The Melatonergic System in Anxiety Disorders and the Role of Melatonin in Conditional Fear

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The Melatonergic System in Anxiety Disorders and the Role of Melatonin in Conditional Fear F. Huang*,1, Z. Yang*, C.-Q. Li† *Yiyang Medical College, Yiyang, Hunan, PR China † School of Basic Medical Sciences, Central South University, Changsha, Hunan, PR China 1 Corresponding author: e-mail address: [email protected]

Contents 1. 2. 3. 4.

Introduction Anxiety and Melatonergic System PTSD and Pavlovian Fear Conditioning and Extinction Methods 4.1 Contextual Fear Conditioning and Test 4.2 Cued Fear Acquisition 4.3 Cued Fear Extinction 5. Results 5.1 Melatonin Impaired Contextual Fear Conditioning and Did Not Affect Fear Expression in Rats 5.2 Melatonin Had no Effect on the Acquisition and Retention of Conditional Cued Fear Response 5.3 Preextinction Injection of Melatonin Facilitated the Acquisition and Retention of Cued Fear Extinction 6. Discussion Acknowledgments References

282 282 285 286 286 287 287 288 288 288 288 289 290 291

Abstract Background: Resistance to extinction of certain conditioned responses forms the basis of anxieties, phobias, and compulsions. There has been an available effective means of extinction-based exposure psychotherapy for the treatment of anxiety disorders, such as posttraumatic stress disorder (PTSD) that has been hypothesized to result from impaired extinction of fear memory. PTSD is considered as a memory disorder within a Pavlovian fear conditioning and extinction framework. Therefore, the aim of this review was to report the preclinical profile of melatonin, a pineal gland hormone, as a potential pharmacological option in the treatment of anxiety disorders such as PTSD, tested with the Pavlovian fear conditioning paradigm.

Vitamins and Hormones ISSN 0083-6729 http://dx.doi.org/10.1016/bs.vh.2016.09.003

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2016 Elsevier Inc. All rights reserved.

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Methods: We performed a literature review regarding studies that evaluated the effects of melatonin on fear conditioning and fear extinction. Results: Results showed that a single administration 30 min before conditioning has no effect on the acquisition of cued fear, but impaired contextual fear conditioning. Compared to rats injected with vehicle, rats injected with melatonin 30 min before extinction training presented a significant lower freezing during both extinction training and extinction test phases. However, melatonin injected immediately after extinction training was ineffective on extinction learning. Conclusion: Melatonin impaired contextual fear conditioning, a hippocampusdependent task. On the contrary, melatonin facilitates the extinction of conditional cued fear without affecting its acquisition or expression, and melatonin facilitates cued fear extinction only when it is present during extinction training. Although further studies are necessary, the research undertaken until now shows that melatonin modulates fear conditioning and fear extinction and consequently melatonin may serve as an agent for the treatment of PTSD.

1. INTRODUCTION Anxiety disorder (or generalized anxiety, as per DSM-IV) (American Psychiatric Association, 1994) is a chronic and disabling disorder with excessive, uncontrollable, and often irrational worry associated with physical symptoms, including fatigue, fidgeting, headaches, nausea, numbness, and sweating. Pathological anxiety may reflect a failure to extinguish conditioned fear. In anxiety disorders such as posttraumatic stress disorder (PTSD), this type of conditioned fear fails to extinguish, and individuals with PTSD reexperience the event for decades after danger has passed (Hayes, VanElzakker, & Shin, 2012). PTSD is a severe anxiety disorder suffered by approximately 10–30% of individuals who have experienced or witnessed a psychologically traumatic event (de Vries & Olff, 2009; Dohrenwend et al., 2006) such as sexual assault, combat, natural disaster, motor vehicle accident, or witnessing the death or serious injury of another individual. Treatments for PTSD and other anxiety disorders have focused on exposure therapy that involves repeated exposure to trauma-related cues (Hofmann, Sawyer, Korte, & Smits, 2009; Hofmann & Smits, 2008).

