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The influence of dopaminergic system in medial prefrontal cortex on ketamine-induced amnesia in passive avoidance task in mice
Author’s Accepted Manuscript The influence of dopaminergic system in medial prefrontal cortex on ketamine-induced amnesia in passive avoidance task in mice Maryam Farahmandfar, Atefeh Bakhtazad, Ardeshir Akbarabadi, Mohammad-Reza Zarrindast www.elsevier.com/locate/ejphar
PII: DOI: Reference:
S0014-2999(16)30199-6 http://dx.doi.org/10.1016/j.ejphar.2016.03.060 EJP70562
To appear in: European Journal of Pharmacology Received date: 25 June 2015 Revised date: 26 March 2016 Accepted date: 31 March 2016 Cite this article as: Maryam Farahmandfar, Atefeh Bakhtazad, Ardeshir Akbarabadi and Mohammad-Reza Zarrindast, The influence of dopaminergic system in medial prefrontal cortex on ketamine-induced amnesia in passive avoidance task in mice, European Journal of Pharmacology, http://dx.doi.org/10.1016/j.ejphar.2016.03.060 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
The influence of dopaminergic system in medial prefrontal cortex on ketamine-induced amnesia in passive avoidance task in mice Maryam Farahmandfar1,2, Atefeh bakhtazad1,2, Ardeshir Akbarabadi2,3, Mohammad-Reza Zarrindast1,2,4,5,6* 1
Department of Neuroscience, School of Advanced Medical Technologies, Tehran University of Medical Sciences, Tehran, Iran 2
Iranian National Center for Addiction Studies, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran 3
Department of Basic Sciences, Faculty of Veterinary Medicine, Islamic Azad University, Garmsar branch, Semnan, Iran 4
Department of Pharmacology, Tehran University of Medical Sciences, Tehran, Iran
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Institute for Cognitive Science Studies (ICSS), Tehran, Iran
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School of Cognitive Sciences, Institute for Research in Fundamental Sciences (IPM), Tehran, Iran
*
Corresponding author at: Department of Pharmacology, Tehran University of Medical Sciences,
Tehran, Iran P.O. Box: 13145784. Tel./Fax: +98 21 66402569. [email protected]
Abstract Dopaminergic modulations of glutamate receptors are essential for the prefrontal cortical (PFC) behavioral and cognitive functions. In order to understand the effect of dopamine/glutamate interactions on learning and memory, we investigated the effects of intra medial prefrontal cortex (mPFC) injections of dopaminergic agents on ketamine-induced amnesia by using a one-trial passive avoidance task in mice. Pre-training administration of ketamine (5, 10 and 15 mg/kg, i.p.) dosedependently decreased the memory acquisition of a one-trial passive avoidance task. Pre-training intra-mPFC administration of SKF 38393, D1 receptor agonist and quinpirol D2 receptor agonist, alone did not affect memory acquisition. However, amnesia induced by pre-training ketamine (15 mg/kg) significantly decreased by pretreatment of SKF 38393 (2 and 4µg/mouse) and quinpirol (0.3, 1 and
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3µg/mouse). Pre-training administration of SCH 23390, D1 receptor antagonist (0.75 and 1 μg/mouse, intra-mPFC), and sulpiride D2 receptor antagonist (3 μg/mouse, intra-mPFC) impaired memory acquisition. In addition, co-pretreatment of different doses of SCH 23390 and sulpiride with lower dose of ketamine (5 mg/kg), which did not induce amnesia by itself, caused inhibition of memory formation. It may be concluded that dopaminergic system of medial prefrontal cortex is involved in the ketamine-induced impairment of memory acquisition.
Keywords: Ketamine; Dopaminergic system; Medial prefrontal cortex; Passive avoidance; Mice
1. Introduction Glutamate N-methyl-D-aspartate (NMDA) receptors, plays an important role in the induction, maintenance and expression of synaptic plasticity associated with the mechanisms of learning and memory (Anis et al., 1983). Ketamine is the non-competitive antagonist of NMDA receptor and one of the most commonly used medicine to produce a dose-related state of unconsciousness and analgesia for painful procedures (Leung et al., 2001; Tverskoy et al., 1996). However, the studies of its impact on learning and memory have always been a clinical concern. Studies have revealed that acute and repeated injection of ketamine and other NMDA-antagonists have an impairing effect on learning and memory in different paradigms such as y-maze discrimination (Peng et al.), active or passive avoidance (Getova and Doncheva) and water maze tasks (Liu et al., 2014; Moosavi et al., 2012) in mice and rats. These studies reported that different stages of memory formation including encoding, consolidation, and retention could be affected by ketamine (Goulart et al., 2010; Moosavi et al., 2012). Furthermore, the exact mechanisms and neurotransmitter circuits involved in ketamine-induced amnesia have yet to be elucidated. There is some evidence indicated that Ketamine-induced cognitive effects are associated with the functional alteration of many neurotansmitter systems at different brain regions such as ventral tegmental area, the basolateral amygdala (BLA), hippocampus and prefrontal
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cortex (Duncan et al., 1998a; Gao et al., 1998; Goulart et al., 2010). It has been demonstrated that subanesthetic doses of ketamine impair prefrontal cortex (PFC) function in the rat and produce symptoms in humans similar to those observed in schizophrenia and dissociative states, including impaired performance of frontal lobe-sensitive tests and cognitions (Duncan et al., 1998b; Moghaddam et al., 1997). The medial prefrontal cortex (mPFC) is a part of the prefrontal cortex, which has been associated with diverse functions including attentional processes, visceromotor activity, decision making, goal directed behavior, and long term memory (Hoover and Vertes, 2007; Vertes, 2004). One of the neurotransmitter that may play an important role in mPFC function is the excitatory amino acidcontaining neurons (Akbarian et al., 1996; Deakin et al., 1989). Neuronal population of mPFC receive widespread inputs from cortical and subcortical areas involved in sensorimotor and limbic functions (Hoover and Vertes, 2007). The integration of these glutamatergic inputs is essential for the mPFC role in executive functions and regulation of learning and memory (Getova and Doncheva, 2011). Morphological and biochemical studies have indicated a close interaction between excitatory amino acid and dopamine afferents in the PFC (Verma and Moghaddam, 1996). mPFC dopamine (DA) signaling has been involved in cognitive, emotional and motivational processes. Dopamine depletion in PFC results in impaired performances in PFC cognitive tasks, and these deficits can be ameliorated by the mixed dopamine receptor agonist apomorphine (Verma and Moghaddam, 1996). The ventral tegmental area (VTA) is the primary source of DA afferents to the mPFC (Hoover and Vertes, 2007). These projections are activated by aversive stimuli and it has been shown that different kinds of aversive experiences increase DA levels within this cortex (Hondo et al., 1994). Interaction of glutamatergic and dopaminergic systems have been extensively described for some of behavioral responses such as locomotor activity (Serrano et al., 2002) and cognitive functions (Alexander et al., 1990; David, 2009; Garside et al., 1996). Although it has been suggested that learning and memory are critically affected by dopaminergic transmission in mPFC (Babaei et al., 2011; Bassareo and Di Chiara, 1997; Phillips et al., 2004), there is no study investigating the role of
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dopamine receptors in this area on the modulation of learning and memory induced by NMDA receptor antagonists. In the present study, we examined the influence of pretreatment of dopaminergic agents in the medial prefrontal cortex on ketamine-induced amnesia in mice by using a one-trial passive avoidance task.
