- Email: [email protected]
hypocretin receptors in reward circuit
CHAPTER
Functional roles of orexin/ hypocretin receptors in reward circuit
6
Abbas Haghparast*,1, Zahra Fatahi*, Reza Arezoomandan†, Sara Karimi‡, Zahra Taslimi§, Shahram Zarrabian¶ *Neuroscience Research Center, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran † School of Behavioral Sciences and Mental Health (Tehran Institute of Psychiatry), Iran University of Medical Sciences, Tehran, Iran ‡ Physiology Research Center, Kashan University of Medical Sciences, Kashan, Iran § Neurophysiology Research Center, Hamadan University of Medical Sciences, Hamadan, Iran ¶ Cognitive and Neuroscience Research Center (CNRC), Tehran Medical Sciences Branch, Islamic Azad University, Tehran, Iran 1 Corresponding author: Tel.: +98-21-2242-9765; Fax: +98-21-2243-1624, e-mail address: [email protected]; [email protected]
Abstract Since its first discovery in 1998, it has become clear that the orexinergic system plays an important role in regulating a number of functions including food, sex, social connections, and most prominently reward-related behaviors. Orexinergic neurons in the lateral hypothalamus project extensively to other brain areas, two most important of which are the ventral tegmental area and the nucleus accumbens that are involved in reward processing. In this review, we have presented the work in our laboratory along with the work of others and have discussed the possible functions we can infer from the research. We discuss the anatomy of the orexinergic system and its components followed by a presentation of other connected brain areas. The second part of this review discusses observed results from the morphine conditioned place preference test that sheds light on the possible role of the involved areas in reward processing. The complex circuits involved in reward processing are only beginning to be understood and we need to deepen our understanding regarding the nature of the interactions between all brain areas involved.
Keywords Orexin/hypocretin, Reward, Lateral hypothalamus, Ventral tegmental area, Nucleus accumbens, Prefrontal cortex, Hippocampus
Progress in Brain Research, Volume 235, ISSN 0079-6123, https://doi.org/10.1016/bs.pbr.2017.08.005 © 2017 Elsevier B.V. All rights reserved.
139
140
CHAPTER 6 Functional roles of orexin receptors in reward circuit
1 INTRODUCTION 1.1 OREXIN In 1998, new neuropeptides were discovered by two separate laboratories and thus separately named orexins A and B, also known as hypocretins 1 and 2 (De Lecea et al., 1998; Mould et al., 2014; Sakurai et al., 1998). The origin of orexin is the Greek term for orexins (appetite), selected based on the fact that the first behavioral effect noted for these peptides was feeding (Sakurai et al., 1998). On the other hand, the hypothalamic location of the orexinergic neurons and the structural similarity with the gut incretin peptides led to selection of the term “hypocretin” (Sunter et al., 2001). Currently, both orexin and hypocretin terms are used in scientific articles. In this review, we will use the term orexin to discuss the orexinergic effect of these peptides.
1.2 OREXIN RECEPTORS Two types of orexin receptors have been characterized that include orexin 1 receptor (OX1R) and orexin 2 receptor (OX2R). OX2R has a similar high affinity for both orexin peptides, whereas OX1R has a 30 nM affinity for binding to orexin A, but a much lower affinity for orexin B (Aston-Jones et al., 2010). The two receptor types also differ in signaling pathways. The OX1R signals mainly via Gq coupling, whereas the OX2R signals through Gq or Gi/o coupling (Boss and Roch, 2015). Orexin receptors couple to at least three G-protein families and possibly other proteins, through which they regulate nonselective cation channels, phospholipases, adenylyl cyclase, and protein and lipid kinases. In the central nervous system, orexin receptors activate nonselective cation channels, inhibit K+ channels, activate Na+/Ca2+ exchange, produce postsynaptic depolarization, and stimulate neurons. However, once located on the presynaptic membrane, they can stimulate the release of neurotransmitters and modulate synaptic plasticity (Kukkonen and Leonard, 2014).
1.3 OREXIN RECEPTORS AND PHARMACOLOGICAL AGENTS Several orexin receptor antagonists have been described (Gunthorpe et al., 2004; Smart and Jerman, 2002). The first and most widely used compound is SB334867, which has a higher affinity for OX1Rs, but blocks the binding of the agonists to both orexin receptors (Li et al., 2014). TCS OX2 29 (Mould et al., 2014) and JNJ-10397049 (Tran et al., 2011) are selective OX2R antagonists. Suvorexant, a dual orexin receptor antagonist, is the first of the new class recently synthesized and has been successfully used for the treatment of insomnia (Bennett et al., 2014).
1.4 THE DISTRIBUTION OF OREXIN RECEPTORS Like many other receptor types, orexin receptors also differ in their distribution in the brain (Kilduff and De Lecea, 2001; Marcus et al., 2001; Trivedi et al., 1998). From a functional viewpoint, the review of the literature shows that loss of signaling at OX2R is associated with symptoms of narcolepsy in animals (Lin et al., 1999;
2 Reward and reward processing
Willie et al., 2003). This abnormality provided the basis for the arousal-related hypothesis of the orexin system (Akanmu and Honda, 2005; Marcus et al., 2001; Willie et al., 2003). Furthermore, the OX2R antagonist, JNJ-10397049, significantly reduced latency to non-REM sleep and increased sleep time (Dugovic et al., 2009; Smith et al., 2003). As the OX1R antagonist (SB334867) had no effect on sleep–wake states, signaling via OX1R was hypothesized to be primarily related to the other functions of the orexin system such as satiety- and reward-related behaviors.
1.5 OREXINERGIC NEURONS AND THEIR CONNECTIVITY Specific neurons in the lateral hypothalamus (LH) produce the orexin neuropeptides. The dorsal, perifornical, posterior, and lateral areas are known as the main origins of orexins A and -B (De Lecea et al., 1998; Peyron et al., 1998; Sakurai et al., 1998). Orexin fibers project to virtually all the areas in the hypothalamus, including the arcuate, paraventricular, lateral, perifornical, and ventromedial areas. In addition, orexinergic neurons make widespread projections and connectivity to other brain areas important for the regulation of feeding and arousal (Brown et al., 2002; Hervieu et al., 2001; Sunter et al., 2001), as well as sleep–wake cycles, cognition, locomotion, and reward processing (Li et al., 2014). Keeping in mind the role of the orexinergic projections and structures in the brain functions, there are also other structures which are involved in each of the functions. For example, the tuberomammillary nucleus, locus coeruleus, ventral periaqueductal gray matter, and dorsal raphe nuclei are involved in arousal (Peyron et al., 1998; Saper et al., 2005); the prefrontal cortex (PFC) and hippocampus (HIP) are involved in cognition; the cuneiform nucleus and lateral vestibular nucleus are concerned with locomotion; and the ventral tegmental area (VTA) and nucleus accumbens (NAc) play a prominent role in the reward system (Li et al., 2014). Besides the nerve projections suggest the involvement of the orexinergic system in drug-related effects, a number of functional studies have also supported a link between orexin and addictive behavior. For instance, stimulation of the LH stimulation potentiated the effect of an ineffective dose of morphine and induced morphine sensitization (Razavi et al., 2014), while chemical stimulation of the LH resulted in a change in conditioned place preference (CPP) suggesting the involvement of orexin A in drug-seeking behavior (Taslimi et al., 2011). Administration of orexin A in the VTA also induced CPP in a dose-dependent manner in rats (Taslimi et al., 2012) and intrahippocampal administration of SB334867 before conditioning sessions, disrupted the rewarding effect of morphine (Riahi et al., 2013). These results clearly indicate a role for orexinergic neurons in reward processing.
2 REWARD AND REWARD PROCESSING Reward is defined as something given in exchange for good behaviors. Understanding the brain circuitry underlying feelings of reward or pleasure is of great interest and a myriad of papers have been published determining regions and connections
141
142
CHAPTER 6 Functional roles of orexin receptors in reward circuit
associated with a number of natural rewards including food, sex, and social connections (Berridge and Robinson, 1998). Several studies have taken the advantage of increasingly sophisticated genetics based tools to observe and to manipulate neuronal activity within specific cell types and circuits to ascertain their role in reward processes. However, much of what we know about the structure of the reward circuit, and the generation of pleasure, were originally identified in the context of drugs of abuse. Thus, our understanding of the circuitry underlying the rewarding aspects of drug use and maladaptive reward underlying addiction, give us a better chance to understand general reward mechanisms. Moreover, while some specific nodes of the reward circuitry—such as dopamine (DA) outputs from the VTA to the NAc—and their importance in drug reward are well established (Cooper et al., 2017), our understanding of the complexity of the reward circuit underlying various aspects of addiction, such as relapse and craving, has recently increased through the use of “circuit-busting” opto- and chemo-genetic approaches. We here summarize the current understanding of the major brain regions in drug reward and the role of the connections between these regions (circuitry) in aspects relevant to addiction to generate a better understanding of the dynamics of these reward circuits that will potentially, help us improve the treatment of drug addiction.
2.1 REWARD CIRCUITRY There are a number of brain structures involved in reward, including the VTA, NAc, PFC, ventral HIP, amygdala, and thalamus. We will discuss the findings regarding each of the mentioned areas and will point out the information regarding brainderived neurotrophic factor (BDNF) in brief.
2.1.1 The VTA The general understanding of the reward circuitry underlying addiction begins with the VTA, a heterogeneous brain region composed largely of DA (60%–65%) and g-amino butyric acid (GABA; 30%–35%) neurons, and a smaller proportion of glutamatergic neurons (2%–3%) (Nair-Roberts et al., 2008; Swanson, 1982). Most studies have focused on the dopaminergic neurons of the VTA as the stimulation of these neurons and release of DA in projection sites, most notably the NAc, is known to produce reward. Earlier works have shown that virtually all known drugs of abuse increase DA release in the NAc (Di Chiara and Imperato, 1988). As the focus of this review is on reward, many of the studies discussed below focus on the VTA dopaminergic neurons although, it is also clear that VTA GABAergic neurons are critical for the reward processing.
2.1.2 The NAc As described above, a major reward-related output of VTA DA activity is the NAc. DA can exert its effects via activating DA receptors located on medium spiny neurons (MSNs), the predominant cell type in the NAc.
2 Reward and reward processing
D1 (dopamine receptor type 1) and D2 (dopamine receptor type 2) neurons in the dorsal striatum are thought to have generally separate projections, with D1 MSNs constituting the “direct” pathway (responsible for increasing thalamocortical drive) and D2 MSNs forming the “indirect” pathway (responsible for decreasing thalamocortical drive). In addition to the cellular heterogeneity (D1 vs D2 neurons), a regional heterogeneity also exists, causing distinct drug-associated behaviors and plasticity differences between the NAc core and shell subregions (Saddoris et al., 2013). MSNs in the NAc core appear to be critical for assigning motivational values to discrete stimuli associated with reward or aversion and particularly updating these values as circumstances change, whereas, those in the NAc shell drive behavioral responses to repeated exposure to rewarding experiences such as chronic drug administration (Meredith et al., 2008). While VTA dopaminergic neurons provide a strong modulatory input into the NAc MSNs, they also receive a considerable large glutamatergic input from a variety of limbic and cortical regions, some of the most notable ones are the PFC, ventral HIP, and basolateral amygdala (BLA) (Floresco, 2015; Sesack and Grace, 2010).
2.1.3 The PFC The PFC input to the NAc is largely associated with executive control and is thought to mediate the goal-directed behaviors such as seeking behavior and planning of action to obtain rewarding substances (Kalivas et al., 2005). The PFC subregions differ in their projection to the NAc. For example, the infralimbic (IL) and prelimbic (PrL) areas of the medial PFC preferentially project to the shell and core areas of the NAc, respectively (Sesack and Grace, 2010).
2.1.4 The ventral HIP The ventral HIP also sends glutamatergic projections to the NAc and is thought to act as a site of integration between spatial/contextual information from the dorsal HIP and emotional information from the BLA and locus coeruleus (French et al., 2003; French and Totterdell, 2003; Oleskevich et al., 1989). Thus, the ventral HIP–NAc connection acts to provide contextually relevant emotional information and influences goal-directed behaviors. This circuit has been implicated in both reward and aversive behaviors and its modulation has been shown to impact locomotor responses to drugs of abuse and cue-induced drug-seeking behaviors (Pascoli et al., 2014; Vezina et al., 1989).