2. ANXIETY AND MELATONERGIC SYSTEM Studies involving the pharmacologic manipulation have been shown to be effective in the treatment of anxiety disorders, including benzodiazepines, selective serotonin reuptake inhibitors, serotonin noradrenaline

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reuptake inhibitors, tricyclic antidepressants, and pregabalin (Baldwin et al., 2014). However, use of these drugs can lead to side effects such as nausea, sexual dysfunction, dependence, and cognitive problems (Buoli, Caldiroli, Caletti, Paoli, & Altamura, 2013). For this reason, there is a growing interest in exploring new pharmacological approaches for the treatment of anxiety. Among these approaches, the melatonergic system has gained considerable attention. The neurohormone melatonin (N-acetyl-5-methoxytryptamine) is prominently synthesized in the pineal gland. Melatonin secretion into the bloodstream occurs primarily at night, with negligible levels secreted during the day, attaining peak concentrations of plasma melatonin between 02:00 and 04:00 h (Pandi-Perumal et al., 2008). This hormone plays an important role in the regulation of circadian and sleep–wake system, melatonin also has several pharmacological effects including sedative, antioxidant, anxiolytic, antidepressant, anticonvulsant, and analgesic activities (Mantovani et al., 2006; Reiter & Korkmaz, 2008). Effects of melatonin are mediated by the activation of two G protein coupled receptors, MT1 (Mel1a) and MT2 (Mel1b) (Reppert, Weaver, & Godson, 1996). The “MT3 receptor” is an enzyme, quinone reductase, and belongs to a group of reductases that participate in the protection against oxidative stress by preventing electron transfer reactions of quinones. Within the CNS, MT1 and MT2 receptors have been localized in the suprachiasmatic nucleus, the cortex, thalamus and cerebellar cortex, the hippocampus. MT1 receptors are also found in several other hypothalamic nuclei and brain areas, such as the caudate putamen, the nucleus accumbens, the substantia nigra, and the ventrotegmental area (Brunner et al., 2006; Dubocovich & Markowska, 2005; Wu et al., 2006). It has been demonstrated that melatonin and its analogs have anxiolytic properties in validated paradigms of anxiety behavior in animals: the tested animal models were the Vogel conflict procedure, the elevated plus-maze procedure (EPMT), the conditioned footshock-induced ultrasonic vocalizations test, the social interaction test, the plus-maze test, the cumulative burying behavior paradigm, hole board test, novelty suppressed feeding test (NSFT), and open field test (OFT) (Boulle et al., 2014; Bustamante-Garcı´a, Lira-Rocha, Espejo-Gonza´lez, Go´mez-Martı´nez, & Picazo, 2014; Golombek, Martini, & Cardinali, 1993; Golus & King, 1981; Millan, Brocco, Gobert, & Dekeyne, 2005; Ochoa-Sanchez et al., 2012; Papp, Litwa, Gruca, & Mocae¨r, 2006; Pierrefiche, Zerbib, & Laborit, 1993; Tian et al., 2010) (Table 1).

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Table 1 Summary of Anxiolytic Effects of Melatonin and Its Analogs in Animals Dosages Authors Animals Drugs (mg/kg) Animal Models Results

Golus and Rats King (1981)

Melatonin

1

Open field test (OFT)

Increased the activity within the central area of the OFT

Golombek Rats et al. (1993)

Melatonin

1

Elevated plusmaze test (EPMT)

Increased the time spent in the open arms of the EPMT

Millan et al. Rats (2005)

Agomelatine 2.5–80

Social interaction test Vogel conflict test Plus-maze test

Enhanced the time devoted to active social interaction Increased the punished responses Enhanced percentage entries into open arms

Papp et al. (2006)

Agomelatine 10–75

Vogel conflict test Conditioned footshockinduced ultrasonic vocalization test

Increased the number of punished responses Decreased vocalization time

Agomelatine 10–75 Melatonin 10–75

EPMT

Enhanced open arms Exploration

UCM765 Melatonin

EPMT Novelty suppressed feeding test (NSFT) OFT

Increased the time spent in the open arm of the EPMT Reduced the latency to eat in a novel environment Increased the activity within the central area of the OFT

Rats

OchoaRats Sanchez et al. (2012)

10 20

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Table 1 Summary of Anxiolytic Effects of Melatonin and Its Analogs in Animals—cont’d Dosages Authors Animals Drugs (mg/kg) Animal Models Results

Bustamante- Rats Garcı´a et al. (2014)