2. Materials and methods 2.1. Animals Male albino NMRI mice (Pasteur institute; Tehran, Iran) weighing 22–30 g were used. The animals were housed 10 per Plexiglas cage, in a room with controlled photoperiod (a 12-h light/dark cycle) and temperature (22±2 °C). They had food and water available ad lib and were allowed to adapt to the laboratory conditions for at least 1 week before the experiments. Each animal was used once only. All experimental procedures were in accordance with the NIH Guide for the Care and Use of Laboratory Animals.
2.2. Drugs The drugs used in the present study were Ketamine (Alfasan Inc., Utrecht, Holland), SKF38393 (1phenyl-7,8-dihydroxy-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride), SCH 23390 (R(_)-7chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride), quinpirole and sulpiride, (Sigma Chemical Co., St Louis, CA, USA). All drugs were dissolved in sterile 0.9% saline, just before the experiment, except for sulpiride that was dissolved in one drop of glacial acetic acid with Hamilton micro syringe. It was then made up to a volume of 5 ml with sterile 0.9% saline and then diluted to the required volume. Control animals received either saline or vehicle. The doses of the drugs were based on previous studies (Nasehi et al., 2013; Zarrindast et al., 2006).
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2.3. Cannula guide implantation Mice were anesthetized with intraperitoneal injection of ketamine hydrochloride (50 mg/kg) plus xylazine (5 mg/kg) and were placed in a stereotaxic apparatus. The skin was then incised and the skull was cleaned. 22-gauge guide cannulae were placed 1 mm above the intended site of injection according to the atlas of Paxinos (Paxinos and Watson, 1982). Stereotaxic coordinates for the mPFC region were AP: +2.1 mm from bregma and V: −1.7 mm from the skull surface. The cannulae were secured with dental acrylic. Stainless steel stylets (27-gauge) were inserted into the guide cannulae to keep them free of debris. All animals were allowed 1 week to recover from the surgery and from the effect of the anesthetic agents.
2.4. Intra-mPFC injections For drug infusion, the animals were gently restrained by hand. The stylets were removed from the guide cannulae and replaced by 27-gauge injection needles (1 mm below the tip of the guide cannulae). The injection solutions were manually administered in a total volume of 0.3 μl/mice over a 60 s period. Injection needles were left in place for an additional 60 s to facilitate the diffusion of the drugs.
2.5. Apparatus The passive avoidance apparatus consisted of a wooden box (30×30×40 cm high) with a steel-rod floor (29 parallel rods, 0.3 cm in diameter, set 1 cm apart). A wooden platform (4×4×4 cm) was set in the center of the grid floor. Intermittent electric shocks (1 Hz, 0.5 s, 40 V DC) were delivered to the grid floor by an insulated stimulator (Grass S44, USA).
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2.6. Training A single-trial step-down passive avoidance task was used. Each mouse was gently placed on the wooden platform. When the mouse stepped down from the platform and placed all its paws on the grid floor, intermittent electric shocks were delivered continuously for 15 s. This training procedure was carried out between 10:00 and 15:00 h. Each mouse was placed on the platform again at 24 h after training and the step-down latency was measured with a stopwatch as passive avoidance behavior. An upper cut-off time of 300 s was set. The criterion for the retention test was for the mouse to place all 4 paws on the grid floor, as for training. The retention test was also carried out between 10:00 and 15:00 h.
2.7. Histology After testing sessions, each mouse was deeply anesthetized and 0.3 μl of a 4% methylene-blue solution was infused into the mPFC as described in the drug section; the mouse was then decapitated and its brain was removed and placed in formaldehyde (10%). After several days, the brains were sliced and the site of injection were verified according to atlas of Paxinos (Fig 1) (Paxinos and Watson, 1982).
2.8. Drug treatment Ten animals were used in each experimental group. The intervals of drug administration were based on previous studies in order to obtain a maximum response.
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2.8.1. Experiment 1: effect of ketamine on memory acquisition The experiment examined the effects of intraperitoneal (i.p.) administration of different doses of ketamine on memory acquisition. Four groups of animal received pre-training administration of saline (10 ml/kg, i.p.) or ketamine (5, 10 and 15 mg/kg, i.p.) 15 min before training. Retention test was done 24h after training.
2.8.2. Experiment 2: effects of SKF38393 on memory acquisition in the presence or absence of ketamine In this experiment, eight groups of animals were used. Four groups of animals were pretreated with either saline (0.3 μl/mouse, intra- mPFC) or SKF38393 (1, 2 and 4 μg/mouse, intra-mPFC) and, after 5 min, they received saline (10 ml/kg, i.p.) 15 min before training (Fig. 2, left panel). The other four groups of animals received intra-mPFC injections of saline (0.3 μl/mouse, intra- mPFC) or SKF38393 (1, 2 and 4 μg/mouse, intramPFC) and, after 5 min, they were injected with ketamine (15 mg/kg, i.p.) 15 min before training, (Fig. 2,right panel).
2.8.3. Experiment 3: effects of SCH 23390 on memory acquisition in the presence or absence of ketamine In this experiment, ten groups of animals were used. Five groups of animals were pretreated with either saline (0.3 μl/mouse, intra- mPFC) or SCH 23390 (0.25, 0.5, 0.75 and 1 μg/mouse, intra-mPFC) and, after 5 min, they received saline (10 ml/kg, i.p.) 15 min before training (Fig. 3, left panel). The other five groups of animals received intra-mPFC injections of saline (0.3 μl/mouse, intra- mPFC) or
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SCH 23390 (0.25, 0.5, 0.75 and 1 μg/mouse, intra-mPFC) and, after 5 min, they were injected with ketamine (5 mg/kg, i.p.) 15 min before training, (Fig. 3,right panel).
2.8.4. Experiment 4: effects of Quinpirol on memory acquisition in the presence or absence of ketamine In this experiment, ten groups of animals were used. Five groups of animals were pretreated with either saline (0.3 μl/mouse, intra- mPFC) or Quinpirol (0.1, 0.3, 1 and 3 μg/mice, intra-mPFC) and, after 5 min, they received saline (10 ml/kg, i.p.) 15 min before training (Fig. 4, left panel). The other five groups of animals received intra-mPFC injections of saline (0.3 μl/mouse, intra- mPFC) or Quinpirol (0.1, 0.3, 1 and 3 μg/mice, intra-mPFC) and, after 5 min, they were injected with ketamine (15 mg/kg, i.p.) 15 min before training, (Fig. 4,right panel).
2.8.5. Experiment 5: effects of Sulpiride on memory acquisition in the presence or absence of ketamine In this experiment, ten groups of animals were used. Five groups of animals were pretreated with either saline (0.3 μl/mouse, intra- mPFC) or Sulpiride (0.1, 0.3, 1 and 3 μg/mice, intra-mPFC) and, after 5 min, they received saline (10 ml/kg, i.p.) 15 min before training (Fig. 5, left panel). The other five groups of animals received intra-mPFC injections of saline (0.3 μl/mouse, intra- mPFC) or Sulpiride (0.1, 0.3, 1 and 3 μg/mice, intra-mPFC)and, after 5 min, they were injected with ketamine (5 mg/kg, i.p.) 15 min before training, (Fig. 3,right panel).
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2.9. Statistical analysis Data are expressed as the median and 95% confidence intervals. As step-down latency did not follow a normal distribution, these data were analyzed 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 used for paired comparisons when appropriate.The criterion for statistical significance was P<0.05. Calculations were performed using the SPSS statistical package.
3. Results 3.1. Effects of pre-training ketamine administration on memory acquisition Fig. 2 shows the effects of pre-training administration of ketamine on step-down latency. Kruskal– Wallis ANOVA (H (3) =12.6, P<0. 01) reveals pre-training administration of ketamine (5, 10 and 15 mg/kg, i.p.) dose-dependently reduced the step-down latency in the one-trial passive avoidance task. Post hoc analysis by Mann–Whitney's U-test indicates ketamine (10 and 15 mg/kg) impaired memory acquisition, thus showing an amnesic effect.