2.1.5 The amygdala The amygdala also sends glutamatergic input to the NAc and its effects are thought to be mediated by D1-like receptor activation (Charara and Grace, 2003; Stuber et al., 2011). In particular, the activation of the projections from BLA to NAc facilitates reward seeking and supports positive reinforcement (Ambroggi et al., 2008; Stuber et al., 2011). Although the role for the activation of the amygdala in emotional learning and role for the projections from the BLA in mediating fear and anxiety
143
144
CHAPTER 6 Functional roles of orexin receptors in reward circuit
behaviors are well established, these effects appear to be mediated distinctly from those BLA projections to the NAc, as the BLA–NAc microcircuit is involved in reward and reinforcement drive (Janak and Tye, 2015).
2.1.6 The thalamus The research has recently characterized the glutamatergic inputs into the NAc from the subregions of the thalamus, especially the midline thalamic nuclei like the paraventricular nucleus (PVT). Compared to the stimulation of glutamatergic inputs from the regions described earlier (ventral HIP, PFC, and amygdala), which produce rewarding effects, direct activation of the PVT–NAc pathway produces aversive effects, driving behavioral aversion in a real-time place preference assay (Zhu et al., 2016). These behavioral changes are likely driven by changes in druginduced plasticity within the medial thalamus–NAc circuit, as cocaine experience has been shown to alter N-methyl-D-aspartate (NMDA) function and plasticity and increase silent synapses within this circuit. The plasticity changes have been shown to be dependent on both MSN cell types (D1 vs non-D1) and the subregions (shell vs core) (Joffe and Grueter, 2016; Neumann et al., 2016). Together, the regions described earlier form a highly integrated circuit, the corticobasal ganglia reward network (Sesack and Grace, 2010), and drug-induced changes in plasticity within the circuit contribute to various facets of addiction (Luscher, 2016).
2.2 REWARD AND NEUROTROPHIC FACTORS Neurotrophic factor signaling and, in particular, the signaling related to BDNF acts on the tropomyosin kinase B (TrkB) receptor, and its downstream effects have been shown to be involved in drug dependence and addiction (Russo et al., 2009). Multiple studies found that BDNF expression increased in response to both self- and investigator-administered cocaine throughout the reward circuitry, which includes the NAc, PFC, VTA, and amygdala (Fumagalli et al., 2013; Graham et al., 2007; Grimm et al., 2003). Changes in BDNF protein and mRNA levels have been examined in multiple brain regions following the administration of many classes of addictive substances. Stimulants produce a widespread, but transient, induction of BDNF protein in the NAc, PFC, VTA, and the central and basolateral nuclei of the amygdala (Graham et al., 2007; Grimm et al., 2003; Le Foll et al., 2005). Both contingent and noncontingent (i.e., yoked animals and self-administering animals) cocaine administrations cause elevated levels of BDNF protein in the NAc (Graham et al., 2007; Liu et al., 2006; Zhang et al., 2002). Likewise, long-term withdrawal of up to 90 days after cocaine self-administration correlates with an increased BDNF protein level in the NAc, VTA, and amygdala (Grimm et al., 2003; Pu et al., 2006), and there is early evidence that epigenetic regulation of the BDNF gene may be involved in mediating this persistent induction (Kumar et al., 2005).
3 Reward processing and drug abuse
2.2.1 Drug-induced changes in BDNF signaling pathways in brain reward regions Several proteins in neurotrophin signaling cascades have been shown to be regulated within the mesolimbic DA system by opiates and stimulants; these include the drug effects on IRS–PI3K–Akt, PLCg, Ras–ERK, and NFkB signaling. Acute or chronic administration of stimulants dramatically increases ERK phosphorylation in numerous brain regions including the NAc, VTA, and PFC (Jenab et al., 2005; Shi and McGinty, 2006; Sun et al., 2007; Valjent et al., 2005). These findings are consistent with stimulant-induced increases in the number of neuronal branches and spines and led us to the Ras–ERK’s established role in neurite outgrowth. In addition, several recent reports have shown that IRS–PI3K–Akt signaling is influenced by drugs of abuse (Brami-Cherrier et al., 2002; McGinty et al., 2008; Muller and Unterwald, 2004; Williams et al., 2007). Alterations in the PLCg and NFkB signaling pathways in drug abuse have not been studied as extensive as those for ERK and Akt. However, recent work shows that both pathways are regulated by drugs of abuse.
3 REWARD PROCESSING AND DRUG ABUSE Harris and his colleagues were the first to show the involvement of orexin neurons of the LH in reward processing and drug abuse (Harris et al., 2005). They found that the LH neurons were activated after conditioning of rats with cocaine, morphine, or food in a CPP paradigm. Notably, the activation of the LH orexin neurons showed correlation with the intensity of reward on the CPP test day. The activation of the LH orexin neurons after acquiring reward, demonstrated a potential implication of these neurons in reward-related phenomena. Following the first demonstration of the role of the LH orexinergic neurons in reward processing, they showed that systemic administration of the OX1R antagonist, SB334867, before the CPP test day significantly attenuated the expression of morphine–CPP (Harris et al., 2005, 2007). They also showed that morphine administration during the conditioning period (in the CPP compartment), but not in the home cage, stimulated the LH neurons and bilateral lesions of the LH area completely blocked the development of morphineinduced CPP (Harris et al., 2007). Taken this as evidence for the direct role of the LH orexinergic neurons in the acquisition of CPP, Taslimi et al. (2011) chemically stimulated the orexinergic neurons by unilateral intra-LH administration of carbachol, as a cholinergic agonist. Their results showed that stimulation of the LH by carbachol during the conditioning phase produced a significant change in the CPP score and the rats showed more preference to the drug-associated compartment in a dose-dependent manner. The results provided evidence for the rewarding property of chemical LH stimulation (Taslimi et al., 2011). The VTA and NAc are two main areas of the mesolimbic dopaminergic system that are critical for the initiation of opioid reinforcement- and reward-related effects, which provides converging evidence considering that orexin receptors are expressed at high levels in both of these areas (Fadel and Deutch, 2002). An electrophysiological study
145
146
CHAPTER 6 Functional roles of orexin receptors in reward circuit
indicated that orexin excited VTA dopaminergic neurons. Furthermore, it has been shown that the orexinergic system can increase DA and glutamate transmission, the main neurotransmitters involved in reward-related phenomena. Vittoz and Berridge (2006) showed that the VTA is implicated in orexin-increased DA efflux in the PFC and suggested that the activation of the VTA dopaminergic neurons contributes to the behavioral effects of orexin (Vittoz and Berridge, 2006). Another study indicated that orexin-B increased glutamatergic transmission in the VTA neurons (Borgland et al., 2008). In our laboratory, we showed that intra-VTA administration of SB334867 just 5 min before carbachol during the conditioning phase, blocked the development of LH stimulation-induced CPP (Taslimi et al., 2011). In another study, we investigated the role of VTA OX2Rs in the induction of CPP by the chemical stimulation of the LH. The results showed that intra-VTA administration of TCS OX2 29, 5 min before intra-LH microinjection of carbachol during the 3-day conditioning phase, modulated the developing rewarding effect of LH stimulation (Yazdi et al., 2015). Harris et al. showed that intra-VTA administration of SB334867 into the VTA prior to each morphine-pairing session could block the induction of morphine CPP (Harris et al., 2007). In another study in our lab, we showed that chemical stimulation of the LH by carbachol potentiated the rewarding effect of morphine. We then examined the role of VTA orexin receptors in the acquisition and expression of morphine CPP induced by concurrent stimulation of the LH and showed that the intra-VTA administration of SB334867, 5 min before carbachol injection, could inhibit the acquisition (development), but not the expression, of LH stimulation-induced morphine CPP in rats (Zarepour et al., 2014).
3.1 THE VTA AND REWARD PROCESSING A number of studies have investigated the direct role of the VTA in reward processing. In our lab, we examined the rewarding effects of direct orexin administration into the VTA and showed that unilateral injection of orexin A into the VTA before each conditioning season induced CPP in a dose-dependent manner (Taslimi et al., 2012). Next, we investigated the role of NAc DA receptors in the development of orexin-induced reward-related behaviors. We microinjected SCH 23390 (as a D1 receptor antagonist) and sulpiride (as a D2 receptor antagonist) unilaterally during the acquisition phase into the NAc 5 min prior to the administration of orexin A into the VTA. The data revealed that blockade of NAc DA receptors inhibited the development of orexin-induced rewarding effects (Taslimi et al., 2012). These results suggest that NAc DA receptors are implicated in the observed rewarding effects, which result from the activation of VTA dopaminergic neurons by orexin. Activation of the orexin receptors, either by the administration of orexin into the VTA or the application of foot-shock stress, has been shown to induce cocaine reinstatement and increase the release of glutamate and DA in the VTA (Wang et al., 2009). In addition, infusions of orexin A into the VTA increased cocaine self-administration (Espana et al., 2011), which shows that enhancement of orexin signaling in the VTA promotes the reinforcing effects of cocaine. The study added to our knowledge about
3 Reward processing and drug abuse
drug self-administration and showed that orexin acts within the VTA to activate the mesocorticolimbic DA system by affecting the VTA neurons. In summary, these studies indicate that orexin projections, specifically those from the LH to the VTA, are involved in neurotransmitter transmission, regulation of reward processing, and CPP learning. They also suggest a substantial role for orexin A receptors within the VTA in the mentioned phenomena.
3.2 THE NAc AND REWARD PROCESSING The NAc is a central component of the basal ganglia that is known as the pleasure center of the brain. The NAc receives dopaminergic projections from the VTA and glutamatergic projections from the medial PFC and plays an important role in reward-related phenomena (Kalivas and Volkow, 2005). On the other hand, the NAc receives orexinergic projections from the LH, which are involved in behavioral responses to psychostimulant consumption (Fadel and Deutch, 2002). In addition, orexin receptors are expressed at high levels in the NAc (Cluderay et al., 2002). It has been shown that the orexinergic system interacts with the DA signaling system in the NAc. An in vivo microdialysis study investigated the effect of the VTA orexin system on DA signaling in the NAc and showed that orexin administration into the VTA increased cocaine-induced enhancement of DA release in the NAc core (Espana et al., 2011). Several studies have investigated the role of the orexinergic system in the NAc in reward processing, by chemical stimulation of the LH by carbachol-induced CPP (Taslimi et al., 2011), for example. We also investigated the involvement of the NAc OX1 and CB1 cannabinoid receptors in the acquisition and expression of reward-related behaviors induced by LH stimulation and showed that blockade of OX1Rs by intra-NAc administration of SB334867 before intra-LH carbachol application inhibited the rewarding effects induced by LH stimulation (Fatahi et al., 2015). Furthermore, intra-NAc injection of SB334867 on the conditioning day modulated the expression of LH stimulation-induced CPP. The study also showed that concurrent blockade of OX1 and CB1 receptors in the NAc, before carbachol injection during the conditioning phase, inhibited the development of LH stimulation-induced CPP. It can be concluded that orexinergic projections from the LH to NAc and the OX1Rs in the NAc are involved in the LH stimulation-induced CPP. In addition, the results suggested an interaction between the OX1 and CB1 receptors within the NAc in the rewarding effect induced by carbachol (Fatahi et al., 2015). Following our investigation on the role of ORX1Rs, we studied the role of OX2Rs within the NAc in the development of reward-related behaviors induced by chemical stimulation of the LH (Yazdi et al., 2015). Our results showed that intra-NAc administration of TCS OX2 29, 5 min before intra-LH microinjection of carbachol during the 3-day conditioning phase, modulated the development of the rewarding effect of LH stimulation (Yazdi et al., 2015). In another study, Qi et al. investigated the role of orexin receptors in the NAc in stress- and priming-induced reinstatement of morphine (Qi et al., 2013). Their results
147
148
CHAPTER 6 Functional roles of orexin receptors in reward circuit
indicated that blockade of OX1Rs and OX2Rs in NAc shell blocked stress-induced reinstatement, but neither of the orexin antagonists had any effect on the reinstatement of morphine-seeking behaviors (Qi et al., 2013).