M3C Melatonin

0.5, 1.0, The cumulative Decreased in 2.0, 2.5 burying burying 2.0 Behavior Behavior paradigm

M3C Melatonin

2.0 and 2.5 2.0

Elevated plusmaze

Pierrefiche Mice et al. (1993)

Melatonin

0.5–5.0

Hole board test Decreased headUnconditioned dip performance conflict test Increased the time spent in the lit box as well as the number of transitions between the two compartments

Tian et al. (2010)

Neu-P11 Melatonin

50 50

EPMT

Mice

Increased the percentage of time spent on the open arms of the EPM

Increased the percentage of time spent in the open arms

Clinically, MLT has elicited anxiolytic effects (Caumo, Levandovski, & Hidalgo, 2009; Srinivasan et al., 2006). It has also been successfully used to facilitate the discontinuation of benzodiazepine therapy in elderly patients (Garfinkel, Zisapel, Wainstein, & Laudon, 1999) and to elicit anxiolytic effects in cataract surgery patients (Khezri & Merate, 2013). In addition, ramelteon and agomelatine, two nonselective MT1/MT2 receptor agonists have produced anxiolytic effects in humans (den Boer, Bosker, & Meesters, 2006; Gross, Nourse, & Wasser, 2009; Stein, Ahokas, & de Bodinat, 2008).

3. PTSD AND PAVLOVIAN FEAR CONDITIONING AND EXTINCTION There has been an available effective means of extinction-based exposure psychotherapy for the treatment of anxiety disorders, such as PTSD (Bentz, Michael, de Quervain, & Wilhelm, 2010; Rothbaum & Davis,

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2003) that has been hypothesized to result from impaired extinction of fear memory (Bremner et al., 2005; Milad, Rauch, Pitman, & Quirk, 2006). PTSD is considered as a memory disorder, within a Pavlovian fear conditioning and extinction framework (Jovanovic & Ressler, 2010; Shin & Handwerger, 2009). Pavlovian fear conditioning involves pairing an initially neutral conditioned stimulus (CS) such as a tone or context with an aversive unconditioned stimulus (US) like a footshock. After several pairings of these stimuli, the CS comes to elicit conditional fear responses such as defensive behavioral responses (e.g., freezing). After conditioning, repeated presentations of the CS in the absence of the US results in a progressive reduction of the conditioned response. This process is called extinction. Numerous studies have suggested that extinction is a form of new, context-dependent learning (Bouton, 1993; Bouton, Westbrook, Corcoran, & Maren, 2006). These studies suggest that the memory formed during conditioning is not eliminated during extinction but rather is suppressed by extinction learning, which likely attribute to plasticity at distinct synapses from those mediating acquisition. PTSD is associated with increased acquisition of fear conditioning and a failure to extinguish or maintain extinction of conditioned fear (VanElzakker, Dahlgren, Davis, Dubois, & Shin, 2014). Therefore, the aim of this literature review was to expose the studies conducted regarding fear learning and extinction with melatonin using the Pavlovian fear conditioning paradigm (Huang, Yang, Liu, & Li, 2014; Yang, Li, & Huang, 2013).

4. METHODS First, we examined the effects of systemic injections of melatonin with good penetration through the blood–brain barrier on contextual fear conditioning and fear expression in rats. Second, we examined the effects of melatonin administration on the acquisition, expression, and extinction of conditional cued fear in rats.

4.1 Contextual Fear Conditioning and Test The behavioral procedure involved three phases: habituation, fear conditioning, and testing. During habituation phase, rats were habituated to the conditioning chamber (CS) for 20 min with no stimuli presented. Twenty-four hours later (fear conditioning phase), rats received a 1 s 0.4 mA footshock (US) beginning 3 min after being placed in the

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chamber. The training session consisted of five of these conditioned and unconditioned stimulus (CS–US) pairings with an intertrial interval of 60 s. The rats remained in the training box for 60 s following the last CS–US pairing, after which they were returned to the home cages. Freezing was used as the measure of fear and is characterized by cessation of movement except that required for respiration (Blanchard & Blanchard, 1969). Freezing activity during intertrial interval was scored with a digital stopwatch from videotapes. Observers scoring freezing were blind to the treatments. Freezing is presented as the percent time spent freezing (time spent freezing/total time
100). Twenty-four hours after fear conditioning (testing phase), rats were placed in the original training chamber for 5 min without any shock, and freezing behavior was scored during the entire duration of context exposure.