3.2. Effects of SKF38393 on memory acquisition in the presence or absence of ketamine Fig. 3 (left panel) shows that intra- mPFC pre-training administration of different doses of SKF38393 (1, 2 and 4 μg/mouse, intra-mPFC), had no effect on memory acquisition [Kruskal–Wallis ANOVA, H (3) =2.74, P>0.05].
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Moreover, Fig. 3 (right panel) indicates that intra- mPFC pre-training administration of the SKF38393 affects ketamine-induced amnesia [Kruskal–Wallis ANOVA, H (3) =4.5, P<0.05]. Mann–Whitney's U-test analysis reveals the agonist doses of 2 and 4 μg/mouse induced full recovery of the memory impairment caused by ketamine (15 mg/kg).
3.3. Effects of SCH 23390 on memory acquisition in the presence or absence of
ketamine Fig. 4 (left panel) shows the effects of intra- mPFC pre-training administration of SCH 23390 on memory acquisition. Kruskal–Wallis ANOVA revealed that pre-training SCH 23390 (0.25, 0.5, 0.75 and 1 μg/mouse, intra-mPFC) dose-dependently suppressed the learning of a one-trial passive avoidance task [H (4) =11.77, P<0.05]. Further analysis with the Mann–Whitney U-test showed that pre-training SCH 23390 (0.75 μg/mouse, P<0.05 and 1 μg/mouse, P<0. 01) impaired the retention latency as compared to the saline control group. In addition, as shown in Fig. 4 (right panel), copretreatment of different doses of SCH 23390 (0.25, 0.5, 0.75 and 1 μg/mouse, intra-mPFC) and 5 mg/kg of ketamine, which alone did not induce amnesia, inhibited memory acquisition and induced amnesia [Kruskal–Wallis ANOVA, H(4) = 20.91, P<0.001].
3.4. Effects of Quinpirol on memory acquisition in the presence or absence of
ketamine As shown in Fig. 5 (left panel), intra- mPFC pre-training administration of different doses of Quinpirol (0.1, 0.3, 1 and 3 μg/mouse, intra-mPFC), had no effect on memory acquisition [Kruskal–Wallis ANOVA, H (4) =0.59, P>0.05].
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Moreover, Fig. 5 (right panel) indicates that intra- mPFC pre-training administration of the Quinpirol affects ketamine-induced amnesia [Kruskal–Wallis ANOVA, H (4) =22.75, P<0.001]. Mann–Whitney's U-test analysis reveals the agonist doses of 0.3, 1 and 3 μg/mouse (P<0.001) induced full recovery of the memory impairment caused by ketamine (15 mg/kg).
3.5. Effects of Sulpiride on memory acquisition in the presence or absence of ketamine Fig. 65 (left panel) shows the effects of intra- mPFC pre-training administration of Sulpiride on memory acquisition. Kruskal–Wallis ANOVA revealed that pre-training Sulpiride (0.1, 0.3, 1 and 3 μg/mouse, intra-mPFC) suppressed the learning of a one-trial passive avoidance task [H(4)=10.35, P<0.05]. Further analysis with the Mann–Whitney U-test showed that pre-training Sulpiride (3 μg/mouse, P<0. 01) impaired the retention latency as compared to the saline control group. In addition, as shown in Fig. 6 (right panel), co-pretreatment of different doses of Sulpiride (0.1, 0.3, 1 and 3 μg/mouse, intra-mPFC) and 5 mg/kg of ketamine, which alone did not induce amnesia, inhibited memory acquisition and induced amnesia [Kruskal–Wallis ANOVA, H(4) = 17.23, P<0.01].
4. Discussion In the present experiments, the role of D1 and D2 dopaminergic receptors in medial prefrontal cortex on the inhibitory memory acquisition was investigated in the presence or absence of ketamine by using passive avoidance task. Previous behavioral studies have documented a number of diverse effects for ketamine such as agitation, hallucinations, anxiety and cognitive problems including
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memory loss, impairments in encoding and processing of information in the episodic memory (Getova and Doncheva, 2011; Malhotra et al., 1997; Newcomer et al., 1999; Olney et al., 1999). Our present experiments showed that pre-training administration of ketamine (10 and 15 mg/kg, i.p.) dose-dependently suppressed the learning of a one-trial passive avoidance task. These results are in line with the previous reports in which pre-training systemic administration of ketamine induce amnesia in various memory paradigms (Imre et al., 2006; Kos et al., 2006; Moosavi et al., 2012; Uchihashi et al., 1994). NMDA receptors are hypothesized to play a crucial role in the induction of synaptic plasticity and encoding or consolidation of long-term memories (Bliss and Collingridge, 1993; Collingridge and Bliss, 1995). On the other hand, recent clinical trials with ketamine, have demonstrated that subanesthetic doses of this drug exacerbate preexisting symptoms of schizophrenia (Lahti et al., 1995). In healthy individuals, ketamine also can produce behaviors that are similar to a broad range of symptoms associated with schizophrenia, including impaired performance in psychological tests sensitive to PFC function (Ghoneim et al., 1985; Oye et al., 1992). It has been suggested that mPFC has important role in memory including working memory, information processing, short-term memory and object recognition (Hoover and Vertes, 2007; Leon et al., 2010). Numerous studies showed that precise regulation of excitatory glutamatergic neurotransmission within the mPFC is essential for various forms of memory formation, and glutamatergic dysfunction is believed to contribute to the impairment of learning and memory (Akbarian et al., 1996; Verma and Moghaddam, 1996). Although the importance of PFC glutamatergic NMDA receptors in cognitive functions is widely recognized, several lines of evidence have highlighted the need of dopamine– glutamate coactivation for a number of PFC functions (Angrist and Gershon, 1974; Garside et al., 1996; Matthysse, 1973). The role of dopamine transmission in the prefrontal cortex during learning and memory has been the focus of interest in many neurochemical and behavioral studies (Babaei et al., 2011; Carr and Sesack, 2000a; Rinaldi et al., 2007). Midbrain dopaminergic neurons send afferents to many target areas, including the several regions of the prefrontal cortex. Dopamine exerts
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its actions within the PFC via receptors grouped into major families, D1-like and D2-like receptors (Carr and Sesack, 2000b; Hoover and Vertes, 2007). Our data in this study indicated that intra-mPFC pre-training administration of SKF 38393, D1 receptor agonist or quinpirol D2 receptor agonist, alone did not affect memory acquisition in passive avoidance task. However, microinjections of the dopamine D1 receptor antagonist, SCH 23390, or the dopamine D2 receptor antagonist, sulpiride into the mPFC significantly decreased memory acquisition. In agreement with our findings, Ichihara, et al reported that systemic low dose administration of SCH23390 or sulpiride impaired the passive avoidance response in mice only when it was given before the training (Ichihara et al., 1992). Impairing effect of both D1 and D2 receptor antagonists have also been reported in spatial and working memory performance in monkeys and rodents (Floresco and Magyar, 2006; Puig et al., 2014; Seamans et al., 1998). On the contrary, Druzin et al. reported that intra-PFC infusions of a D2 receptor agonist disrupt performance of rats in a delayed-response learning task and that this D2 receptors modulation of WM may be linear (i.e., lower/higher levels of D2 receptors activation are associated with better/poorer performance) (Druzin et al., 2000). Another study also found that intra-PFC infusions of a D1 receptor antagonist, but not a D2 receptor antagonist, could disrupt performance in the water maze performance (Arnsten and Pliszka, 2011). Compelling evidence suggest that aversive learning responses (inhibitory avoidance task) engages different brain circuitry than reward-based learning task (Yang and Liang, 2014), suggesting that memory processing could differ between tasks. Also, distinct experimental procedures such as time of drug administration (before vs. after training) or intrinsic characteristics of the tasks (multi-trial vs. single trial) could explain the differences observed (Gonzalez et al., 2014). For example, it has been demonstrated that the mPFC behaves as a rapid learning node within a neural network, necessary to the acquisition, consolidation and retrieval phases of single trial inhibitory avoidance memory but the role of mPFC in multi-trial reward related working memory is limited to the retrieval phase
