane. Especially when the activation of D1/D5 receptors cause an increase in the early and late long-term potentiation (LTP) (Huang and Kandel, 1995; Otmakhova and Lisman, 2000; Lemon and

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Fig. 2. The effects of pre-training intra-CA1 administration of saline, sulpiride and quinpirole on memory acquisition and locomotor activity. The animals received pre-training intra-CA1 injections of vehicle (1 ll/mouse), saline (1 ll/mouse), sulpiride (0.25, 0.5 and 1 lg/mouse, left panel) and quinpirole (0.1, 0.25 and 0.5 lg/mouse, right panel) 5 min before training. The memory was measured 24 h after injection of drugs. Test session step-down latencies are expressed as median and quartile for 10 animals. Furthermore, locomotor activity was examined 5 min after memory testing. The step-down latency bars are expressed as median and quartile but locomotion bars are in mean ± S.E.M. (n = 8, all groups; ⁄⁄P < 0.01 and ⁄⁄⁄P < 0.001 when compared to saline/saline group).

Manahan-Vaughan, 2006; O’Carroll et al., 2006; Granado et al., 2008; Rossato et al., 2009; Rozas et al., 2012). On the other hand, dopamine D1 agonist, SKF38393 may be increases dopamine release in postsynaptic D1 receptors whose cause impairment of memory. The dopamine D2 antagonist, sulpiride may block presynaptic dopamine D2 receptors, and so releases dopamine, that in turn, activates postsynaptic dopamine receptors and thus decreases the formation of memory acquisition. In addition, dopamine D2 receptor agonist, quinpirole, shows an affinity for dopamine D2/D3 receptors. It has been revealed that the activation of dopamine D2 and D3 receptor subtypes have opposing functional consequences on behaviors (Richtand et al., 2001). The activation of presynaptic dopamine D2 receptors prevents both dopamine synthesis and release. Some studies propose that dopamine D3 receptors might function as both release- and synthesis-inhibiting autoreceptors in some

systems (Meller et al., 1993; Tang et al., 1994). So, impairment of memory induced by pre-training intra-CA1 infusion of quinpirole may be either due to pre- or postsynaptic stimulation of dopamine D2-like receptors or may be mediated via activation of different dopamine receptors. The same effect of dopaminergic antagonist and agonist may be due to the fact that dopaminergic receptors are localized both pre- and postsynaptically to dopaminergic projections (Millan, 2003). Presynaptic dopamine heteroreceptors placed on GABAergic terminals (Millan, 2003; Feuerstein, 2008). Liu et al. (2005) reported that in the presence of GABA-A receptor antagonist bicuculline, induction of LTP facilitated in dopamine neurons. Recently, Rozas et al. (2012) demonstrated that SCH23390 inhibitor act over postsynaptic D1 receptors in glutamatergic synapsis of CA1 area of rat hippocampus (Ataee et al., 2010). The dopaminergic system is essential for memory processes in the CA1 region

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Fig. 3. The effects of dopamine D1 receptor drugs on memory acquisition and locomotor activity in the present and absence of harmaline. Left panel indicates the effects of pre-train administration of harmaline (0.25, 0.5 and 1 mg/kg, i.p.) on memory acquisition and locomotor activity. Middle and right panels display the effects of pre-train administration of SCH23390 (0.001 lg/mouse, intra-CA1) and SKF39393 (0.1 lg/mouse, intra-CA1), respectively with harmaline (0.25, 0.5 and 1 mg/kg, i.p.) on one-trail avoidance task and locomotor activity. The memory was measured 24 h after administration of drugs. Test session step-down latencies are expressed as median and quartile for 10 mice. In addition, locomotor activity was examined 5 min after memory testing. The step-down latency bars are expressed as median and quartile but locomotion bars are in mean ± S.E.M. (n = 8, all groups; ⁄P < 0.05 and ⁄⁄⁄P < 0.001 when compared to saline/saline group. +++p < 0.001 when compared with harmaline/saline group).