3.3 THE HIP AND REWARD PROCESSING It is well established that the HIP plays a critical role in learning and memory and is involved in drug- and context-induced seeking behaviors that can form addictive memories (Nestler, 2001). In addition, the HIP has an important role in rewardrelated learning tasks such as the CPP paradigm (Riahi et al., 2013). The HIP receives orexinergic projections from the LH and all the regions of the HIP express both OX1 and OX2 receptors (Nambu et al., 1999). An in vivo single unit recording from the hippocampal area showed that orexin administration into the lateral cerebral ventricle predominantly excited hippocampal pyramidal neurons. Furthermore, chemical stimulation of the LH by carbachol injection also excited hippocampal neurons (Riahi et al., 2015). In our laboratory, we examined the function of OX1Rs and OX2Rs in the dentate gyrus (DG) in the acquisition, expression, and extinction of lateral hypothalamic induced CPP (Parsania et al., 2016) and showed that intraDG administration of OX1R and OX2R antagonists before carbachol administration during the conditioning phase blocked the rewarding effect of LH stimulation and also decreased the expression of LH-induced CPP. Furthermore, the OX1R, but not OX2R, antagonist shortened the maintenance of carbachol-induced CPP (Parsania et al., 2016). In another study, we investigated the role of hippocampal OX2Rs in the acquisition, expression, and extinction of morphine-induced CPP. The results showed that intra-CA1 injection of TCS OX2 29 during the conditioning phase inhibited the induction of morphine–CPP in both postconditioning and expression phases. Furthermore, the administration of OX2R shortened the maintenance time of morphine-seeking behaviors (Sadeghi et al., 2016). We also investigated the role of the OX1 and OX2 receptors in the DG in stress- and drug priming-induced reinstatement. On the reinstatement day, the animals received intra-DG administration of SB334867 and TCS OX2 29, and then were tested for morphine priming- and forced swim stress-induced reinstatement. The results revealed that intra-DG administration of OX1 and OX2 receptor antagonists attenuated drug priming-induced reinstatement, but had only a trivial effect on the forced swim stress-induced reinstatement (Ebrahimian et al., 2016).
4 REWARD PROMOTION Orexin activates the VTA DA projecting neurons to the NAc and promotes the rewarding effects of a rewarding drug (Volkow et al., 2011). Therefore, in our laboratory, we investigated the involvement of NAc D1-like and D2-like DA receptors in the development of reward-related behaviors induced by the chemical
References
stimulation of the LH (Haghparast et al., 2013). The results showed that blockade of D1-like or D2-like DA receptors in the NAc modulated the acquisition of CPP induced by LH stimulation.
5 CONCLUSION Rewarding experiences involve our emotions and affect our future actions partly through recall of our past memories. The complex circuits involved in reward processing, as one of the distinguished functions of the orexinergic system, are only beginning to be understood. This is mainly because of the fact that reward is an integrated part of simple behaviors like food intake as well as complex ones such as social connections. Considering the wide spread and uneven distribution of the orexin receptors in the brain, we now partly know how the orexinergic system interacts with the other neurotransmitter systems such as the glutamatergic, GABAergic, and even the cannabinoid system. The dopaminergic output from the VTA into the NAc has a prominent role in reward and its processes. The critical role of GABAergic neurons of the VTA, however, has been investigated far less. The NAc is not only heterogeneous in its dopaminergic receptors but also shows heterogeneity in its subregions. The NAc also receives notable glutamatergic inputs from frontal and subcortical regions of the brain, one of the most important of which is from the HIP. The great role of HIP in encoding the environment cues and its events have now been understood to the extent that we know how a past environmental cue can trigger a certain action which has been practiced over time. The literature mentioned in this review shed light on our present knowledge of the key players in the mentioned brain areas. The results clearly indicate that the application of orexin directly into a target site of interest or chemical stimulation of orexinergic neurons in LH produces similar results on the behavior of rodents in the addiction tests, which is an indication of the fact that orexin exerts part of its effects through dopaminergic neurons in the VTA and NAc, and possibly the excitation of the glutamatergic neurons. Although it was first understood that OX1Rs have a dominant role in drug-seeking behavior and drug dependency, more and more evidence is reported by the laboratories regarding the involvement of OX2Rs in the rewarding effects of orexin.
REFERENCES Akanmu, M.A., Honda, K., 2005. Selective stimulation of orexin receptor type 2 promotes wakefulness in freely behaving rats. Brain Res. 1048, 138–145. Ambroggi, F., Ishikawa, A., Fields, H.L., Nicola, S.M., 2008. Basolateral amygdala neurons facilitate reward-seeking behavior by exciting nucleus accumbens neurons. Neuron 59, 648–661. Aston-Jones, G., Smith, R.J., Sartor, G.C., Moorman, D.E., Massi, L., Tahsili-Fahadan, P., Richardson, K.A., 2010. Lateral hypothalamic orexin/hypocretin neurons: a role in reward-seeking and addiction. Brain Res. 1314, 74–90.
149
150
CHAPTER 6 Functional roles of orexin receptors in reward circuit
Bennett, T., Bray, D., Neville, M.W., 2014. Suvorexant, a dual orexin receptor antagonist for the management of insomnia. Pharmacol. Ther 39, 264. Berridge, K.C., Robinson, T.E., 1998. What is the role of dopamine in reward: hedonic impact, reward learning, or incentive salience? Brain Res. Brain Res. Rev. 28, 309–369. Borgland, S.L., Storm, E., Bonci, A., 2008. Orexin B/hypocretin 2 increases glutamatergic transmission to ventral tegmental area neurons. Eur. J. Neurosci. 28, 1545–1556. Boss, C., Roch, C., 2015. Recent trends in orexin research—2010 to 2015. Bioorg. Med. Chem. Lett. 25, 2875–2887. Brami-Cherrier, K., Valjent, E., Garcia, M., Pages, C., Hipskind, R.A., Caboche, J., 2002. Dopamine induces a PI3-kinase-independent activation of Akt in striatal neurons: a new route to cAMP response element-binding protein phosphorylation. J. Neurosci. 22, 8911–8921. Brown, R.E., Sergeeva, O.A., Eriksson, K.S., Haas, H.L., 2002. Convergent excitation of dorsal raphe serotonin neurons by multiple arousal systems (orexin/hypocretin, histamine and noradrenaline). J. Neurosci. 22, 8850–8859. Charara, A., Grace, A.A., 2003. Dopamine receptor subtypes selectively modulate excitatory afferents from the hippocampus and amygdala to rat nucleus accumbens neurons. Neuropsychopharmacology 28, 1412–1421. Cluderay, J.E., Harrison, D.C., Hervieu, G.J., 2002. Protein distribution of the orexin-2 receptor in the rat central nervous system. Regul. Pept. 104, 131–144. Cooper, S., Robison, A.J., Mazei-Robison, M.S., 2017. Reward circuitry in addiction. Neurotherapeutics 14 (3), 687–697. De Lecea, L., Kilduff, T., Peyron, C., Gao, X.-B., Foye, P., Danielson, P., Fukuhara, C., Battenberg, E., Gautvik, V., Bartlett, F.N., 1998. The hypocretins: hypothalamus-specific peptides with neuroexcitatory activity. Proc. Natl. Acad. Sci. 95, 322–327. Di Chiara, G., Imperato, A., 1988. Drugs abused by humans preferentially increase synaptic dopamine concentrations in the mesolimbic system of freely moving rats. Proc. Natl. Acad. Sci. U.S.A. 85, 5274–5278. Dugovic, C., Shelton, J.E., Aluisio, L.E., Fraser, I.C., Jiang, X., Sutton, S.W., Bonaventure, P., Yun, S., Li, X., Lord, B., 2009. Blockade of orexin-1 receptors attenuates orexin-2 receptor antagonism-induced sleep promotion in the rat. J. Pharmacol. Exp. Ther. 330, 142–151. Ebrahimian, F., Naghavi, F.S., Yazdi, F., Sadeghzadeh, F., Taslimi, Z., Haghparast, A., 2016. Differential roles of orexin receptors within the dentate gyrus in stress- and drug priminginduced reinstatement of conditioned place preference in rats. Behav. Neurosci. 130, 91–102. Espana, R.A., Melchior, J.R., Roberts, D.C., Jones, S.R., 2011. Hypocretin 1/orexin a in the ventral tegmental area enhances dopamine responses to cocaine and promotes cocaine self-administration. Psychopharmacology (Berl) 214, 415–426. Fadel, J., Deutch, A.Y., 2002. Anatomical substrates of orexin-dopamine interactions: lateral hypothalamic projections to the ventral tegmental area. Neuroscience 111, 379–387. Fatahi, Z., Assar, N., Mahmoudi, D., Pahlevani, P., Moradi, M., Haghparast, A., 2015. Functional interaction between the orexin-1 and CB1 receptors within the nucleus accumbens in the conditioned place preference induced by the lateral hypothalamus stimulation. Pharmacol. Biochem. Behav. 132, 42–48. Floresco, S.B., 2015. The nucleus accumbens: an interface between cognition, emotion, and action. Annu. Rev. Psychol. 66, 25–52. French, S.J., Totterdell, S., 2003. Individual nucleus accumbens-projection neurons receive both basolateral amygdala and ventral subicular afferents in rats. Neuroscience 119, 19–31.
References
French, S.J., Hailstone, J.C., Totterdell, S., 2003. Basolateral amygdala efferents to the ventral subiculum preferentially innervate pyramidal cell dendritic spines. Brain Res. 981, 160–167. Fumagalli, F., Moro, F., Caffino, L., Orru, A., Cassina, C., Giannotti, G., Di Clemente, A., Racagni, G., Riva, M.A., Cervo, L., 2013. Region-specific effects on BDNF expression after contingent or non-contingent cocaine i.v. self-administration in rats. Int. J. Neuropsychopharmacol. 16, 913–918. Graham, D.L., Edwards, S., Bachtell, R.K., Dileone, R.J., Rios, M., Self, D.W., 2007. Dynamic BDNF activity in nucleus accumbens with cocaine use increases self-administration and relapse. Nat. Neurosci. 10, 1029–1037. Grimm, J.W., LU, L., Hayashi, T., Hope, B.T., Su, T.P., Shaham, Y., 2003. Time-dependent increases in brain-derived neurotrophic factor protein levels within the mesolimbic dopamine system after withdrawal from cocaine: implications for incubation of cocaine craving. J. Neurosci. 23, 742–747. Gunthorpe, M., Rami, H., Jerman, J., Smart, D., Gill, C., Soffin, E., Hannan, S.L., Lappin, S., Egerton, J., Smith, G., 2004. Identification and characterisation of SB-366791, a potent and selective vanilloid receptor (VR1/TRPV1) antagonist. Neuropharmacology 46, 133–149. Haghparast, A., Omranifard, A., Arezoomandan, R., Ghalandari-Shamami, M., Taslimi, Z., Vafaei, A.A., Rashidy-Pour, A., 2013. Involvement of dopaminergic receptors of the rat nucleus accumbens in decreasing the conditioned place preference induced by lateral hypothalamus stimulation. Neurosci. Lett. 556, 10–14. Harris, G.C., Wimmer, M., Aston-Jones, G., 2005. A role for lateral hypothalamic orexin neurons in reward seeking. Nature 437, 556–559. Harris, G.C., Wimmer, M., Randall-Thompson, J.F., Aston-Jones, G., 2007. Lateral hypothalamic orexin neurons are critically involved in learning to associate an environment with morphine reward. Behav. Brain Res. 183, 43–51. Hervieu, G., Cluderay, J., Harrison, D., Roberts, J., Leslie, R., 2001. Gene expression and protein distribution of the orexin-1 receptor in the rat brain and spinal cord. Neuroscience 103, 777–797. Janak, P.H., Tye, K.M., 2015. From circuits to behaviour in the amygdala. Nature 517, 284–292. Jenab, S., Festa, E.D., Nazarian, A., Wu, H.B., Sun, W.L., Hazim, R., Russo, S.J., QuinonesJenab, V., 2005. Cocaine induction of ERK proteins in dorsal striatum of Fischer rats. Brain Res. Mol. Brain Res. 142, 134–138. Joffe, M.E., Grueter, B.A., 2016. Cocaine experience enhances thalamo-accumbens N-methyl-D-aspartate receptor function. Biol. Psychiatry 80, 671–681. Kalivas, P.W., Volkow, N.D., 2005. The neural basis of addiction: a pathology of motivation and choice. Am. J. Psychiatry 162, 1403–1413. Kalivas, P.W., Volkow, N., Seamans, J., 2005. Unmanageable motivation in addiction: a pathology in prefrontal-accumbens glutamate transmission. Neuron 45, 647–650. Kilduff, T.S., De Lecea, L., 2001. Mapping of the mRNAs for the hypocretin/orexin and melanin-concentrating hormone receptors: networks of overlapping peptide systems. J Comp Neurol 435, 1–5. Kukkonen, J., Leonard, C., 2014. Orexin/hypocretin receptor signalling cascades. Br. J. Pharmacol. 171, 314–331. Kumar, A., Choi, K.H., Renthal, W., Tsankova, N.M., Theobald, D.E., Truong, H.T., Russo, S.J., Laplant, Q., Sasaki, T.S., Whistler, K.N., Neve, R.L., Self, D.W., Nestler, E.J., 2005. Chromatin remodeling is a key mechanism underlying cocaineinduced plasticity in striatum. Neuron 48, 303–314.