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(Gonzalez et al., 2013). The exact mechanisms of mPFC dopamine modulation of different kinds of learning and memory processes are still unclear. In mPFC, dopaminergic terminals arising from the ventral tegmental area (VTA) make synaptic contacts with prefrontal pyramidal glutamatergic neurons and GABA interneurons (Carr and Sesack, 2000a; Hoover and Vertes, 2007). It has been hypothesized that many cognitive function of mPFC including arousal, attention, motivation and working memory can be modulated by the interaction of these neurotransmitter systems (Tseng and O'Donnell, 2004). Although many investigations demonstrated that direct and indirect connections of the amygdala and hippocampus to the medial prefrontal cortex may play an important role in learning and memory (Kim et al., 2011; Shin et al., 2006), the role of dopaminergic and glutamatergic interactions of these areas in the hippocampus or amygdala dependent memory needs to be more elucidated. Our result showed that amnesia induced by pre-training ketamine (15 mg/kg) significantly decreased by pretreatment of SKF 38393 (2 and 4µg/mouse) and quinpirol (0.3, 1 and 3µg/mouse). The results indicate that the maximum restoration effect of quinpirol is higher than SKF38393, which is may be due to their different signaling pathways. In addition, co-pretreatment of different doses of SCH 23390 and sulpiride with lower dose of ketamine (5 mg/kg), which did not induce amnesia by itself, caused inhibition of memory formation. Given the evidence implicating the important role of NMDA receptors within the basolateral complex and central nucleus of amygdala in development and expression of fear-motivated tests (Fendt, 2001; Izquierdo et al., 1999; Jellestad and Bakke, 1985; Zimmerman et al., 2007), we can suggest that modulation of glutamatergic projection from mPFC to the amygdala by dopamine receptors may have a significant influence on passive avoidance learning. The present results confirm and extend previous findings reported by others using electrophysiological techniques suggesting an involvement of the mPFC dopamine receptors in the regulation of glutamatergic neurons. For example, it has been shown that SKF38393 increased cell
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excitability of pyramidal neurons in the PFC and D1 antagonist, SCH23390, blocked this effect (Wang and O'Donnell, 2001). Chen et al. also reported that application of the D1 receptor agonist SKF81297 caused a prominent increase of the steady-state NMDA evoked current in the PFC pyramidal neurons by the activation of PKC in the postsynaptic neurons (Chen et al., 2004). However, there is findings suggest that ketamine may disrupt dopaminergic neurotransmission in the PFC as well as cognitive functions associated with this region through the non-NMDA glutamate receptors (Moghaddam et al., 1997). The overall nature of a DA modulation of glutamatergic transmission is still a matter of controversy, with evidence supporting both positive and negative interactions. Levine et al. reported that such interactions may depend on the receptor subtype involved for each transmitter; for example, D2 receptor typically decreased non-NMDA responses, whereas D1 receptors enhanced NMDA responses (Levine et al., 1996a; Levine et al., 1996b). On the other hand, it has been revealed that dopamine modulation of glutamatergic synaptic transmission involves multiple cellular mechanisms including activation of GABAergic interneurons and postsynaptic signaling cascades (Seamans et al., 2001). Electrophysiological evidence showed that activation of both D1 and D2 receptors could result in the excitatory effect on pyramidal projection neurons. Postsynaptical effect of D1 receptors in the excitatory circuits and presynaptical action of D2 receptors in the inhibitory circuits act cooperatively to drive a Hebbian synaptic plasticity in the PFC. (Xu and Yao, 2010). Dopamine is known to modulate GABA release in multiple brain regions such as PFC through the activation of D2 receptors (Rao et al., 2000; Seamans et al., 2001). Thus, the possible mechanism of our findings in this study for the inhibition of ketamine-induced amnesia by D2 receptor agonist, quinpirol, may be through the disinhibitory action of D2 receptors on the mPFC projection neurons, which leads to increase in the neuronal activity and excessive glutamate and dopamine release in the prefrontal cortex and limbic striatal regions. Therefore, D1 receptor agonists mediate the activation of mPFC glutamatergic projection and D2 receptor agonists suppress local GABAergic interneurons, gating the induction of LTP in the pyramidal neuron.
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In conclusion, the current study demonstrated the involvement of intra-mPFC D1/D2 receptors in the actions of ketamine on memory processing in rats using the passive avoidance task. Our findings demonstrate that increasing or decreasing dopamine neurotransmission by dopaminergic agents potentiates or attenuates ketamine-induced amnesia in this model of cognition. These data provide support to the notion that there is possible interaction between the NMDA and dopaminergic systems in behavioral and cognitive responses by showing such interaction in the mPFC on memory retention in this experimental model. However, future molecular and neurochemical studies are necessary to identify the involvement of mPFC dopaminergic neurons in the effect of NMDA receptors on memory processing.
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Legends Fig. 1. Location of the injection cannulae tips in the mPFC regions, verified according to atlas of Paxinos (Paxinos and Watson, 1982), for all mice included in the data analyses. Fig. 2. The effects of pre-training administration of ketamine on the step down latencies in mice. The animals were trained 15 min after either saline (10 ml/kg, i.p.) or ketamine (5, 10 and 15 mg/kg, i.p.) administration and were tested 24h later. Each value represents the median and quartile of 10 animals. **P<0.01 and ***P<0.001, compared to the control group. Fig. 3. The effects of pre-training administration of different doses of SKF38393 with or without ketamine on the step down latencies. All animals received saline (0.3 μl/mouse, intra-mPFC) or SKF38393 (1, 2 and 4 μg/mouse, intra-mPFC) with or without ketamine (15 mg/kg, i.p.) 15 min before training. Each value represents the median and quartile of 10 animals. *P<0.05 and ***P<0.001, compared with the respective control group. +++ P<0.001 compared with the corresponding value of SKF38393/saline group. Fig. 4. The effects of pre-training administration of different doses of SCH 23390 with or without ketamine on the step down latencies. All animals received saline (0.3 μl/mouse, intra-mPFC) or SCH 23390 (0.25, 0.5, 0.75 and 1 μg/mouse, intra-mPFC) with or without ketamine (5 mg/kg, i.p.) 15 min before training. Each value represents the median and quartile of 10 animals. *P<0.05, **P<0.01 and
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***P<0.001, compared with the respective control group. + P<0.05 compared with the corresponding value of SCH 23390/saline group. Fig.5. The effects of pre-training administration of different doses of quinpirol with or without ketamine on the step down latencies. All animals received saline (0.3 μl/mouse, intra-mPFC) or quinpirol (0.1, 0.3, 1 and 3 μg/mouse, intra-mPFC)with or without ketamine (15 mg/kg, i.p.) 15 min before training. Each value represents the median and quartile of 10 animals. ***P<0.001, compared with the respective control group. +++ P<0.001 compared with the corresponding value of quinpirol/saline group. Fig. 6. The effects of pre-training administration of different doses of sulpiride with or without ketamine on the step down latencies. All animals received saline (0.3 μl/mouse, intra-mPFC) or Sulpiride (0.1, 0.3, 1 and 3 μg/mouse, intra-mPFC) with or without ketamine (5 mg/kg, i.p.) 15 min before training. Each value represents the median and quartile of 10 animals. *P<0.05, **P<0.01 and ***P<0.001, compared with the respective control. + P<0.05 compared with the corresponding value of sulpiride /saline group.