4.2 Cued Fear Acquisition The behavioral procedure involved three phases: habituation (context A), fear conditioning (context A), and testing (context B), each separated by 24 h to allow for memory consolidation. During habituation phase (Day 0), rats were habituated to the conditioning chamber (context A) for 20 min with no stimuli presented. On day 1 (fear conditioning phase), rats were allowed to explore the chamber for 3 min. At the end of 3 min rats were subjected to five trials of audio tone (CS) and foot shock (US) with an intertrial interval of 60 s. Audio tone (4 kHz, 80 dB, 20 s duration) was followed immediately by a footshock (0.5 mA, 0.5 s duration) from the metal grid floor. The rats remained in the training box for 60 s following the last CS–US pairing, after which they were returned to the home cages. On day 2 (testing phase), after a 3 min acclimation, rats received five tone alone presentations with an intertrial interval of 60 s.

4.3 Cued Fear Extinction The behavioral procedure involved four phases: habituation (context A), fear conditioning (context A), extinction training (context B), and extinction test (context B), each separated by 24 h to allow for memory consolidation. In both experiments, cued fear was induced in nondrugged, naı¨ve rats described earlier. Rats were matched into two groups that received either melatonin or vehicle based on freezing scores during fear conditioning. Twenty-four hours after fear conditioning (day 2, extinction training phase), rats were placed in context B and were allowed to acclimate for

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3 min. Following this, rats received 14 tone (4 kHz, 80 dB, 20 s duration) alone presentations with an intertrial interval of 60 s. The rats were immediately returned to their home cages 60 s after the last tone presentation. On day 3 (extinction test phase), rats received 14 tone alone presentations in context B as described on day 2.

5. RESULTS 5.1 Melatonin Impaired Contextual Fear Conditioning and Did Not Affect Fear Expression in Rats Melatonin or vehicle was injected intraperitoneally (i.p.) at dose of 2.5 mg/kg 30 min before contextual fear conditioning. During the contextual fear conditioning phase, there was a significant difference between groups (group, F (1, 16) ¼ 123.282, p < 0.001; group*time block, F (5, 80) ¼ 39.175, p < 0.001), and the melatonin group presented a significant lower freezing in comparison to the vehicle group. During the test phase, a significantly lower freezing was also observed in the melatonin group ( p < 0.01). These data suggested that melatonin impaired contextual fear conditioning. However, when melatonin or vehicle was injected 30 min before testing, there was no significant difference between groups, both during the conditioning phase and the test phase, indicating that melatonin did not affect fear expression.

5.2 Melatonin Had no Effect on the Acquisition and Retention of Conditional Cued Fear Response Melatonin or vehicle was injected i.p. at dose of 2.5 mg/kg 30 min before cued fear conditioning. During the conditioning phase, the melatonin and vehicle groups showed equivalent fear learning. At 24 h postconditioning, the rats were presented with the CS in a novel context. There was no a significant group effect of percent freezing. These data suggest that melatonin does not affect the acquisition and retention of cued fear.

5.3 Preextinction Injection of Melatonin Facilitated the Acquisition and Retention of Cued Fear Extinction Next, we assessed the effects of melatonin on the expression and extinction of cued fear memory. Two groups of naı¨ve rats underwent fear conditioning. One day after training, rats were injected with melatonin or vehicle 30 min before extinction training. The next day, they were subjected to a drug-free extinction test. During the extinction training phase, a significantly

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lower freezing was observed in the melatonin group in comparison to the vehicle group (group, F (1, 18) ¼ 749.594, p < 0.001; group
trail, F (13, 234) ¼ 28.065, p < 0.001). During the extinction test phase, the melatonin group presented a significant lower freezing (p < 0.001). These results suggest that injection of melatonin 30 min before the extinction training facilitates the acquisition and retention of extinction learning. We also administered melatonin immediately after extinction training to determine the effects of melatonin on extinction when it is administrated at different time points. During the extinction training phase and test phase, there was no a significant effect of group (F (1, 10) ¼ 0.049, p > 0.05) and no significant trial-by-group interaction (F (13, 130) ¼ 1.566, p > 0.05). These results suggest that melatonin administration immediately after extinction training has no effect on the extinction of conditional cued fear.