151
152
CHAPTER 6 Functional roles of orexin receptors in reward circuit
Le Foll, B., Diaz, J., Sokoloff, P., 2005. A single cocaine exposure increases BDNF and D3 receptor expression: implications for drug-conditioning. Neuroreport 16, 175–178. Li, J., Hu, Z., Lecea, L., 2014. The hypocretins/orexins: integrators of multiple physiological functions. Br. J. Pharmacol. 171, 332–350. Lin, L., Faraco, J., Li, R., Kadotani, H., Rogers, W., Lin, X., Qiu, X., De Jong, P.J., Nishino, S., Mignot, E., 1999. The sleep disorder canine narcolepsy is caused by a mutation in the hypocretin (orexin) receptor 2 gene. Cell 98, 365–376. Liu, Q.R., Lu, L., Zhu, X.G., Gong, J.P., Shaham, Y., Uhl, G.R., 2006. Rodent BDNF genes, novel promoters, novel splice variants, and regulation by cocaine. Brain Res. 1067, 1–12. Luscher, C., 2016. The emergence of a circuit model for addiction. Annu. Rev. Neurosci. 39, 257–276. Marcus, J.N., Aschkenasi, C.J., Lee, C.E., Chemelli, R.M., Saper, C.B., Yanagisawa, M., Elmquist, J.K., 2001. Differential expression of orexin receptors 1 and 2 in the rat brain. J Comp Neurol 435, 6–25. Mcginty, J.F., Shi, X.D., Schwendt, M., Saylor, A., Toda, S., 2008. Regulation of psychostimulant-induced signaling and gene expression in the striatum. J. Neurochem. 104, 1440–1449. Meredith, G.E., Baldo, B.A., Andrezjewski, M.E., Kelley, A.E., 2008. The structural basis for mapping behavior onto the ventral striatum and its subdivisions. Brain Struct. Funct. 213, 17–27. Mould, R., Brown, J., Marshall, F., Langmead, C., 2014. Binding kinetics differentiates functional antagonism of orexin-2 receptor ligands. Br. J. Pharmacol. 171, 351–363. Muller, D.L., Unterwald, E.M., 2004. In vivo regulation of extracellular signal-regulated protein kinase (ERK) and protein kinase B (Akt) phosphorylation by acute and chronic morphine. J. Pharmacol. Exp. Ther. 310, 774–782. Nair-Roberts, R.G., Chatelain-Badie, S.D., Benson, E., White-Cooper, H., Bolam, J.P., Ungless, M.A., 2008. Stereological estimates of dopaminergic, GABAergic and glutamatergic neurons in the ventral tegmental area, substantia nigra and retrorubral field in the rat. Neuroscience 152, 1024–1031. Nambu, T., Sakurai, T., Mizukami, K., Hosoya, Y., Yanagisawa, M., Goto, K., 1999. Distribution of orexin neurons in the adult rat brain. Brain Res. 827, 243–260. Nestler, E.J., 2001. Neurobiology. Total recall-the memory of addiction. Science 292, 2266–2267. Neumann, P.A., Wang, Y., Yan, Y., Wang, Y., Ishikawa, M., Cui, R., Huang, Y.H., Sesack, S.R., Schluter, O.M., Dong, Y., 2016. Cocaine-induced synaptic alterations in thalamus to nucleus accumbens projection. Neuropsychopharmacology 41, 2399–2410. Oleskevich, S., Descarries, L., Lacaille, J.C., 1989. Quantified distribution of the noradrenaline innervation in the hippocampus of adult rat. J. Neurosci. 9, 3803–3815. Parsania, S., Moradi, M., Fatahi, Z., Haghparast, A., 2016. Involvement of orexin-1 and orexin-2 receptors within the dentate gyrus of the hippocampus in the acquisition, expression and extinction of lateral hypothalamic-induced conditioned place preference in the rats. Brain Res. 1639, 149–160. Pascoli, V., Terrier, J., Espallergues, J., Valjent, E., O’connor, E.C., Luscher, C., 2014. Contrasting forms of cocaine-evoked plasticity control components of relapse. Nature 509, 459–464. Peyron, C., Tighe, D.K., Van Den Pol, A.N., De Lecea, L., Heller, H.C., Sutcliffe, J.G., Kilduff, T.S., 1998. Neurons containing hypocretin (orexin) project to multiple neuronal systems. J. Neurosci. 18, 9996–10015.
References
Pu, L., Liu, Q.S., Poo, M.M., 2006. BDNF-dependent synaptic sensitization in midbrain dopamine neurons after cocaine withdrawal. Nat. Neurosci. 9, 605–607. Qi, K., Wei, C., Li, Y., Sui, N., 2013. Orexin receptors within the nucleus accumbens shell mediate the stress but not drug priming-induced reinstatement of morphine conditioned place preference. Front. Behav. Neurosci. 7, 144. Razavi, Y., Karimi, S., Bani-Ardalan, M., Haghparast, A., 2014. Chemical stimulation of the lateral hypothalamus potentiated the sensitization to morphine in rats: involvement of orexin-1 receptor in the ventral tegmental area. EXCLI J. 13, 1120–1130. Riahi, E., Khodagholi, F., Haghparast, A., 2013. Role of dorsal hippocampal orexin-1 receptors in associating morphine reward with contextual stimuli. Behav. Pharmacol. 24, 237–248. Riahi, E., Arezoomandan, R., Fatahi, Z., Haghparast, A., 2015. The electrical activity of hippocampal pyramidal neuron is subjected to descending control by the brain orexin/hypocretin system. Neurobiol. Learn. Mem. 119, 93–101. Russo, S.J., Mazei-Robison, M.S., Ables, J.L., Nestler, E.J., 2009. Neurotrophic factors and structural plasticity in addiction. Neuropharmacology 56 (Suppl. 1), 73–82. Saddoris, M.P., Sugam, J.A., Cacciapaglia, F., Carelli, R.M., 2013. Rapid dopamine dynamics in the accumbens core and shell: learning and action. Front. Biosci. (Elite Ed.) 5, 273–288. Sadeghi, B., Ezzatpanah, S., Haghparast, A., 2016. Effects of dorsal hippocampal orexin-2 receptor antagonism on the acquisition, expression, and extinction of morphine-induced place preference in rats. Psychopharmacology 233, 2329–2341. Sakurai, T., Amemiya, A., Ishii, M., Matsuzaki, I., Chemelli, R.M., Tanaka, H., Williams, S.C., Richardson, J.A., Kozlowski, G.P., Wilson, S., 1998. Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior. Cell 92, 573–585. SAPER, C.B., Lu, J., Chou, T.C., Gooley, J., 2005. The hypothalamic integrator for circadian rhythms. Trends Neurosci. 28, 152–157. Sesack, S.R., Grace, A.A., 2010. Cortico-basal ganglia reward network: microcircuitry. Neuropsychopharmacology 35, 27–47. Shi, X., Mcginty, J.F., 2006. Extracellular signal-regulated mitogen-activated protein kinase inhibitors decrease amphetamine-induced behavior and neuropeptide gene expression in the striatum. Neuroscience 138, 1289–1298. Smart, D., Jerman, J.C., 2002. The physiology and pharmacology of the orexins. Pharmacol. Ther. 94, 51–61. Smith, M., Piper, D., Duxon, M., Upton, N., 2003. Evidence implicating a role for orexin-1 receptor modulation of paradoxical sleep in the rat. Neurosci. Lett. 341, 256–258. Stuber, G.D., Sparta, D.R., Stamatakis, A.M., Van Leeuwen, W.A., Hardjoprajitno, J.E., Cho, S., Tye, K.M., Kempadoo, K.A., Zhang, F., Deisseroth, K., Bonci, A., 2011. Excitatory transmission from the amygdala to nucleus accumbens facilitates reward seeking. Nature 475, 377–380. Sun, W.L., Zhou, L., Hazim, R., Quinones-Jenab, V., Jenab, S., 2007. Effects of acute cocaine on ERK and DARPP-32 phosphorylation pathways in the caudate-putamen of Fischer rats. Brain Res. 1178, 12–19. Sunter, D., Morgan, I., Edwards, C.M.B., Dakin, C.L., Murphy, K.G., Gardiner, J., Taheri, S., Rayes, E., Bloom, S.R., 2001. Orexins: effects on behavior and localisation of orexin receptor 2 messenger ribonucleic acid in the rat brainstem. Brain Res. 907, 27–34. Swanson, L.W., 1982. The projections of the ventral tegmental area and adjacent regions: a combined fluorescent retrograde tracer and immunofluorescence study in the rat. Brain Res. Bull. 9, 321–353.
153
154
CHAPTER 6 Functional roles of orexin receptors in reward circuit
Taslimi, Z., Haghparast, A., Hassanpour-Ezatti, M., Safari, M.S., 2011. Chemical stimulation of the lateral hypothalamus induces conditioned place preference in rats: involvement of OX1 and CB1 receptors in the ventral tegmental area. Behav. Brain Res. 217, 41–46. Taslimi, Z., Arezoomandan, R., Omranifard, A., Ghalandari-Shamami, M., Riahi, E., Vafaei, A.A., Rashidy-Pour, A., Haghparast, A., 2012. Orexin A in the ventral tegmental area induces conditioned place preference in a dose-dependent manner: involvement of D1/D2 receptors in the nucleus accumbens. Peptides 37, 225–232. Tran, D.-T., Bonaventure, P., Hack, M., Mirzadegan, T., Dvorak, C., Letavic, M., Carruthers, N., Lovenberg, T., Sutton, S.W., 2011. Chimeric, mutant orexin receptors show key interactions between orexin receptors, peptides and antagonists. Eur. J. Pharmacol. 667, 120–128. Trivedi, P., Yu, H., Macneil, D.J., Van Der Ploeg, L., Guan, X.-M., 1998. Distribution of orexin receptor mRNA in the rat brain. FEBS Lett. 438, 71–75. Valjent, E., Pascoli, V., Svenningsson, P., Paul, S., Enslen, H., Corvol, J.C., Stipanovich, A., Caboche, J., Lombroso, P.J., Nairn, A.C., Greengard, P., Herve, D., Girault, J.A., 2005. Regulation of a protein phosphatase cascade allows convergent dopamine and glutamate signals to activate ERK in the striatum. Proc. Natl. Acad. Sci. U.S.A. 102, 491–496. Vezina, P., Giovino, A.A., Wise, R.A., Stewart, J., 1989. Environment-specific crosssensitization between the locomotor activating effects of morphine and amphetamine. Pharmacol. Biochem. Behav. 32, 581–584. Vittoz, N.M., Berridge, C.W., 2006. Hypocretin/orexin selectively increases dopamine efflux within the prefrontal cortex: involvement of the ventral tegmental area. Neuropsychopharmacology 31, 384–395. Volkow, N.D., Wang, G.J., Fowler, J.S., Tomasi, D., Telang, F., 2011. Addiction: beyond dopamine reward circuitry. Proc. Natl. Acad. Sci. U.S.A. 108, 15037–15042. Wang, B., You, Z.B., Wise, R.A., 2009. Reinstatement of cocaine seeking by hypocretin (orexin) in the ventral tegmental area: independence from the local corticotropin-releasing factor network. Biol. Psychiatry 65, 857–862. Williams, J.M., Owens, W.A., Turner, G.H., Saunders, C., Dipace, C., Blakely, R.D., France, C.P., Gore, J.C., Daws, L.C., Avison, M.J., Galli, A., 2007. Hypoinsulinemia regulates amphetamine-induced reverse transport of dopamine. PLoS Biol. 5, e274. Willie, J.T., Chemelli, R.M., Sinton, C.M., Tokita, S., Williams, S.C., Kisanuki, Y.Y., Marcus, J.N., Lee, C., Elmquist, J.K., Kohlmeier, K.A., 2003. Distinct narcolepsy syndromes in orexin receptor-2 and orexin null mice: molecular genetic dissection of nonREM and REM sleep regulatory processes. Neuron 38, 715–730. Yazdi, F., Jahangirvand, M., Pirasteh, A.H., Moradi, M., Haghparast, A., 2015. Functional interaction between OX2 and CB1 receptors in the ventral tegmental area and the nucleus accumbens in response to place preference induced by chemical stimulation of the lateral hypothalamus. Pharmacol. Biochem. Behav. 139, 39–46. Zarepour, L., Fatahi, Z., Sarihi, A., Haghparast, A., 2014. Blockade of orexin-1 receptors in the ventral tegmental area could attenuate the lateral hypothalamic stimulation-induced potentiation of rewarding properties of morphine. Neuropeptides 48, 179–185. Zhang, D., Zhang, L., Lou, D.W., Nakabeppu, Y., Zhang, J., Xu, M., 2002. The dopamine D1 receptor is a critical mediator for cocaine-induced gene expression. J. Neurochem. 82, 1453–1464. Zhu, Y., Wienecke, C.F., Nachtrab, G., Chen, X., 2016. A thalamic input to the nucleus accumbens mediates opiate dependence. Nature 530, 219–222.