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PII: DOI: Reference:
S0014-2999(16)30199-6 http://dx.doi.org/10.1016/j.ejphar.2016.03.060 EJP70562
To appear in: European Journal of Pharmacology Received date: 25 June 2015 Revised date: 26 March 2016 Accepted date: 31 March 2016 Cite this article as: Maryam Farahmandfar, Atefeh Bakhtazad, Ardeshir Akbarabadi and Mohammad-Reza Zarrindast, The influence of dopaminergic system in medial prefrontal cortex on ketamine-induced amnesia in passive avoidance task in mice, European Journal of Pharmacology, http://dx.doi.org/10.1016/j.ejphar.2016.03.060 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
The influence of dopaminergic system in medial prefrontal cortex on ketamine-induced amnesia in passive avoidance task in mice Maryam Farahmandfar1,2, Atefeh bakhtazad1,2, Ardeshir Akbarabadi2,3, Mohammad-Reza Zarrindast1,2,4,5,6* 1
Department of Neuroscience, School of Advanced Medical Technologies, Tehran University of Medical Sciences, Tehran, Iran 2
Iranian National Center for Addiction Studies, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran 3
Department of Basic Sciences, Faculty of Veterinary Medicine, Islamic Azad University, Garmsar branch, Semnan, Iran 4
Department of Pharmacology, Tehran University of Medical Sciences, Tehran, Iran
5
Institute for Cognitive Science Studies (ICSS), Tehran, Iran
6
School of Cognitive Sciences, Institute for Research in Fundamental Sciences (IPM), Tehran, Iran
*
Corresponding author at: Department of Pharmacology, Tehran University of Medical Sciences,
Tehran, Iran P.O. Box: 13145784. Tel./Fax: +98 21 66402569. [email protected]
Abstract Dopaminergic modulations of glutamate receptors are essential for the prefrontal cortical (PFC) behavioral and cognitive functions. In order to understand the effect of dopamine/glutamate interactions on learning and memory, we investigated the effects of intra medial prefrontal cortex (mPFC) injections of dopaminergic agents on ketamine-induced amnesia by using a one-trial passive avoidance task in mice. Pre-training administration of ketamine (5, 10 and 15 mg/kg, i.p.) dosedependently decreased the memory acquisition of a one-trial passive avoidance task. Pre-training intra-mPFC administration of SKF 38393, D1 receptor agonist and quinpirol D2 receptor agonist, alone did not affect memory acquisition. However, amnesia induced by pre-training ketamine (15 mg/kg) significantly decreased by pretreatment of SKF 38393 (2 and 4µg/mouse) and quinpirol (0.3, 1 and
1
3µg/mouse). Pre-training administration of SCH 23390, D1 receptor antagonist (0.75 and 1 μg/mouse, intra-mPFC), and sulpiride D2 receptor antagonist (3 μg/mouse, intra-mPFC) impaired memory acquisition. In addition, co-pretreatment of different doses of SCH 23390 and sulpiride with lower dose of ketamine (5 mg/kg), which did not induce amnesia by itself, caused inhibition of memory formation. It may be concluded that dopaminergic system of medial prefrontal cortex is involved in the ketamine-induced impairment of memory acquisition.
Keywords: Ketamine; Dopaminergic system; Medial prefrontal cortex; Passive avoidance; Mice
1. Introduction Glutamate N-methyl-D-aspartate (NMDA) receptors, plays an important role in the induction, maintenance and expression of synaptic plasticity associated with the mechanisms of learning and memory (Anis et al., 1983). Ketamine is the non-competitive antagonist of NMDA receptor and one of the most commonly used medicine to produce a dose-related state of unconsciousness and analgesia for painful procedures (Leung et al., 2001; Tverskoy et al., 1996). However, the studies of its impact on learning and memory have always been a clinical concern. Studies have revealed that acute and repeated injection of ketamine and other NMDA-antagonists have an impairing effect on learning and memory in different paradigms such as y-maze discrimination (Peng et al.), active or passive avoidance (Getova and Doncheva) and water maze tasks (Liu et al., 2014; Moosavi et al., 2012) in mice and rats. These studies reported that different stages of memory formation including encoding, consolidation, and retention could be affected by ketamine (Goulart et al., 2010; Moosavi et al., 2012). Furthermore, the exact mechanisms and neurotransmitter circuits involved in ketamine-induced amnesia have yet to be elucidated. There is some evidence indicated that Ketamine-induced cognitive effects are associated with the functional alteration of many neurotansmitter systems at different brain regions such as ventral tegmental area, the basolateral amygdala (BLA), hippocampus and prefrontal
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cortex (Duncan et al., 1998a; Gao et al., 1998; Goulart et al., 2010). It has been demonstrated that subanesthetic doses of ketamine impair prefrontal cortex (PFC) function in the rat and produce symptoms in humans similar to those observed in schizophrenia and dissociative states, including impaired performance of frontal lobe-sensitive tests and cognitions (Duncan et al., 1998b; Moghaddam et al., 1997). The medial prefrontal cortex (mPFC) is a part of the prefrontal cortex, which has been associated with diverse functions including attentional processes, visceromotor activity, decision making, goal directed behavior, and long term memory (Hoover and Vertes, 2007; Vertes, 2004). One of the neurotransmitter that may play an important role in mPFC function is the excitatory amino acidcontaining neurons (Akbarian et al., 1996; Deakin et al., 1989). Neuronal population of mPFC receive widespread inputs from cortical and subcortical areas involved in sensorimotor and limbic functions (Hoover and Vertes, 2007). The integration of these glutamatergic inputs is essential for the mPFC role in executive functions and regulation of learning and memory (Getova and Doncheva, 2011). Morphological and biochemical studies have indicated a close interaction between excitatory amino acid and dopamine afferents in the PFC (Verma and Moghaddam, 1996). mPFC dopamine (DA) signaling has been involved in cognitive, emotional and motivational processes. Dopamine depletion in PFC results in impaired performances in PFC cognitive tasks, and these deficits can be ameliorated by the mixed dopamine receptor agonist apomorphine (Verma and Moghaddam, 1996). The ventral tegmental area (VTA) is the primary source of DA afferents to the mPFC (Hoover and Vertes, 2007). These projections are activated by aversive stimuli and it has been shown that different kinds of aversive experiences increase DA levels within this cortex (Hondo et al., 1994). Interaction of glutamatergic and dopaminergic systems have been extensively described for some of behavioral responses such as locomotor activity (Serrano et al., 2002) and cognitive functions (Alexander et al., 1990; David, 2009; Garside et al., 1996). Although it has been suggested that learning and memory are critically affected by dopaminergic transmission in mPFC (Babaei et al., 2011; Bassareo and Di Chiara, 1997; Phillips et al., 2004), there is no study investigating the role of
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dopamine receptors in this area on the modulation of learning and memory induced by NMDA receptor antagonists. In the present study, we examined the influence of pretreatment of dopaminergic agents in the medial prefrontal cortex on ketamine-induced amnesia in mice by using a one-trial passive avoidance task.
2. Materials and methods 2.1. Animals Male albino NMRI mice (Pasteur institute; Tehran, Iran) weighing 22–30 g were used. The animals were housed 10 per Plexiglas cage, in a room with controlled photoperiod (a 12-h light/dark cycle) and temperature (22±2 °C). They had food and water available ad lib and were allowed to adapt to the laboratory conditions for at least 1 week before the experiments. Each animal was used once only. All experimental procedures were in accordance with the NIH Guide for the Care and Use of Laboratory Animals.