(Seamans et al., 1998; Umegaki et al., 2001; Gangarossa et al., 2012). However, the specific receptor subtypes mediating the behavioral effects of dopamine in the different phases (acquisition, consolidation and retrieval) of memory remain poorly understood. Some findings suggest that dopaminergic system plays a role in the acquisition of habits, skills (Chagniel et al., 2012), hippocampal-mediated acquisition of new paired associates at or around the time of encoding (Bethus et al., 2010). Also, it has been reported that hippocampal dopamine

D1 and D2 receptors are involved in acquisition of different working memory and memory performance, respectively (Rezayof et al., 2007). Through the activation of dopamine D1 receptors located in pyramidal neurons, the hippocampal dopaminergic system mediates the acquisition of novel information, which can be transformed into long-term memory if it is biologically significant. Furthermore, it has been demonstrated that the activation of the D1 receptors are activated during the formation of a persistent memory trace in the

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Fig. 4. The effects of dopamine D2 receptor drugs on memory acquisition and locomotor activity in the present and absence of harmaline. Left panel shows the effects of pre-train administration of harmaline (0.25, 0.5 and 1 mg/kg, i.p.) on memory acquisition and locomotor activity. Middle and right panels indicate the effects of pre-train administration of sulpiride (0.25 lg/mouse, intra-CA1) and quinpirole (0.1 lg/mouse, intra-CA1), respectively with harmaline (0.25, 0.5 and 1 mg/kg, i.p.) on one-trail avoidance task and locomotor activity. The memory was measured 24 h after injection of drugs. Test session step-down latencies are expressed as median and quartile for 10 mice. Also, locomotor activity was examined 5 min after memory testing. The step-down latency bars are expressed as median and quartile but locomotion bars are in mean ± S.E.M. (n = 8, all groups; ⁄⁄P < 0.01 and ⁄⁄⁄P < 0.001 when compared to saline/saline group. +P < 0.05, ++P < 0.01 and +++p < 0.001 when compared with harmaline/saline group).

hippocampus, which would be in accordance with the facilitation of the induction of long-term potentiation mediated by the stimulation of D1 receptors (GonzalezBurgos and Feria-Velasco, 2008). Electrophysiological experiments have revealed that stimulation of presynaptic D1 receptors depresses both inhibitory and excitatory transmission, while activation of presynaptic D2 receptors suppresses excitatory transmission (Vanderschuren et al., 1999). In agreement with the present results there are evidence showing that SCH23390 (Rezayof et al., 2007; Zarrindast et al., 2012), SKF38393 (Zarrindast

et al., 2012), and sulpiride (Hale and Crowe, 2003) impaired learning and memory. Nevertheless, some investigators indicted that SCH23390 (Nasehi et al., 2010), SKF38393 (Tarantino et al., 2011), sulpiride (Rezayof et al., 2007; Nasehi et al., 2010), and quinpirole (Rezayof et al., 2007), had no effect on learning and memory. The controversial results may be due to methods, route of injection and/or the doses of drugs used. Moreover, the obtained results showed that pretraining administration of harmaline impaired memory acquisition, but had no effect on locomotor activity.

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Fig. 5. The effects of dopamine D1/D2 receptor drugs and SKF on memory acquisition and locomotor activity in the present and absence of harmaline. Left panel shows the effects of pre-train administration of saline (1 ll/mouse), harmaline (1 mg/kg, i.p.), sulpiride (0.25 lg/mouse, intraCA1), SCH23390 (0.001 lg/mouse, intra-CA1) and quinpirole (0.1 lg/mouse, intra-CA1) on memory acquisition and locomotor activity. Right panel indicate the effects of pre-train co-administration of SKF (0.01 lg/mouse, intra-CA1)/sulpiride (0.25 lg/mouse, intra-CA1), or SCH23390 (0.001 lg/mouse, intra-CA1)/sulpiride (0.25 lg/mouse, intra-CA1), or SKF (0.01 lg/mouse, intra-CA1)/quinpirole (0.1 lg/mouse, intra-CA1), with harmaline (1 mg/kg, i.p.) on one-trail avoidance task and locomotor activity. The memory was measured 24 h after infusion of drugs. Test session step-down latencies are expressed as median and quartile for 10 animals. Moreover, locomotor activity was examined 5 min after memory testing. The step-down latency bars are expressed as median and quartile but locomotion bars are in mean ± S.E.M. (n = 8, all groups; ⁄P < 0.05, ⁄⁄ P < 0.01 and ⁄⁄⁄P < 0.001 when compared to saline/saline group. +P < 0.05 and +++P < 0.001 when compared with harmaline/saline group).