Functional roles of orexin/ hypocretin receptors in reward circuit
6
Abbas Haghparast*,1, Zahra Fatahi*, Reza Arezoomandan†, Sara Karimi‡, Zahra Taslimi§, Shahram Zarrabian¶ *Neuroscience Research Center, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran † School of Behavioral Sciences and Mental Health (Tehran Institute of Psychiatry), Iran University of Medical Sciences, Tehran, Iran ‡ Physiology Research Center, Kashan University of Medical Sciences, Kashan, Iran § Neurophysiology Research Center, Hamadan University of Medical Sciences, Hamadan, Iran ¶ Cognitive and Neuroscience Research Center (CNRC), Tehran Medical Sciences Branch, Islamic Azad University, Tehran, Iran 1 Corresponding author: Tel.: +98-21-2242-9765; Fax: +98-21-2243-1624, e-mail address: [email protected]; [email protected]
Abstract Since its first discovery in 1998, it has become clear that the orexinergic system plays an important role in regulating a number of functions including food, sex, social connections, and most prominently reward-related behaviors. Orexinergic neurons in the lateral hypothalamus project extensively to other brain areas, two most important of which are the ventral tegmental area and the nucleus accumbens that are involved in reward processing. In this review, we have presented the work in our laboratory along with the work of others and have discussed the possible functions we can infer from the research. We discuss the anatomy of the orexinergic system and its components followed by a presentation of other connected brain areas. The second part of this review discusses observed results from the morphine conditioned place preference test that sheds light on the possible role of the involved areas in reward processing. The complex circuits involved in reward processing are only beginning to be understood and we need to deepen our understanding regarding the nature of the interactions between all brain areas involved.
Keywords Orexin/hypocretin, Reward, Lateral hypothalamus, Ventral tegmental area, Nucleus accumbens, Prefrontal cortex, Hippocampus
Progress in Brain Research, Volume 235, ISSN 0079-6123, https://doi.org/10.1016/bs.pbr.2017.08.005 © 2017 Elsevier B.V. All rights reserved.
139
140
CHAPTER 6 Functional roles of orexin receptors in reward circuit
1 INTRODUCTION 1.1 OREXIN In 1998, new neuropeptides were discovered by two separate laboratories and thus separately named orexins A and B, also known as hypocretins 1 and 2 (De Lecea et al., 1998; Mould et al., 2014; Sakurai et al., 1998). The origin of orexin is the Greek term for orexins (appetite), selected based on the fact that the first behavioral effect noted for these peptides was feeding (Sakurai et al., 1998). On the other hand, the hypothalamic location of the orexinergic neurons and the structural similarity with the gut incretin peptides led to selection of the term “hypocretin” (Sunter et al., 2001). Currently, both orexin and hypocretin terms are used in scientific articles. In this review, we will use the term orexin to discuss the orexinergic effect of these peptides.
1.2 OREXIN RECEPTORS Two types of orexin receptors have been characterized that include orexin 1 receptor (OX1R) and orexin 2 receptor (OX2R). OX2R has a similar high affinity for both orexin peptides, whereas OX1R has a 30 nM affinity for binding to orexin A, but a much lower affinity for orexin B (Aston-Jones et al., 2010). The two receptor types also differ in signaling pathways. The OX1R signals mainly via Gq coupling, whereas the OX2R signals through Gq or Gi/o coupling (Boss and Roch, 2015). Orexin receptors couple to at least three G-protein families and possibly other proteins, through which they regulate nonselective cation channels, phospholipases, adenylyl cyclase, and protein and lipid kinases. In the central nervous system, orexin receptors activate nonselective cation channels, inhibit K+ channels, activate Na+/Ca2+ exchange, produce postsynaptic depolarization, and stimulate neurons. However, once located on the presynaptic membrane, they can stimulate the release of neurotransmitters and modulate synaptic plasticity (Kukkonen and Leonard, 2014).
1.3 OREXIN RECEPTORS AND PHARMACOLOGICAL AGENTS Several orexin receptor antagonists have been described (Gunthorpe et al., 2004; Smart and Jerman, 2002). The first and most widely used compound is SB334867, which has a higher affinity for OX1Rs, but blocks the binding of the agonists to both orexin receptors (Li et al., 2014). TCS OX2 29 (Mould et al., 2014) and JNJ-10397049 (Tran et al., 2011) are selective OX2R antagonists. Suvorexant, a dual orexin receptor antagonist, is the first of the new class recently synthesized and has been successfully used for the treatment of insomnia (Bennett et al., 2014).
1.4 THE DISTRIBUTION OF OREXIN RECEPTORS Like many other receptor types, orexin receptors also differ in their distribution in the brain (Kilduff and De Lecea, 2001; Marcus et al., 2001; Trivedi et al., 1998). From a functional viewpoint, the review of the literature shows that loss of signaling at OX2R is associated with symptoms of narcolepsy in animals (Lin et al., 1999;
2 Reward and reward processing
Willie et al., 2003). This abnormality provided the basis for the arousal-related hypothesis of the orexin system (Akanmu and Honda, 2005; Marcus et al., 2001; Willie et al., 2003). Furthermore, the OX2R antagonist, JNJ-10397049, significantly reduced latency to non-REM sleep and increased sleep time (Dugovic et al., 2009; Smith et al., 2003). As the OX1R antagonist (SB334867) had no effect on sleep–wake states, signaling via OX1R was hypothesized to be primarily related to the other functions of the orexin system such as satiety- and reward-related behaviors.
1.5 OREXINERGIC NEURONS AND THEIR CONNECTIVITY Specific neurons in the lateral hypothalamus (LH) produce the orexin neuropeptides. The dorsal, perifornical, posterior, and lateral areas are known as the main origins of orexins A and -B (De Lecea et al., 1998; Peyron et al., 1998; Sakurai et al., 1998). Orexin fibers project to virtually all the areas in the hypothalamus, including the arcuate, paraventricular, lateral, perifornical, and ventromedial areas. In addition, orexinergic neurons make widespread projections and connectivity to other brain areas important for the regulation of feeding and arousal (Brown et al., 2002; Hervieu et al., 2001; Sunter et al., 2001), as well as sleep–wake cycles, cognition, locomotion, and reward processing (Li et al., 2014). Keeping in mind the role of the orexinergic projections and structures in the brain functions, there are also other structures which are involved in each of the functions. For example, the tuberomammillary nucleus, locus coeruleus, ventral periaqueductal gray matter, and dorsal raphe nuclei are involved in arousal (Peyron et al., 1998; Saper et al., 2005); the prefrontal cortex (PFC) and hippocampus (HIP) are involved in cognition; the cuneiform nucleus and lateral vestibular nucleus are concerned with locomotion; and the ventral tegmental area (VTA) and nucleus accumbens (NAc) play a prominent role in the reward system (Li et al., 2014). Besides the nerve projections suggest the involvement of the orexinergic system in drug-related effects, a number of functional studies have also supported a link between orexin and addictive behavior. For instance, stimulation of the LH stimulation potentiated the effect of an ineffective dose of morphine and induced morphine sensitization (Razavi et al., 2014), while chemical stimulation of the LH resulted in a change in conditioned place preference (CPP) suggesting the involvement of orexin A in drug-seeking behavior (Taslimi et al., 2011). Administration of orexin A in the VTA also induced CPP in a dose-dependent manner in rats (Taslimi et al., 2012) and intrahippocampal administration of SB334867 before conditioning sessions, disrupted the rewarding effect of morphine (Riahi et al., 2013). These results clearly indicate a role for orexinergic neurons in reward processing.
2 REWARD AND REWARD PROCESSING Reward is defined as something given in exchange for good behaviors. Understanding the brain circuitry underlying feelings of reward or pleasure is of great interest and a myriad of papers have been published determining regions and connections
141
142
CHAPTER 6 Functional roles of orexin receptors in reward circuit
associated with a number of natural rewards including food, sex, and social connections (Berridge and Robinson, 1998). Several studies have taken the advantage of increasingly sophisticated genetics based tools to observe and to manipulate neuronal activity within specific cell types and circuits to ascertain their role in reward processes. However, much of what we know about the structure of the reward circuit, and the generation of pleasure, were originally identified in the context of drugs of abuse. Thus, our understanding of the circuitry underlying the rewarding aspects of drug use and maladaptive reward underlying addiction, give us a better chance to understand general reward mechanisms. Moreover, while some specific nodes of the reward circuitry—such as dopamine (DA) outputs from the VTA to the NAc—and their importance in drug reward are well established (Cooper et al., 2017), our understanding of the complexity of the reward circuit underlying various aspects of addiction, such as relapse and craving, has recently increased through the use of “circuit-busting” opto- and chemo-genetic approaches. We here summarize the current understanding of the major brain regions in drug reward and the role of the connections between these regions (circuitry) in aspects relevant to addiction to generate a better understanding of the dynamics of these reward circuits that will potentially, help us improve the treatment of drug addiction.
2.1 REWARD CIRCUITRY There are a number of brain structures involved in reward, including the VTA, NAc, PFC, ventral HIP, amygdala, and thalamus. We will discuss the findings regarding each of the mentioned areas and will point out the information regarding brainderived neurotrophic factor (BDNF) in brief.
2.1.1 The VTA The general understanding of the reward circuitry underlying addiction begins with the VTA, a heterogeneous brain region composed largely of DA (60%–65%) and g-amino butyric acid (GABA; 30%–35%) neurons, and a smaller proportion of glutamatergic neurons (2%–3%) (Nair-Roberts et al., 2008; Swanson, 1982). Most studies have focused on the dopaminergic neurons of the VTA as the stimulation of these neurons and release of DA in projection sites, most notably the NAc, is known to produce reward. Earlier works have shown that virtually all known drugs of abuse increase DA release in the NAc (Di Chiara and Imperato, 1988). As the focus of this review is on reward, many of the studies discussed below focus on the VTA dopaminergic neurons although, it is also clear that VTA GABAergic neurons are critical for the reward processing.
2.1.2 The NAc As described above, a major reward-related output of VTA DA activity is the NAc. DA can exert its effects via activating DA receptors located on medium spiny neurons (MSNs), the predominant cell type in the NAc.
2 Reward and reward processing
D1 (dopamine receptor type 1) and D2 (dopamine receptor type 2) neurons in the dorsal striatum are thought to have generally separate projections, with D1 MSNs constituting the “direct” pathway (responsible for increasing thalamocortical drive) and D2 MSNs forming the “indirect” pathway (responsible for decreasing thalamocortical drive). In addition to the cellular heterogeneity (D1 vs D2 neurons), a regional heterogeneity also exists, causing distinct drug-associated behaviors and plasticity differences between the NAc core and shell subregions (Saddoris et al., 2013). MSNs in the NAc core appear to be critical for assigning motivational values to discrete stimuli associated with reward or aversion and particularly updating these values as circumstances change, whereas, those in the NAc shell drive behavioral responses to repeated exposure to rewarding experiences such as chronic drug administration (Meredith et al., 2008). While VTA dopaminergic neurons provide a strong modulatory input into the NAc MSNs, they also receive a considerable large glutamatergic input from a variety of limbic and cortical regions, some of the most notable ones are the PFC, ventral HIP, and basolateral amygdala (BLA) (Floresco, 2015; Sesack and Grace, 2010).
2.1.3 The PFC The PFC input to the NAc is largely associated with executive control and is thought to mediate the goal-directed behaviors such as seeking behavior and planning of action to obtain rewarding substances (Kalivas et al., 2005). The PFC subregions differ in their projection to the NAc. For example, the infralimbic (IL) and prelimbic (PrL) areas of the medial PFC preferentially project to the shell and core areas of the NAc, respectively (Sesack and Grace, 2010).
2.1.4 The ventral HIP The ventral HIP also sends glutamatergic projections to the NAc and is thought to act as a site of integration between spatial/contextual information from the dorsal HIP and emotional information from the BLA and locus coeruleus (French et al., 2003; French and Totterdell, 2003; Oleskevich et al., 1989). Thus, the ventral HIP–NAc connection acts to provide contextually relevant emotional information and influences goal-directed behaviors. This circuit has been implicated in both reward and aversive behaviors and its modulation has been shown to impact locomotor responses to drugs of abuse and cue-induced drug-seeking behaviors (Pascoli et al., 2014; Vezina et al., 1989).
2.1.5 The amygdala The amygdala also sends glutamatergic input to the NAc and its effects are thought to be mediated by D1-like receptor activation (Charara and Grace, 2003; Stuber et al., 2011). In particular, the activation of the projections from BLA to NAc facilitates reward seeking and supports positive reinforcement (Ambroggi et al., 2008; Stuber et al., 2011). Although the role for the activation of the amygdala in emotional learning and role for the projections from the BLA in mediating fear and anxiety
143
144
CHAPTER 6 Functional roles of orexin receptors in reward circuit
behaviors are well established, these effects appear to be mediated distinctly from those BLA projections to the NAc, as the BLA–NAc microcircuit is involved in reward and reinforcement drive (Janak and Tye, 2015).