6. DISCUSSION In our literature review, melatonin exerts opposing influences on the acquisition and extinction of conditional fear is in accordance with many other studies showing that acquisition and extinction are distinct learning processes. There exist behavioral, systems, and molecular differences between acquisition and extinction (Bouton et al., 2006; Lattal, Radulovic, & Lukowiak, 2006; Lai, Franke, & Gan, 2012; Marsicano et al., 2002). Furthermore, in line with this finding, it has been found that melatonin facilitates the extinction of active avoidance reflex, whereas memory acquisition is not influenced (Kova´cs, Gajari, Telegdy, & Lissak, 1974). In this review, on one hand, melatonin impaired contextual fear conditioning in rats. Considerable evidence suggests that the amygdala is an important site of the neural circuits related to both cued and contextual fear conditioning. However, the hippocampus is usually required only for contextual task (LeDoux, 2000; Maren, 2001). In the brain, melatonin receptors [MT(1)/MT(2)] have been found in regions implicated in cognition and memory, such as the hippocampus (Pandi-Perumal et al., 2008). In this review, on the other hand, melatonin facilitated the acquisition and retention of cued fear extinction in rats. Converging evidence has identified a network of brain structures including the amygdala, prefrontal cortex, and hippocampus (Cho, Deisseroth, & Bolshakov, 2013; Maren & Quirk, 2004; Sotres-Bayon, Bush, & LeDoux, 2004, 2007) that supports the acquisition, storage, retrieval, and contextual modulation of fear extinction. In the brain, binding sites of melatonin have been found in the amygdala,

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hippocampus, and prefrontal cortex (Ekmekcioglu, 2006; Savaskan et al., 2005; Uz et al., 2005), three regions that are involved in fear extinction (Bouton et al., 2006, Sotres-Bayon et al., 2004). Although the mechanisms through which melatonin acts on extinction remains to be determined, the effects of melatonin may be through the direct modulation of memory formation circuits. Melatonin has shown to play an important role in structural remodeling of synaptic connections during memory and learning processes (Baydas et al., 2002). Other researches also demonstrated the ability of melatonin to modulate neuronal firing in the hippocampus and other brain regions (Baydas, Ozveren, Akdemir, Tuzcu, & Yasar, 2005; Gorfine & Zisapel, 2007; Wang, Suthana, Chaudhury, Weaver, & Colwell, 2005). Further, a previous research showed that MT(2) receptor knockout mice demonstrate a significantly reduced longterm potentiation as well as impaired memory performance tested in an elevated plus-maze paradigm (Larson et al., 2006). Thus, melatonin may regulate learning and memory through its influence on synaptic connections in central nervous system neurons. Alternatively, melatonin may have an indirect effect on memory formation via some neurotrophin such as brainderived neurotrophic factor (BDNF). Melatonin has been shown to increase the production of BDNF (Kong et al., 2008) that may play an important role in cued fear extinction (Heldt, Stanek, Chhatwal, & Ressler, 2007). Further, melatonin modulates neurotransmitters such as gamma-amino butyric acid (Rosenstein & Cardinali, 1986) and glutamate (Vimala, Bhutada, & Patel, 2014) which are involved in extinction learning (Davis & Myers, 2002). There has been an available effective means of extinction-based exposure psychotherapy for the treatment of anxiety disorders, such as PTSD (Bentz et al., 2010; Rothbaum & Davis, 2003) that has been hypothesized to result from impaired extinction of fear memory (Bremner et al., 2005; Milad et al., 2006). Furthermore, decreased melatonin levels in patients with PTSD were reported in clinical studies (McFarlane, Barton, Briggs, & Kennaway, 2010). Therefore, facilitating effects of melatonin on fear extinction suggest that melatonin may serve as an agent for the treatment of anxiety disorders such as PTSD. Further studies will need to investigate the neurobiological mechanism through which melatonin modulates anxiety disorders.

ACKNOWLEDGMENTS This work was supported by National Natural Science Foundation of China (31171151 and 31371212) and Scientific Research Fund of Hunan Provincial Education Department (14B184).

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