2.2. Drugs The drugs used in the present study were Ketamine (Alfasan Inc., Utrecht, Holland), SKF38393 (1phenyl-7,8-dihydroxy-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride), SCH 23390 (R(_)-7chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride), quinpirole and sulpiride, (Sigma Chemical Co., St Louis, CA, USA). All drugs were dissolved in sterile 0.9% saline, just before the experiment, except for sulpiride that was dissolved in one drop of glacial acetic acid with Hamilton micro syringe. It was then made up to a volume of 5 ml with sterile 0.9% saline and then diluted to the required volume. Control animals received either saline or vehicle. The doses of the drugs were based on previous studies (Nasehi et al., 2013; Zarrindast et al., 2006).
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2.3. Cannula guide implantation Mice were anesthetized with intraperitoneal injection of ketamine hydrochloride (50 mg/kg) plus xylazine (5 mg/kg) and were placed in a stereotaxic apparatus. The skin was then incised and the skull was cleaned. 22-gauge guide cannulae were placed 1 mm above the intended site of injection according to the atlas of Paxinos (Paxinos and Watson, 1982). Stereotaxic coordinates for the mPFC region were AP: +2.1 mm from bregma and V: −1.7 mm from the skull surface. The cannulae were secured with dental acrylic. Stainless steel stylets (27-gauge) were inserted into the guide cannulae to keep them free of debris. All animals were allowed 1 week to recover from the surgery and from the effect of the anesthetic agents.
2.4. Intra-mPFC injections For drug infusion, the animals were gently restrained by hand. The stylets were removed from the guide cannulae and replaced by 27-gauge injection needles (1 mm below the tip of the guide cannulae). The injection solutions were manually administered in a total volume of 0.3 μl/mice over a 60 s period. Injection needles were left in place for an additional 60 s to facilitate the diffusion of the drugs.
2.5. Apparatus The passive avoidance apparatus consisted of a wooden box (30×30×40 cm high) with a steel-rod floor (29 parallel rods, 0.3 cm in diameter, set 1 cm apart). A wooden platform (4×4×4 cm) was set in the center of the grid floor. Intermittent electric shocks (1 Hz, 0.5 s, 40 V DC) were delivered to the grid floor by an insulated stimulator (Grass S44, USA).
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2.6. Training A single-trial step-down passive avoidance task was used. Each mouse was gently placed on the wooden platform. When the mouse stepped down from the platform and placed all its paws on the grid floor, intermittent electric shocks were delivered continuously for 15 s. This training procedure was carried out between 10:00 and 15:00 h. Each mouse was placed on the platform again at 24 h after training and the step-down latency was measured with a stopwatch as passive avoidance behavior. An upper cut-off time of 300 s was set. The criterion for the retention test was for the mouse to place all 4 paws on the grid floor, as for training. The retention test was also carried out between 10:00 and 15:00 h.
2.7. Histology After testing sessions, each mouse was deeply anesthetized and 0.3 μl of a 4% methylene-blue solution was infused into the mPFC as described in the drug section; the mouse was then decapitated and its brain was removed and placed in formaldehyde (10%). After several days, the brains were sliced and the site of injection were verified according to atlas of Paxinos (Fig 1) (Paxinos and Watson, 1982).
2.8. Drug treatment Ten animals were used in each experimental group. The intervals of drug administration were based on previous studies in order to obtain a maximum response.
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2.8.1. Experiment 1: effect of ketamine on memory acquisition The experiment examined the effects of intraperitoneal (i.p.) administration of different doses of ketamine on memory acquisition. Four groups of animal received pre-training administration of saline (10 ml/kg, i.p.) or ketamine (5, 10 and 15 mg/kg, i.p.) 15 min before training. Retention test was done 24h after training.
2.8.2. Experiment 2: effects of SKF38393 on memory acquisition in the presence or absence of ketamine In this experiment, eight groups of animals were used. Four groups of animals were pretreated with either saline (0.3 μl/mouse, intra- mPFC) or SKF38393 (1, 2 and 4 μg/mouse, intra-mPFC) and, after 5 min, they received saline (10 ml/kg, i.p.) 15 min before training (Fig. 2, left panel). The other four groups of animals received intra-mPFC injections of saline (0.3 μl/mouse, intra- mPFC) or SKF38393 (1, 2 and 4 μg/mouse, intramPFC) and, after 5 min, they were injected with ketamine (15 mg/kg, i.p.) 15 min before training, (Fig. 2,right panel).
2.8.3. Experiment 3: effects of SCH 23390 on memory acquisition in the presence or absence of ketamine In this experiment, ten groups of animals were used. Five groups of animals were pretreated with either saline (0.3 μl/mouse, intra- mPFC) or SCH 23390 (0.25, 0.5, 0.75 and 1 μg/mouse, intra-mPFC) and, after 5 min, they received saline (10 ml/kg, i.p.) 15 min before training (Fig. 3, left panel). The other five groups of animals received intra-mPFC injections of saline (0.3 μl/mouse, intra- mPFC) or
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SCH 23390 (0.25, 0.5, 0.75 and 1 μg/mouse, intra-mPFC) and, after 5 min, they were injected with ketamine (5 mg/kg, i.p.) 15 min before training, (Fig. 3,right panel).
2.8.4. Experiment 4: effects of Quinpirol on memory acquisition in the presence or absence of ketamine In this experiment, ten groups of animals were used. Five groups of animals were pretreated with either saline (0.3 μl/mouse, intra- mPFC) or Quinpirol (0.1, 0.3, 1 and 3 μg/mice, intra-mPFC) and, after 5 min, they received saline (10 ml/kg, i.p.) 15 min before training (Fig. 4, left panel). The other five groups of animals received intra-mPFC injections of saline (0.3 μl/mouse, intra- mPFC) or Quinpirol (0.1, 0.3, 1 and 3 μg/mice, intra-mPFC) and, after 5 min, they were injected with ketamine (15 mg/kg, i.p.) 15 min before training, (Fig. 4,right panel).
2.8.5. Experiment 5: effects of Sulpiride on memory acquisition in the presence or absence of ketamine In this experiment, ten groups of animals were used. Five groups of animals were pretreated with either saline (0.3 μl/mouse, intra- mPFC) or Sulpiride (0.1, 0.3, 1 and 3 μg/mice, intra-mPFC) and, after 5 min, they received saline (10 ml/kg, i.p.) 15 min before training (Fig. 5, left panel). The other five groups of animals received intra-mPFC injections of saline (0.3 μl/mouse, intra- mPFC) or Sulpiride (0.1, 0.3, 1 and 3 μg/mice, intra-mPFC)and, after 5 min, they were injected with ketamine (5 mg/kg, i.p.) 15 min before training, (Fig. 3,right panel).
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2.9. Statistical analysis Data are expressed as the median and 95% confidence intervals. As step-down latency did not follow a normal distribution, these data were analyzed 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 used for paired comparisons when appropriate.The criterion for statistical significance was P<0.05. Calculations were performed using the SPSS statistical package.
3. Results 3.1. Effects of pre-training ketamine administration on memory acquisition Fig. 2 shows the effects of pre-training administration of ketamine on step-down latency. Kruskal– Wallis ANOVA (H (3) =12.6, P<0. 01) reveals pre-training administration of ketamine (5, 10 and 15 mg/kg, i.p.) dose-dependently reduced the step-down latency in the one-trial passive avoidance task. Post hoc analysis by Mann–Whitney's U-test indicates ketamine (10 and 15 mg/kg) impaired memory acquisition, thus showing an amnesic effect.