2.1.6 The thalamus The research has recently characterized the glutamatergic inputs into the NAc from the subregions of the thalamus, especially the midline thalamic nuclei like the paraventricular nucleus (PVT). Compared to the stimulation of glutamatergic inputs from the regions described earlier (ventral HIP, PFC, and amygdala), which produce rewarding effects, direct activation of the PVT–NAc pathway produces aversive effects, driving behavioral aversion in a real-time place preference assay (Zhu et al., 2016). These behavioral changes are likely driven by changes in druginduced plasticity within the medial thalamus–NAc circuit, as cocaine experience has been shown to alter N-methyl-D-aspartate (NMDA) function and plasticity and increase silent synapses within this circuit. The plasticity changes have been shown to be dependent on both MSN cell types (D1 vs non-D1) and the subregions (shell vs core) (Joffe and Grueter, 2016; Neumann et al., 2016). Together, the regions described earlier form a highly integrated circuit, the corticobasal ganglia reward network (Sesack and Grace, 2010), and drug-induced changes in plasticity within the circuit contribute to various facets of addiction (Luscher, 2016).
2.2 REWARD AND NEUROTROPHIC FACTORS Neurotrophic factor signaling and, in particular, the signaling related to BDNF acts on the tropomyosin kinase B (TrkB) receptor, and its downstream effects have been shown to be involved in drug dependence and addiction (Russo et al., 2009). Multiple studies found that BDNF expression increased in response to both self- and investigator-administered cocaine throughout the reward circuitry, which includes the NAc, PFC, VTA, and amygdala (Fumagalli et al., 2013; Graham et al., 2007; Grimm et al., 2003). Changes in BDNF protein and mRNA levels have been examined in multiple brain regions following the administration of many classes of addictive substances. Stimulants produce a widespread, but transient, induction of BDNF protein in the NAc, PFC, VTA, and the central and basolateral nuclei of the amygdala (Graham et al., 2007; Grimm et al., 2003; Le Foll et al., 2005). Both contingent and noncontingent (i.e., yoked animals and self-administering animals) cocaine administrations cause elevated levels of BDNF protein in the NAc (Graham et al., 2007; Liu et al., 2006; Zhang et al., 2002). Likewise, long-term withdrawal of up to 90 days after cocaine self-administration correlates with an increased BDNF protein level in the NAc, VTA, and amygdala (Grimm et al., 2003; Pu et al., 2006), and there is early evidence that epigenetic regulation of the BDNF gene may be involved in mediating this persistent induction (Kumar et al., 2005).
3 Reward processing and drug abuse
2.2.1 Drug-induced changes in BDNF signaling pathways in brain reward regions Several proteins in neurotrophin signaling cascades have been shown to be regulated within the mesolimbic DA system by opiates and stimulants; these include the drug effects on IRS–PI3K–Akt, PLCg, Ras–ERK, and NFkB signaling. Acute or chronic administration of stimulants dramatically increases ERK phosphorylation in numerous brain regions including the NAc, VTA, and PFC (Jenab et al., 2005; Shi and McGinty, 2006; Sun et al., 2007; Valjent et al., 2005). These findings are consistent with stimulant-induced increases in the number of neuronal branches and spines and led us to the Ras–ERK’s established role in neurite outgrowth. In addition, several recent reports have shown that IRS–PI3K–Akt signaling is influenced by drugs of abuse (Brami-Cherrier et al., 2002; McGinty et al., 2008; Muller and Unterwald, 2004; Williams et al., 2007). Alterations in the PLCg and NFkB signaling pathways in drug abuse have not been studied as extensive as those for ERK and Akt. However, recent work shows that both pathways are regulated by drugs of abuse.
3 REWARD PROCESSING AND DRUG ABUSE Harris and his colleagues were the first to show the involvement of orexin neurons of the LH in reward processing and drug abuse (Harris et al., 2005). They found that the LH neurons were activated after conditioning of rats with cocaine, morphine, or food in a CPP paradigm. Notably, the activation of the LH orexin neurons showed correlation with the intensity of reward on the CPP test day. The activation of the LH orexin neurons after acquiring reward, demonstrated a potential implication of these neurons in reward-related phenomena. Following the first demonstration of the role of the LH orexinergic neurons in reward processing, they showed that systemic administration of the OX1R antagonist, SB334867, before the CPP test day significantly attenuated the expression of morphine–CPP (Harris et al., 2005, 2007). They also showed that morphine administration during the conditioning period (in the CPP compartment), but not in the home cage, stimulated the LH neurons and bilateral lesions of the LH area completely blocked the development of morphineinduced CPP (Harris et al., 2007). Taken this as evidence for the direct role of the LH orexinergic neurons in the acquisition of CPP, Taslimi et al. (2011) chemically stimulated the orexinergic neurons by unilateral intra-LH administration of carbachol, as a cholinergic agonist. Their results showed that stimulation of the LH by carbachol during the conditioning phase produced a significant change in the CPP score and the rats showed more preference to the drug-associated compartment in a dose-dependent manner. The results provided evidence for the rewarding property of chemical LH stimulation (Taslimi et al., 2011). The VTA and NAc are two main areas of the mesolimbic dopaminergic system that are critical for the initiation of opioid reinforcement- and reward-related effects, which provides converging evidence considering that orexin receptors are expressed at high levels in both of these areas (Fadel and Deutch, 2002). An electrophysiological study
145
146
CHAPTER 6 Functional roles of orexin receptors in reward circuit
indicated that orexin excited VTA dopaminergic neurons. Furthermore, it has been shown that the orexinergic system can increase DA and glutamate transmission, the main neurotransmitters involved in reward-related phenomena. Vittoz and Berridge (2006) showed that the VTA is implicated in orexin-increased DA efflux in the PFC and suggested that the activation of the VTA dopaminergic neurons contributes to the behavioral effects of orexin (Vittoz and Berridge, 2006). Another study indicated that orexin-B increased glutamatergic transmission in the VTA neurons (Borgland et al., 2008). In our laboratory, we showed that intra-VTA administration of SB334867 just 5 min before carbachol during the conditioning phase, blocked the development of LH stimulation-induced CPP (Taslimi et al., 2011). In another study, we investigated the role of VTA OX2Rs in the induction of CPP by the chemical stimulation of the LH. The results showed that intra-VTA administration of TCS OX2 29, 5 min before intra-LH microinjection of carbachol during the 3-day conditioning phase, modulated the developing rewarding effect of LH stimulation (Yazdi et al., 2015). Harris et al. showed that intra-VTA administration of SB334867 into the VTA prior to each morphine-pairing session could block the induction of morphine CPP (Harris et al., 2007). In another study in our lab, we showed that chemical stimulation of the LH by carbachol potentiated the rewarding effect of morphine. We then examined the role of VTA orexin receptors in the acquisition and expression of morphine CPP induced by concurrent stimulation of the LH and showed that the intra-VTA administration of SB334867, 5 min before carbachol injection, could inhibit the acquisition (development), but not the expression, of LH stimulation-induced morphine CPP in rats (Zarepour et al., 2014).
3.1 THE VTA AND REWARD PROCESSING A number of studies have investigated the direct role of the VTA in reward processing. In our lab, we examined the rewarding effects of direct orexin administration into the VTA and showed that unilateral injection of orexin A into the VTA before each conditioning season induced CPP in a dose-dependent manner (Taslimi et al., 2012). Next, we investigated the role of NAc DA receptors in the development of orexin-induced reward-related behaviors. We microinjected SCH 23390 (as a D1 receptor antagonist) and sulpiride (as a D2 receptor antagonist) unilaterally during the acquisition phase into the NAc 5 min prior to the administration of orexin A into the VTA. The data revealed that blockade of NAc DA receptors inhibited the development of orexin-induced rewarding effects (Taslimi et al., 2012). These results suggest that NAc DA receptors are implicated in the observed rewarding effects, which result from the activation of VTA dopaminergic neurons by orexin. Activation of the orexin receptors, either by the administration of orexin into the VTA or the application of foot-shock stress, has been shown to induce cocaine reinstatement and increase the release of glutamate and DA in the VTA (Wang et al., 2009). In addition, infusions of orexin A into the VTA increased cocaine self-administration (Espana et al., 2011), which shows that enhancement of orexin signaling in the VTA promotes the reinforcing effects of cocaine. The study added to our knowledge about
3 Reward processing and drug abuse
drug self-administration and showed that orexin acts within the VTA to activate the mesocorticolimbic DA system by affecting the VTA neurons. In summary, these studies indicate that orexin projections, specifically those from the LH to the VTA, are involved in neurotransmitter transmission, regulation of reward processing, and CPP learning. They also suggest a substantial role for orexin A receptors within the VTA in the mentioned phenomena.
3.2 THE NAc AND REWARD PROCESSING The NAc is a central component of the basal ganglia that is known as the pleasure center of the brain. The NAc receives dopaminergic projections from the VTA and glutamatergic projections from the medial PFC and plays an important role in reward-related phenomena (Kalivas and Volkow, 2005). On the other hand, the NAc receives orexinergic projections from the LH, which are involved in behavioral responses to psychostimulant consumption (Fadel and Deutch, 2002). In addition, orexin receptors are expressed at high levels in the NAc (Cluderay et al., 2002). It has been shown that the orexinergic system interacts with the DA signaling system in the NAc. An in vivo microdialysis study investigated the effect of the VTA orexin system on DA signaling in the NAc and showed that orexin administration into the VTA increased cocaine-induced enhancement of DA release in the NAc core (Espana et al., 2011). Several studies have investigated the role of the orexinergic system in the NAc in reward processing, by chemical stimulation of the LH by carbachol-induced CPP (Taslimi et al., 2011), for example. We also investigated the involvement of the NAc OX1 and CB1 cannabinoid receptors in the acquisition and expression of reward-related behaviors induced by LH stimulation and showed that blockade of OX1Rs by intra-NAc administration of SB334867 before intra-LH carbachol application inhibited the rewarding effects induced by LH stimulation (Fatahi et al., 2015). Furthermore, intra-NAc injection of SB334867 on the conditioning day modulated the expression of LH stimulation-induced CPP. The study also showed that concurrent blockade of OX1 and CB1 receptors in the NAc, before carbachol injection during the conditioning phase, inhibited the development of LH stimulation-induced CPP. It can be concluded that orexinergic projections from the LH to NAc and the OX1Rs in the NAc are involved in the LH stimulation-induced CPP. In addition, the results suggested an interaction between the OX1 and CB1 receptors within the NAc in the rewarding effect induced by carbachol (Fatahi et al., 2015). Following our investigation on the role of ORX1Rs, we studied the role of OX2Rs within the NAc in the development of reward-related behaviors induced by chemical stimulation of the LH (Yazdi et al., 2015). Our results showed that intra-NAc administration of TCS OX2 29, 5 min before intra-LH microinjection of carbachol during the 3-day conditioning phase, modulated the development of the rewarding effect of LH stimulation (Yazdi et al., 2015). In another study, Qi et al. investigated the role of orexin receptors in the NAc in stress- and priming-induced reinstatement of morphine (Qi et al., 2013). Their results
147
148
CHAPTER 6 Functional roles of orexin receptors in reward circuit
indicated that blockade of OX1Rs and OX2Rs in NAc shell blocked stress-induced reinstatement, but neither of the orexin antagonists had any effect on the reinstatement of morphine-seeking behaviors (Qi et al., 2013).