Injecting mice before training allows us to examine on the first stage of memory processing, i.e., the acquisition or encoding phase (Daumas et al., 2005; Garelick and Storm, 2005). For the study of the acquisition of memory, we have done pre-training infusion of harmaline and for the interpretation of the results, normal memory is compared with memory impairment. Previous behavioral

studies have known a number of different effects for harmaline, such as alteration in associative and motor learning and calcium channel opening, with a resultant increase in neuronal excitability (Moura et al., 2006). In according with our results it has been shown that harmaline blocks both associative and motor learning (Moura et al., 2006; Nasehi et al., 2010, 2012). However, some

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Fig. 6. Showed schematic graph demonstrating how the subtypes of dopamine receptors in the hippocampus could interact with the effects of harmaline to influence memory.

studies reported that harmaline principally increased long term memory (Moura et al., 2006; Nasehi et al., 2010). Harmaline has been revealed to lower voltage-gated calcium channel currents, resulting in decreased neuron excitation. Calcium influx stimulates cellular signaling pathways involved in memory processes (Moura et al., 2006). Consequently, we can suggest that harmaline decreased memory acquisition by reduction of neuron excitation. In addition, our present data indicated that in animals trained under harmaline (i.p.) injection, pre-train intra-CA1 administration of SCH23390 and sulpiride reverse amnesia induced by harmaline, whereas, pre-train intraCA1 injection of SKF38393 and quinpirole significantly enhanced amnesia induced by harmaline. The b-carboline alkaloids indicate modest affinity to 5-HT, dopamine and benzodiazepine receptors (Glennon et al., 2000). These alkaloids influence central neurotransmitters such as dopamine (Moura et al., 2006; Nasehi et al., 2010, 2012), via inhibition of monoamine reuptake systems (Kleven and Woolverton, 1993; Baum et al., 1996; Yang et al., 2011), and inhibition MAO-A or B (Glennon et al., 2000; Touiki et al., 2005). Some evidences displayed that harmaline change the extracellular and tissue level of dopamine (Kim et al., 1970; Glick et al., 1994, 1996). It seems that both SCH23390 and sulpiride activate postsynaptic receptors, thus through inhibition dopamine release may weaken amnesia induced by

harmaline. The controversial effects of sulpiride may be due to blockade of either pre- or postsynaptic D2 receptors (Zarrindast et al., 2010). Furthermore, we propose that there is a synergistic effect between harmaline, SKF38393 and quinpirole, which potentiate amnesic response by increasing dopamine levels. It seems that harmaline could increase dopamine levels through inhibiting of MAOA. Also, our experiments indicate that pre-train intra-CA1 infusion of SKF reduce the amnesia induced by harmaline. This may be supported by the inhibition of calcium channel currents via a calcium channel blocker (SKF96365 injection in the CA1 region) which blocks harmaline-induced amnesia. On the other hand, co-administration of SKF/sulpiride or SCH23390/sulpiride increased amnesia caused by harmaline. It seems likely that blockade of the presynaptic D2 receptors by administration of sulpiride or SKF96365 in the CA1 area which in turn activates the postsynaptic D1 receptors hence increase amnesia induced by harmaline. This may be supported by inhibition of neurotransmitter exocytosis from presynaptic neurons by a calcium uptake inhibitor (SKF96365 injection in the CA1 area) which blocks the effect of sulpiride on presynaptic D2 receptors. Furthermore, similar to SKF, blockade of D1 receptors by SCH23390 and presynaptic D2 receptors through infusion of sulpiride may be potentiated amnesia caused by harmaline. Furthermore, our results

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exhibit that co-administration of SKF/quinpirole did not alter memory impairment induced by harmaline. We propose that quinpirole may stimulate pre- or postsynaptic neurons whose change dopamine release hence did not alter amnesia induced by harmaline. Altogether, these findings suggest an involvement of D1 and D2 receptors modulation in the harmaline-induced impairment of memory acquisition. Acknowledgments—The authors thank the Iran National Science Foundation (INSF) for providing the financial support for the project.

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(Accepted 4 November 2014) (Available online 15 November 2014)