3.2. Effects of SKF38393 on memory acquisition in the presence or absence of ketamine Fig. 3 (left panel) shows that intra- mPFC pre-training administration of different doses of SKF38393 (1, 2 and 4 μg/mouse, intra-mPFC), had no effect on memory acquisition [Kruskal–Wallis ANOVA, H (3) =2.74, P>0.05].
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Moreover, Fig. 3 (right panel) indicates that intra- mPFC pre-training administration of the SKF38393 affects ketamine-induced amnesia [Kruskal–Wallis ANOVA, H (3) =4.5, P<0.05]. Mann–Whitney's U-test analysis reveals the agonist doses of 2 and 4 μg/mouse induced full recovery of the memory impairment caused by ketamine (15 mg/kg).
3.3. Effects of SCH 23390 on memory acquisition in the presence or absence of
ketamine Fig. 4 (left panel) shows the effects of intra- mPFC pre-training administration of SCH 23390 on memory acquisition. Kruskal–Wallis ANOVA revealed that pre-training SCH 23390 (0.25, 0.5, 0.75 and 1 μg/mouse, intra-mPFC) dose-dependently suppressed the learning of a one-trial passive avoidance task [H (4) =11.77, P<0.05]. Further analysis with the Mann–Whitney U-test showed that pre-training SCH 23390 (0.75 μg/mouse, P<0.05 and 1 μg/mouse, P<0. 01) impaired the retention latency as compared to the saline control group. In addition, as shown in Fig. 4 (right panel), copretreatment of different doses of SCH 23390 (0.25, 0.5, 0.75 and 1 μg/mouse, intra-mPFC) and 5 mg/kg of ketamine, which alone did not induce amnesia, inhibited memory acquisition and induced amnesia [Kruskal–Wallis ANOVA, H(4) = 20.91, P<0.001].
3.4. Effects of Quinpirol on memory acquisition in the presence or absence of
ketamine As shown in Fig. 5 (left panel), intra- mPFC pre-training administration of different doses of Quinpirol (0.1, 0.3, 1 and 3 μg/mouse, intra-mPFC), had no effect on memory acquisition [Kruskal–Wallis ANOVA, H (4) =0.59, P>0.05].
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Moreover, Fig. 5 (right panel) indicates that intra- mPFC pre-training administration of the Quinpirol affects ketamine-induced amnesia [Kruskal–Wallis ANOVA, H (4) =22.75, P<0.001]. Mann–Whitney's U-test analysis reveals the agonist doses of 0.3, 1 and 3 μg/mouse (P<0.001) induced full recovery of the memory impairment caused by ketamine (15 mg/kg).
3.5. Effects of Sulpiride on memory acquisition in the presence or absence of ketamine Fig. 65 (left panel) shows the effects of intra- mPFC pre-training administration of Sulpiride on memory acquisition. Kruskal–Wallis ANOVA revealed that pre-training Sulpiride (0.1, 0.3, 1 and 3 μg/mouse, intra-mPFC) suppressed the learning of a one-trial passive avoidance task [H(4)=10.35, P<0.05]. Further analysis with the Mann–Whitney U-test showed that pre-training Sulpiride (3 μg/mouse, P<0. 01) impaired the retention latency as compared to the saline control group. In addition, as shown in Fig. 6 (right panel), co-pretreatment of different doses of Sulpiride (0.1, 0.3, 1 and 3 μg/mouse, intra-mPFC) and 5 mg/kg of ketamine, which alone did not induce amnesia, inhibited memory acquisition and induced amnesia [Kruskal–Wallis ANOVA, H(4) = 17.23, P<0.01].
4. Discussion In the present experiments, the role of D1 and D2 dopaminergic receptors in medial prefrontal cortex on the inhibitory memory acquisition was investigated in the presence or absence of ketamine by using passive avoidance task. Previous behavioral studies have documented a number of diverse effects for ketamine such as agitation, hallucinations, anxiety and cognitive problems including
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memory loss, impairments in encoding and processing of information in the episodic memory (Getova and Doncheva, 2011; Malhotra et al., 1997; Newcomer et al., 1999; Olney et al., 1999). Our present experiments showed that pre-training administration of ketamine (10 and 15 mg/kg, i.p.) dose-dependently suppressed the learning of a one-trial passive avoidance task. These results are in line with the previous reports in which pre-training systemic administration of ketamine induce amnesia in various memory paradigms (Imre et al., 2006; Kos et al., 2006; Moosavi et al., 2012; Uchihashi et al., 1994). NMDA receptors are hypothesized to play a crucial role in the induction of synaptic plasticity and encoding or consolidation of long-term memories (Bliss and Collingridge, 1993; Collingridge and Bliss, 1995). On the other hand, recent clinical trials with ketamine, have demonstrated that subanesthetic doses of this drug exacerbate preexisting symptoms of schizophrenia (Lahti et al., 1995). In healthy individuals, ketamine also can produce behaviors that are similar to a broad range of symptoms associated with schizophrenia, including impaired performance in psychological tests sensitive to PFC function (Ghoneim et al., 1985; Oye et al., 1992). It has been suggested that mPFC has important role in memory including working memory, information processing, short-term memory and object recognition (Hoover and Vertes, 2007; Leon et al., 2010). Numerous studies showed that precise regulation of excitatory glutamatergic neurotransmission within the mPFC is essential for various forms of memory formation, and glutamatergic dysfunction is believed to contribute to the impairment of learning and memory (Akbarian et al., 1996; Verma and Moghaddam, 1996). Although the importance of PFC glutamatergic NMDA receptors in cognitive functions is widely recognized, several lines of evidence have highlighted the need of dopamine– glutamate coactivation for a number of PFC functions (Angrist and Gershon, 1974; Garside et al., 1996; Matthysse, 1973). The role of dopamine transmission in the prefrontal cortex during learning and memory has been the focus of interest in many neurochemical and behavioral studies (Babaei et al., 2011; Carr and Sesack, 2000a; Rinaldi et al., 2007). Midbrain dopaminergic neurons send afferents to many target areas, including the several regions of the prefrontal cortex. Dopamine exerts
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its actions within the PFC via receptors grouped into major families, D1-like and D2-like receptors (Carr and Sesack, 2000b; Hoover and Vertes, 2007). Our data in this study indicated that intra-mPFC pre-training administration of SKF 38393, D1 receptor agonist or quinpirol D2 receptor agonist, alone did not affect memory acquisition in passive avoidance task. However, microinjections of the dopamine D1 receptor antagonist, SCH 23390, or the dopamine D2 receptor antagonist, sulpiride into the mPFC significantly decreased memory acquisition. In agreement with our findings, Ichihara, et al reported that systemic low dose administration of SCH23390 or sulpiride impaired the passive avoidance response in mice only when it was given before the training (Ichihara et al., 1992). Impairing effect of both D1 and D2 receptor antagonists have also been reported in spatial and working memory performance in monkeys and rodents (Floresco and Magyar, 2006; Puig et al., 2014; Seamans et al., 1998). On the contrary, Druzin et al. reported that intra-PFC infusions of a D2 receptor agonist disrupt performance of rats in a delayed-response learning task and that this D2 receptors modulation of WM may be linear (i.e., lower/higher levels of D2 receptors activation are associated with better/poorer performance) (Druzin et al., 2000). Another study also found that intra-PFC infusions of a D1 receptor antagonist, but not a D2 receptor antagonist, could disrupt performance in the water maze performance (Arnsten and Pliszka, 2011). Compelling evidence suggest that aversive learning responses (inhibitory avoidance task) engages different brain circuitry than reward-based learning task (Yang and Liang, 2014), suggesting that memory processing could differ between tasks. Also, distinct experimental procedures such as time of drug administration (before vs. after training) or intrinsic characteristics of the tasks (multi-trial vs. single trial) could explain the differences observed (Gonzalez et al., 2014). For example, it has been demonstrated that the mPFC behaves as a rapid learning node within a neural network, necessary to the acquisition, consolidation and retrieval phases of single trial inhibitory avoidance memory but the role of mPFC in multi-trial reward related working memory is limited to the retrieval phase