3.3 THE HIP AND REWARD PROCESSING It is well established that the HIP plays a critical role in learning and memory and is involved in drug- and context-induced seeking behaviors that can form addictive memories (Nestler, 2001). In addition, the HIP has an important role in rewardrelated learning tasks such as the CPP paradigm (Riahi et al., 2013). The HIP receives orexinergic projections from the LH and all the regions of the HIP express both OX1 and OX2 receptors (Nambu et al., 1999). An in vivo single unit recording from the hippocampal area showed that orexin administration into the lateral cerebral ventricle predominantly excited hippocampal pyramidal neurons. Furthermore, chemical stimulation of the LH by carbachol injection also excited hippocampal neurons (Riahi et al., 2015). In our laboratory, we examined the function of OX1Rs and OX2Rs in the dentate gyrus (DG) in the acquisition, expression, and extinction of lateral hypothalamic induced CPP (Parsania et al., 2016) and showed that intraDG administration of OX1R and OX2R antagonists before carbachol administration during the conditioning phase blocked the rewarding effect of LH stimulation and also decreased the expression of LH-induced CPP. Furthermore, the OX1R, but not OX2R, antagonist shortened the maintenance of carbachol-induced CPP (Parsania et al., 2016). In another study, we investigated the role of hippocampal OX2Rs in the acquisition, expression, and extinction of morphine-induced CPP. The results showed that intra-CA1 injection of TCS OX2 29 during the conditioning phase inhibited the induction of morphine–CPP in both postconditioning and expression phases. Furthermore, the administration of OX2R shortened the maintenance time of morphine-seeking behaviors (Sadeghi et al., 2016). We also investigated the role of the OX1 and OX2 receptors in the DG in stress- and drug priming-induced reinstatement. On the reinstatement day, the animals received intra-DG administration of SB334867 and TCS OX2 29, and then were tested for morphine priming- and forced swim stress-induced reinstatement. The results revealed that intra-DG administration of OX1 and OX2 receptor antagonists attenuated drug priming-induced reinstatement, but had only a trivial effect on the forced swim stress-induced reinstatement (Ebrahimian et al., 2016).
4 REWARD PROMOTION Orexin activates the VTA DA projecting neurons to the NAc and promotes the rewarding effects of a rewarding drug (Volkow et al., 2011). Therefore, in our laboratory, we investigated the involvement of NAc D1-like and D2-like DA receptors in the development of reward-related behaviors induced by the chemical
References
stimulation of the LH (Haghparast et al., 2013). The results showed that blockade of D1-like or D2-like DA receptors in the NAc modulated the acquisition of CPP induced by LH stimulation.
5 CONCLUSION Rewarding experiences involve our emotions and affect our future actions partly through recall of our past memories. The complex circuits involved in reward processing, as one of the distinguished functions of the orexinergic system, are only beginning to be understood. This is mainly because of the fact that reward is an integrated part of simple behaviors like food intake as well as complex ones such as social connections. Considering the wide spread and uneven distribution of the orexin receptors in the brain, we now partly know how the orexinergic system interacts with the other neurotransmitter systems such as the glutamatergic, GABAergic, and even the cannabinoid system. The dopaminergic output from the VTA into the NAc has a prominent role in reward and its processes. The critical role of GABAergic neurons of the VTA, however, has been investigated far less. The NAc is not only heterogeneous in its dopaminergic receptors but also shows heterogeneity in its subregions. The NAc also receives notable glutamatergic inputs from frontal and subcortical regions of the brain, one of the most important of which is from the HIP. The great role of HIP in encoding the environment cues and its events have now been understood to the extent that we know how a past environmental cue can trigger a certain action which has been practiced over time. The literature mentioned in this review shed light on our present knowledge of the key players in the mentioned brain areas. The results clearly indicate that the application of orexin directly into a target site of interest or chemical stimulation of orexinergic neurons in LH produces similar results on the behavior of rodents in the addiction tests, which is an indication of the fact that orexin exerts part of its effects through dopaminergic neurons in the VTA and NAc, and possibly the excitation of the glutamatergic neurons. Although it was first understood that OX1Rs have a dominant role in drug-seeking behavior and drug dependency, more and more evidence is reported by the laboratories regarding the involvement of OX2Rs in the rewarding effects of orexin.
REFERENCES Akanmu, M.A., Honda, K., 2005. Selective stimulation of orexin receptor type 2 promotes wakefulness in freely behaving rats. Brain Res. 1048, 138–145. Ambroggi, F., Ishikawa, A., Fields, H.L., Nicola, S.M., 2008. Basolateral amygdala neurons facilitate reward-seeking behavior by exciting nucleus accumbens neurons. Neuron 59, 648–661. Aston-Jones, G., Smith, R.J., Sartor, G.C., Moorman, D.E., Massi, L., Tahsili-Fahadan, P., Richardson, K.A., 2010. Lateral hypothalamic orexin/hypocretin neurons: a role in reward-seeking and addiction. Brain Res. 1314, 74–90.
149
150
CHAPTER 6 Functional roles of orexin receptors in reward circuit
Bennett, T., Bray, D., Neville, M.W., 2014. Suvorexant, a dual orexin receptor antagonist for the management of insomnia. Pharmacol. Ther 39, 264. Berridge, K.C., Robinson, T.E., 1998. What is the role of dopamine in reward: hedonic impact, reward learning, or incentive salience? Brain Res. Brain Res. Rev. 28, 309–369. Borgland, S.L., Storm, E., Bonci, A., 2008. Orexin B/hypocretin 2 increases glutamatergic transmission to ventral tegmental area neurons. Eur. J. Neurosci. 28, 1545–1556. Boss, C., Roch, C., 2015. Recent trends in orexin research—2010 to 2015. Bioorg. Med. Chem. Lett. 25, 2875–2887. Brami-Cherrier, K., Valjent, E., Garcia, M., Pages, C., Hipskind, R.A., Caboche, J., 2002. Dopamine induces a PI3-kinase-independent activation of Akt in striatal neurons: a new route to cAMP response element-binding protein phosphorylation. J. Neurosci. 22, 8911–8921. Brown, R.E., Sergeeva, O.A., Eriksson, K.S., Haas, H.L., 2002. Convergent excitation of dorsal raphe serotonin neurons by multiple arousal systems (orexin/hypocretin, histamine and noradrenaline). J. Neurosci. 22, 8850–8859. Charara, A., Grace, A.A., 2003. Dopamine receptor subtypes selectively modulate excitatory afferents from the hippocampus and amygdala to rat nucleus accumbens neurons. Neuropsychopharmacology 28, 1412–1421. Cluderay, J.E., Harrison, D.C., Hervieu, G.J., 2002. Protein distribution of the orexin-2 receptor in the rat central nervous system. Regul. Pept. 104, 131–144. Cooper, S., Robison, A.J., Mazei-Robison, M.S., 2017. Reward circuitry in addiction. Neurotherapeutics 14 (3), 687–697. De Lecea, L., Kilduff, T., Peyron, C., Gao, X.-B., Foye, P., Danielson, P., Fukuhara, C., Battenberg, E., Gautvik, V., Bartlett, F.N., 1998. The hypocretins: hypothalamus-specific peptides with neuroexcitatory activity. Proc. Natl. Acad. Sci. 95, 322–327. Di Chiara, G., Imperato, A., 1988. Drugs abused by humans preferentially increase synaptic dopamine concentrations in the mesolimbic system of freely moving rats. Proc. Natl. Acad. Sci. U.S.A. 85, 5274–5278. Dugovic, C., Shelton, J.E., Aluisio, L.E., Fraser, I.C., Jiang, X., Sutton, S.W., Bonaventure, P., Yun, S., Li, X., Lord, B., 2009. Blockade of orexin-1 receptors attenuates orexin-2 receptor antagonism-induced sleep promotion in the rat. J. Pharmacol. Exp. Ther. 330, 142–151. Ebrahimian, F., Naghavi, F.S., Yazdi, F., Sadeghzadeh, F., Taslimi, Z., Haghparast, A., 2016. Differential roles of orexin receptors within the dentate gyrus in stress- and drug priminginduced reinstatement of conditioned place preference in rats. Behav. Neurosci. 130, 91–102. Espana, R.A., Melchior, J.R., Roberts, D.C., Jones, S.R., 2011. Hypocretin 1/orexin a in the ventral tegmental area enhances dopamine responses to cocaine and promotes cocaine self-administration. Psychopharmacology (Berl) 214, 415–426. Fadel, J., Deutch, A.Y., 2002. Anatomical substrates of orexin-dopamine interactions: lateral hypothalamic projections to the ventral tegmental area. Neuroscience 111, 379–387. Fatahi, Z., Assar, N., Mahmoudi, D., Pahlevani, P., Moradi, M., Haghparast, A., 2015. Functional interaction between the orexin-1 and CB1 receptors within the nucleus accumbens in the conditioned place preference induced by the lateral hypothalamus stimulation. Pharmacol. Biochem. Behav. 132, 42–48. Floresco, S.B., 2015. The nucleus accumbens: an interface between cognition, emotion, and action. Annu. Rev. Psychol. 66, 25–52. French, S.J., Totterdell, S., 2003. Individual nucleus accumbens-projection neurons receive both basolateral amygdala and ventral subicular afferents in rats. Neuroscience 119, 19–31.
References
French, S.J., Hailstone, J.C., Totterdell, S., 2003. Basolateral amygdala efferents to the ventral subiculum preferentially innervate pyramidal cell dendritic spines. Brain Res. 981, 160–167. Fumagalli, F., Moro, F., Caffino, L., Orru, A., Cassina, C., Giannotti, G., Di Clemente, A., Racagni, G., Riva, M.A., Cervo, L., 2013. Region-specific effects on BDNF expression after contingent or non-contingent cocaine i.v. self-administration in rats. Int. J. Neuropsychopharmacol. 16, 913–918. Graham, D.L., Edwards, S., Bachtell, R.K., Dileone, R.J., Rios, M., Self, D.W., 2007. Dynamic BDNF activity in nucleus accumbens with cocaine use increases self-administration and relapse. Nat. Neurosci. 10, 1029–1037. Grimm, J.W., LU, L., Hayashi, T., Hope, B.T., Su, T.P., Shaham, Y., 2003. Time-dependent increases in brain-derived neurotrophic factor protein levels within the mesolimbic dopamine system after withdrawal from cocaine: implications for incubation of cocaine craving. J. Neurosci. 23, 742–747. Gunthorpe, M., Rami, H., Jerman, J., Smart, D., Gill, C., Soffin, E., Hannan, S.L., Lappin, S., Egerton, J., Smith, G., 2004. Identification and characterisation of SB-366791, a potent and selective vanilloid receptor (VR1/TRPV1) antagonist. Neuropharmacology 46, 133–149. Haghparast, A., Omranifard, A., Arezoomandan, R., Ghalandari-Shamami, M., Taslimi, Z., Vafaei, A.A., Rashidy-Pour, A., 2013. Involvement of dopaminergic receptors of the rat nucleus accumbens in decreasing the conditioned place preference induced by lateral hypothalamus stimulation. Neurosci. Lett. 556, 10–14. Harris, G.C., Wimmer, M., Aston-Jones, G., 2005. A role for lateral hypothalamic orexin neurons in reward seeking. Nature 437, 556–559. Harris, G.C., Wimmer, M., Randall-Thompson, J.F., Aston-Jones, G., 2007. Lateral hypothalamic orexin neurons are critically involved in learning to associate an environment with morphine reward. Behav. Brain Res. 183, 43–51. Hervieu, G., Cluderay, J., Harrison, D., Roberts, J., Leslie, R., 2001. Gene expression and protein distribution of the orexin-1 receptor in the rat brain and spinal cord. Neuroscience 103, 777–797. Janak, P.H., Tye, K.M., 2015. From circuits to behaviour in the amygdala. Nature 517, 284–292. Jenab, S., Festa, E.D., Nazarian, A., Wu, H.B., Sun, W.L., Hazim, R., Russo, S.J., QuinonesJenab, V., 2005. Cocaine induction of ERK proteins in dorsal striatum of Fischer rats. Brain Res. Mol. Brain Res. 142, 134–138. Joffe, M.E., Grueter, B.A., 2016. Cocaine experience enhances thalamo-accumbens N-methyl-D-aspartate receptor function. Biol. Psychiatry 80, 671–681. Kalivas, P.W., Volkow, N.D., 2005. The neural basis of addiction: a pathology of motivation and choice. Am. J. Psychiatry 162, 1403–1413. Kalivas, P.W., Volkow, N., Seamans, J., 2005. Unmanageable motivation in addiction: a pathology in prefrontal-accumbens glutamate transmission. Neuron 45, 647–650. Kilduff, T.S., De Lecea, L., 2001. Mapping of the mRNAs for the hypocretin/orexin and melanin-concentrating hormone receptors: networks of overlapping peptide systems. J Comp Neurol 435, 1–5. Kukkonen, J., Leonard, C., 2014. Orexin/hypocretin receptor signalling cascades. Br. J. Pharmacol. 171, 314–331. Kumar, A., Choi, K.H., Renthal, W., Tsankova, N.M., Theobald, D.E., Truong, H.T., Russo, S.J., Laplant, Q., Sasaki, T.S., Whistler, K.N., Neve, R.L., Self, D.W., Nestler, E.J., 2005. Chromatin remodeling is a key mechanism underlying cocaineinduced plasticity in striatum. Neuron 48, 303–314.
151
152
CHAPTER 6 Functional roles of orexin receptors in reward circuit
Le Foll, B., Diaz, J., Sokoloff, P., 2005. A single cocaine exposure increases BDNF and D3 receptor expression: implications for drug-conditioning. Neuroreport 16, 175–178. Li, J., Hu, Z., Lecea, L., 2014. The hypocretins/orexins: integrators of multiple physiological functions. Br. J. Pharmacol. 171, 332–350. Lin, L., Faraco, J., Li, R., Kadotani, H., Rogers, W., Lin, X., Qiu, X., De Jong, P.J., Nishino, S., Mignot, E., 1999. The sleep disorder canine narcolepsy is caused by a mutation in the hypocretin (orexin) receptor 2 gene. Cell 98, 365–376. Liu, Q.R., Lu, L., Zhu, X.G., Gong, J.P., Shaham, Y., Uhl, G.R., 2006. Rodent BDNF genes, novel promoters, novel splice variants, and regulation by cocaine. Brain Res. 1067, 1–12. Luscher, C., 2016. The emergence of a circuit model for addiction. Annu. Rev. Neurosci. 39, 257–276. Marcus, J.N., Aschkenasi, C.J., Lee, C.E., Chemelli, R.M., Saper, C.B., Yanagisawa, M., Elmquist, J.K., 2001. Differential expression of orexin receptors 1 and 2 in the rat brain. J Comp Neurol 435, 6–25. Mcginty, J.F., Shi, X.D., Schwendt, M., Saylor, A., Toda, S., 2008. Regulation of psychostimulant-induced signaling and gene expression in the striatum. J. Neurochem. 104, 1440–1449. Meredith, G.E., Baldo, B.A., Andrezjewski, M.E., Kelley, A.E., 2008. The structural basis for mapping behavior onto the ventral striatum and its subdivisions. Brain Struct. Funct. 213, 17–27. Mould, R., Brown, J., Marshall, F., Langmead, C., 2014. Binding kinetics differentiates functional antagonism of orexin-2 receptor ligands. Br. J. Pharmacol. 171, 351–363. Muller, D.L., Unterwald, E.M., 2004. In vivo regulation of extracellular signal-regulated protein kinase (ERK) and protein kinase B (Akt) phosphorylation by acute and chronic morphine. J. Pharmacol. Exp. Ther. 310, 774–782. Nair-Roberts, R.G., Chatelain-Badie, S.D., Benson, E., White-Cooper, H., Bolam, J.P., Ungless, M.A., 2008. Stereological estimates of dopaminergic, GABAergic and glutamatergic neurons in the ventral tegmental area, substantia nigra and retrorubral field in the rat. Neuroscience 152, 1024–1031. Nambu, T., Sakurai, T., Mizukami, K., Hosoya, Y., Yanagisawa, M., Goto, K., 1999. Distribution of orexin neurons in the adult rat brain. Brain Res. 827, 243–260. Nestler, E.J., 2001. Neurobiology. Total recall-the memory of addiction. Science 292, 2266–2267. Neumann, P.A., Wang, Y., Yan, Y., Wang, Y., Ishikawa, M., Cui, R., Huang, Y.H., Sesack, S.R., Schluter, O.M., Dong, Y., 2016. Cocaine-induced synaptic alterations in thalamus to nucleus accumbens projection. Neuropsychopharmacology 41, 2399–2410. Oleskevich, S., Descarries, L., Lacaille, J.C., 1989. Quantified distribution of the noradrenaline innervation in the hippocampus of adult rat. J. Neurosci. 9, 3803–3815. Parsania, S., Moradi, M., Fatahi, Z., Haghparast, A., 2016. Involvement of orexin-1 and orexin-2 receptors within the dentate gyrus of the hippocampus in the acquisition, expression and extinction of lateral hypothalamic-induced conditioned place preference in the rats. Brain Res. 1639, 149–160. Pascoli, V., Terrier, J., Espallergues, J., Valjent, E., O’connor, E.C., Luscher, C., 2014. Contrasting forms of cocaine-evoked plasticity control components of relapse. Nature 509, 459–464. Peyron, C., Tighe, D.K., Van Den Pol, A.N., De Lecea, L., Heller, H.C., Sutcliffe, J.G., Kilduff, T.S., 1998. Neurons containing hypocretin (orexin) project to multiple neuronal systems. J. Neurosci. 18, 9996–10015.
References
Pu, L., Liu, Q.S., Poo, M.M., 2006. BDNF-dependent synaptic sensitization in midbrain dopamine neurons after cocaine withdrawal. Nat. Neurosci. 9, 605–607. Qi, K., Wei, C., Li, Y., Sui, N., 2013. Orexin receptors within the nucleus accumbens shell mediate the stress but not drug priming-induced reinstatement of morphine conditioned place preference. Front. Behav. Neurosci. 7, 144. Razavi, Y., Karimi, S., Bani-Ardalan, M., Haghparast, A., 2014. Chemical stimulation of the lateral hypothalamus potentiated the sensitization to morphine in rats: involvement of orexin-1 receptor in the ventral tegmental area. EXCLI J. 13, 1120–1130. Riahi, E., Khodagholi, F., Haghparast, A., 2013. Role of dorsal hippocampal orexin-1 receptors in associating morphine reward with contextual stimuli. Behav. Pharmacol. 24, 237–248. Riahi, E., Arezoomandan, R., Fatahi, Z., Haghparast, A., 2015. The electrical activity of hippocampal pyramidal neuron is subjected to descending control by the brain orexin/hypocretin system. Neurobiol. Learn. Mem. 119, 93–101. Russo, S.J., Mazei-Robison, M.S., Ables, J.L., Nestler, E.J., 2009. Neurotrophic factors and structural plasticity in addiction. Neuropharmacology 56 (Suppl. 1), 73–82. Saddoris, M.P., Sugam, J.A., Cacciapaglia, F., Carelli, R.M., 2013. Rapid dopamine dynamics in the accumbens core and shell: learning and action. Front. Biosci. (Elite Ed.) 5, 273–288. Sadeghi, B., Ezzatpanah, S., Haghparast, A., 2016. Effects of dorsal hippocampal orexin-2 receptor antagonism on the acquisition, expression, and extinction of morphine-induced place preference in rats. Psychopharmacology 233, 2329–2341. Sakurai, T., Amemiya, A., Ishii, M., Matsuzaki, I., Chemelli, R.M., Tanaka, H., Williams, S.C., Richardson, J.A., Kozlowski, G.P., Wilson, S., 1998. Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior. Cell 92, 573–585. SAPER, C.B., Lu, J., Chou, T.C., Gooley, J., 2005. The hypothalamic integrator for circadian rhythms. Trends Neurosci. 28, 152–157. Sesack, S.R., Grace, A.A., 2010. Cortico-basal ganglia reward network: microcircuitry. Neuropsychopharmacology 35, 27–47. Shi, X., Mcginty, J.F., 2006. Extracellular signal-regulated mitogen-activated protein kinase inhibitors decrease amphetamine-induced behavior and neuropeptide gene expression in the striatum. Neuroscience 138, 1289–1298. Smart, D., Jerman, J.C., 2002. The physiology and pharmacology of the orexins. Pharmacol. Ther. 94, 51–61. Smith, M., Piper, D., Duxon, M., Upton, N., 2003. Evidence implicating a role for orexin-1 receptor modulation of paradoxical sleep in the rat. Neurosci. Lett. 341, 256–258. Stuber, G.D., Sparta, D.R., Stamatakis, A.M., Van Leeuwen, W.A., Hardjoprajitno, J.E., Cho, S., Tye, K.M., Kempadoo, K.A., Zhang, F., Deisseroth, K., Bonci, A., 2011. Excitatory transmission from the amygdala to nucleus accumbens facilitates reward seeking. Nature 475, 377–380. Sun, W.L., Zhou, L., Hazim, R., Quinones-Jenab, V., Jenab, S., 2007. Effects of acute cocaine on ERK and DARPP-32 phosphorylation pathways in the caudate-putamen of Fischer rats. Brain Res. 1178, 12–19. Sunter, D., Morgan, I., Edwards, C.M.B., Dakin, C.L., Murphy, K.G., Gardiner, J., Taheri, S., Rayes, E., Bloom, S.R., 2001. Orexins: effects on behavior and localisation of orexin receptor 2 messenger ribonucleic acid in the rat brainstem. Brain Res. 907, 27–34. Swanson, L.W., 1982. The projections of the ventral tegmental area and adjacent regions: a combined fluorescent retrograde tracer and immunofluorescence study in the rat. Brain Res. Bull. 9, 321–353.
153
154
CHAPTER 6 Functional roles of orexin receptors in reward circuit
Taslimi, Z., Haghparast, A., Hassanpour-Ezatti, M., Safari, M.S., 2011. Chemical stimulation of the lateral hypothalamus induces conditioned place preference in rats: involvement of OX1 and CB1 receptors in the ventral tegmental area. Behav. Brain Res. 217, 41–46. Taslimi, Z., Arezoomandan, R., Omranifard, A., Ghalandari-Shamami, M., Riahi, E., Vafaei, A.A., Rashidy-Pour, A., Haghparast, A., 2012. Orexin A in the ventral tegmental area induces conditioned place preference in a dose-dependent manner: involvement of D1/D2 receptors in the nucleus accumbens. Peptides 37, 225–232. Tran, D.-T., Bonaventure, P., Hack, M., Mirzadegan, T., Dvorak, C., Letavic, M., Carruthers, N., Lovenberg, T., Sutton, S.W., 2011. Chimeric, mutant orexin receptors show key interactions between orexin receptors, peptides and antagonists. Eur. J. Pharmacol. 667, 120–128. Trivedi, P., Yu, H., Macneil, D.J., Van Der Ploeg, L., Guan, X.-M., 1998. Distribution of orexin receptor mRNA in the rat brain. FEBS Lett. 438, 71–75. Valjent, E., Pascoli, V., Svenningsson, P., Paul, S., Enslen, H., Corvol, J.C., Stipanovich, A., Caboche, J., Lombroso, P.J., Nairn, A.C., Greengard, P., Herve, D., Girault, J.A., 2005. Regulation of a protein phosphatase cascade allows convergent dopamine and glutamate signals to activate ERK in the striatum. Proc. Natl. Acad. Sci. U.S.A. 102, 491–496. Vezina, P., Giovino, A.A., Wise, R.A., Stewart, J., 1989. Environment-specific crosssensitization between the locomotor activating effects of morphine and amphetamine. Pharmacol. Biochem. Behav. 32, 581–584. Vittoz, N.M., Berridge, C.W., 2006. Hypocretin/orexin selectively increases dopamine efflux within the prefrontal cortex: involvement of the ventral tegmental area. Neuropsychopharmacology 31, 384–395. Volkow, N.D., Wang, G.J., Fowler, J.S., Tomasi, D., Telang, F., 2011. Addiction: beyond dopamine reward circuitry. Proc. Natl. Acad. Sci. U.S.A. 108, 15037–15042. Wang, B., You, Z.B., Wise, R.A., 2009. Reinstatement of cocaine seeking by hypocretin (orexin) in the ventral tegmental area: independence from the local corticotropin-releasing factor network. Biol. Psychiatry 65, 857–862. Williams, J.M., Owens, W.A., Turner, G.H., Saunders, C., Dipace, C., Blakely, R.D., France, C.P., Gore, J.C., Daws, L.C., Avison, M.J., Galli, A., 2007. Hypoinsulinemia regulates amphetamine-induced reverse transport of dopamine. PLoS Biol. 5, e274. Willie, J.T., Chemelli, R.M., Sinton, C.M., Tokita, S., Williams, S.C., Kisanuki, Y.Y., Marcus, J.N., Lee, C., Elmquist, J.K., Kohlmeier, K.A., 2003. Distinct narcolepsy syndromes in orexin receptor-2 and orexin null mice: molecular genetic dissection of nonREM and REM sleep regulatory processes. Neuron 38, 715–730. Yazdi, F., Jahangirvand, M., Pirasteh, A.H., Moradi, M., Haghparast, A., 2015. Functional interaction between OX2 and CB1 receptors in the ventral tegmental area and the nucleus accumbens in response to place preference induced by chemical stimulation of the lateral hypothalamus. Pharmacol. Biochem. Behav. 139, 39–46. Zarepour, L., Fatahi, Z., Sarihi, A., Haghparast, A., 2014. Blockade of orexin-1 receptors in the ventral tegmental area could attenuate the lateral hypothalamic stimulation-induced potentiation of rewarding properties of morphine. Neuropeptides 48, 179–185. Zhang, D., Zhang, L., Lou, D.W., Nakabeppu, Y., Zhang, J., Xu, M., 2002. The dopamine D1 receptor is a critical mediator for cocaine-induced gene expression. J. Neurochem. 82, 1453–1464. Zhu, Y., Wienecke, C.F., Nachtrab, G., Chen, X., 2016. A thalamic input to the nucleus accumbens mediates opiate dependence. Nature 530, 219–222.