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(Gonzalez et al., 2013). The exact mechanisms of mPFC dopamine modulation of different kinds of learning and memory processes are still unclear. In mPFC, dopaminergic terminals arising from the ventral tegmental area (VTA) make synaptic contacts with prefrontal pyramidal glutamatergic neurons and GABA interneurons (Carr and Sesack, 2000a; Hoover and Vertes, 2007). It has been hypothesized that many cognitive function of mPFC including arousal, attention, motivation and working memory can be modulated by the interaction of these neurotransmitter systems (Tseng and O'Donnell, 2004). Although many investigations demonstrated that direct and indirect connections of the amygdala and hippocampus to the medial prefrontal cortex may play an important role in learning and memory (Kim et al., 2011; Shin et al., 2006), the role of dopaminergic and glutamatergic interactions of these areas in the hippocampus or amygdala dependent memory needs to be more elucidated. Our result showed that amnesia induced by pre-training ketamine (15 mg/kg) significantly decreased by pretreatment of SKF 38393 (2 and 4µg/mouse) and quinpirol (0.3, 1 and 3µg/mouse). The results indicate that the maximum restoration effect of quinpirol is higher than SKF38393, which is may be due to their different signaling pathways. In addition, co-pretreatment of different doses of SCH 23390 and sulpiride with lower dose of ketamine (5 mg/kg), which did not induce amnesia by itself, caused inhibition of memory formation. Given the evidence implicating the important role of NMDA receptors within the basolateral complex and central nucleus of amygdala in development and expression of fear-motivated tests (Fendt, 2001; Izquierdo et al., 1999; Jellestad and Bakke, 1985; Zimmerman et al., 2007), we can suggest that modulation of glutamatergic projection from mPFC to the amygdala by dopamine receptors may have a significant influence on passive avoidance learning. The present results confirm and extend previous findings reported by others using electrophysiological techniques suggesting an involvement of the mPFC dopamine receptors in the regulation of glutamatergic neurons. For example, it has been shown that SKF38393 increased cell
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excitability of pyramidal neurons in the PFC and D1 antagonist, SCH23390, blocked this effect (Wang and O'Donnell, 2001). Chen et al. also reported that application of the D1 receptor agonist SKF81297 caused a prominent increase of the steady-state NMDA evoked current in the PFC pyramidal neurons by the activation of PKC in the postsynaptic neurons (Chen et al., 2004). However, there is findings suggest that ketamine may disrupt dopaminergic neurotransmission in the PFC as well as cognitive functions associated with this region through the non-NMDA glutamate receptors (Moghaddam et al., 1997). The overall nature of a DA modulation of glutamatergic transmission is still a matter of controversy, with evidence supporting both positive and negative interactions. Levine et al. reported that such interactions may depend on the receptor subtype involved for each transmitter; for example, D2 receptor typically decreased non-NMDA responses, whereas D1 receptors enhanced NMDA responses (Levine et al., 1996a; Levine et al., 1996b). On the other hand, it has been revealed that dopamine modulation of glutamatergic synaptic transmission involves multiple cellular mechanisms including activation of GABAergic interneurons and postsynaptic signaling cascades (Seamans et al., 2001). Electrophysiological evidence showed that activation of both D1 and D2 receptors could result in the excitatory effect on pyramidal projection neurons. Postsynaptical effect of D1 receptors in the excitatory circuits and presynaptical action of D2 receptors in the inhibitory circuits act cooperatively to drive a Hebbian synaptic plasticity in the PFC. (Xu and Yao, 2010). Dopamine is known to modulate GABA release in multiple brain regions such as PFC through the activation of D2 receptors (Rao et al., 2000; Seamans et al., 2001). Thus, the possible mechanism of our findings in this study for the inhibition of ketamine-induced amnesia by D2 receptor agonist, quinpirol, may be through the disinhibitory action of D2 receptors on the mPFC projection neurons, which leads to increase in the neuronal activity and excessive glutamate and dopamine release in the prefrontal cortex and limbic striatal regions. Therefore, D1 receptor agonists mediate the activation of mPFC glutamatergic projection and D2 receptor agonists suppress local GABAergic interneurons, gating the induction of LTP in the pyramidal neuron.
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In conclusion, the current study demonstrated the involvement of intra-mPFC D1/D2 receptors in the actions of ketamine on memory processing in rats using the passive avoidance task. Our findings demonstrate that increasing or decreasing dopamine neurotransmission by dopaminergic agents potentiates or attenuates ketamine-induced amnesia in this model of cognition. These data provide support to the notion that there is possible interaction between the NMDA and dopaminergic systems in behavioral and cognitive responses by showing such interaction in the mPFC on memory retention in this experimental model. However, future molecular and neurochemical studies are necessary to identify the involvement of mPFC dopaminergic neurons in the effect of NMDA receptors on memory processing.
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Legends Fig. 1. Location of the injection cannulae tips in the mPFC regions, verified according to atlas of Paxinos (Paxinos and Watson, 1982), for all mice included in the data analyses. Fig. 2. The effects of pre-training administration of ketamine on the step down latencies in mice. The animals were trained 15 min after either saline (10 ml/kg, i.p.) or ketamine (5, 10 and 15 mg/kg, i.p.) administration and were tested 24h later. Each value represents the median and quartile of 10 animals. **P<0.01 and ***P<0.001, compared to the control group. Fig. 3. The effects of pre-training administration of different doses of SKF38393 with or without ketamine on the step down latencies. All animals received saline (0.3 μl/mouse, intra-mPFC) or SKF38393 (1, 2 and 4 μg/mouse, intra-mPFC) with or without ketamine (15 mg/kg, i.p.) 15 min before training. Each value represents the median and quartile of 10 animals. *P<0.05 and ***P<0.001, compared with the respective control group. +++ P<0.001 compared with the corresponding value of SKF38393/saline group. Fig. 4. The effects of pre-training administration of different doses of SCH 23390 with or without ketamine on the step down latencies. All animals received saline (0.3 μl/mouse, intra-mPFC) or SCH 23390 (0.25, 0.5, 0.75 and 1 μg/mouse, intra-mPFC) with or without ketamine (5 mg/kg, i.p.) 15 min before training. Each value represents the median and quartile of 10 animals. *P<0.05, **P<0.01 and
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***P<0.001, compared with the respective control group. + P<0.05 compared with the corresponding value of SCH 23390/saline group. Fig.5. The effects of pre-training administration of different doses of quinpirol with or without ketamine on the step down latencies. All animals received saline (0.3 μl/mouse, intra-mPFC) or quinpirol (0.1, 0.3, 1 and 3 μg/mouse, intra-mPFC)with or without ketamine (15 mg/kg, i.p.) 15 min before training. Each value represents the median and quartile of 10 animals. ***P<0.001, compared with the respective control group. +++ P<0.001 compared with the corresponding value of quinpirol/saline group. Fig. 6. The effects of pre-training administration of different doses of sulpiride with or without ketamine on the step down latencies. All animals received saline (0.3 μl/mouse, intra-mPFC) or Sulpiride (0.1, 0.3, 1 and 3 μg/mouse, intra-mPFC) with or without ketamine (5 mg/kg, i.p.) 15 min before training. Each value represents the median and quartile of 10 animals. *P<0.05, **P<0.01 and ***P<0.001, compared with the respective control. + P<0.05 compared with the corresponding value of sulpiride /saline group.
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