The globus pallidus as a target for neuropeptides and endocannabinoids participating in central activities

Journal Pre-proof The globus pallidus as a target for neuropeptides and endocannabinoids participating in central activities Xin-Yi Chen, Yan Xue, Hua Chen, Lei Chen

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S0196-9781(19)30188-3

DOI:

https://doi.org/10.1016/j.peptides.2019.170210

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PEP 170210

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Peptides

Received Date:

29 May 2019

Revised Date:

14 November 2019

Accepted Date:

21 November 2019

Please cite this article as: Chen X-Yi, Xue Y, Chen H, Chen L, The globus pallidus as a target for neuropeptides and endocannabinoids participating in central activities, Peptides (2019), doi: https://doi.org/10.1016/j.peptides.2019.170210

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The globus pallidus as a target for neuropeptides and endocannabinoids participating in central activities Running Title: Neuropeptides and endocannabinoids in globus pallidus

Xin-Yi Chena,b,#, Yan Xueb, Hua Chena,*, Lei Chenb,*

Department of Pathology, Qingdao Municipal Hospital, Qingdao University,

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a

Qingdao, China b

Department of Physiology and Pathophysiology, School of Basic Medicine, Qingdao

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University, Qingdao, China

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*Corresponding author: Dr. L. Chen, Department of Physiology and Pathophysiology, Qingdao University, Qingdao, China; Email: [email protected]. Dr. H. Chen,

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Department of Pathology, Qingdao Municipal Hospital, Qingdao University, Qingdao, China; Email: [email protected].

Present address: Department of Medicine and Therapeutics, The Chinese University

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of Hong Kong, Hong Kong.

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HIGHLIGHTS 

The globus pallidus contains a high level of neuropeptides including enkephalin, substance P, neurotensin, orexin, somatostatin and pituitary adenylate cyclase-activating polypeptide, as well as endocannabinoids.

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Neuropeptides and endocannabinoids modulate the neuronal activity of the globus pallidus through multiple mechanisms. 1

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Pallidal neuropeptides and endocannabinoids are associated with the pathophysiology of neurological disorders, such as Parkinson's disease and Huntington's disease.

Abstract The globus pallidus in the basal ganglia plays an important role in movement regulation. Neuropeptides and endocannabinoids are neuronal signalling molecules

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that influence the functions of the whole brain. Endocannabinoids, enkephalin, substance P, neurotensin, orexin, somatostatin and pituitary adenylate cyclase-

activating polypeptides are richly concentrated in the globus pallidus. Neuropeptides

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and endocannabinoids exert excitatory or inhibitory effects in the globus pallidus

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mainly by modulating GABAergic, glutamatergic and dopaminergic neurotransmission, as well as many ionic mechanisms. Pallidal neuropeptides and

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endocannabinoids are associated with the pathophysiology of a number of neurological disorders, such as Parkinson's disease, Huntington's disease,

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schizophrenia, and depression. The levels of neuropeptides and endocannabinoid and their receptors in the globus pallidus change in neurological diseases. It has been

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demonstrated that spontaneous firing activity of globus pallidus neurons is closely related to the manifestations of Parkinson's disease. Therefore, the neuropeptides and

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endocannabinoids in the globus pallidus may function as potential targets for treatment in some neurological diseases. In this review, we highlight the morphology and function of neuropeptides and endocannabinoids in the globus pallidus and their involvement in neurological diseases.

Keywords: globus pallidus, neuropeptides, endocannabinoids, enkephalin, substance 2

P, neurotensin, orexin, somatostatin, pituitary adenylate cyclase-activating polypeptide

1. Introduction The globus pallidus in rodents, external segment of the globus pallidus in primates, is a crucial brain region within the basal ganglia circuitry. Neurons in the globus pallidus are GABAergic except for approximately 5% that are cholinergic neurons. Many

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publications have shown two major subtypes of neurons in the globus pallidus (Mallet et al., 2012; Abdi et al., 2015; Dodson et al., 2015; Hernández et al., 2015; Hegeman

et al., 2016). The prototypic neurons (accounting for 70% of globus pallidus neurons)

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project mainly to the subthalamic nucleus (Mallet et al., 2012; Abdi et al., 2015;

Hernández et al., 2015). The majority of these neurons are parvalbumin-positive

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neurons (accounting for approximately 55% of globus pallidus neurons) expressing

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the transcription factor Nkx2.1 or Lhx6 (Mallet et al., 2012; Abdi et al., 2015). The other type of globus pallidus neurons is 'arkypallidal' neurons (accounting for 25% of globus pallidus neurons), which project mainly to the striatum. These 'arkypallidal'

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neurons express the transcription factor Npas1 (Mallet et al., 2012; Abdi et al., 2015; Hernández et al., 2015). A recent study also showed different types of pallidal

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neurons, such as arkypallidal and low-firing prototypical and high-firing prototypical

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neurons (Abrahao and Lovinger, 2018). The globus pallidus plays an important role in movement control (Mink and

Thach, 1991). It is known that abnormal firing activities in globus pallidus neurons are closely associated with the manifestation of movement disorders such as Parkinson's disease, Huntington's disease and tardive dyskinesia. According to the traditional basal ganglia circuits, the depletion of dopamine in the substantia nigra 3

pars compacta leads to the abnormal hypoactivity in globus pallidus neurons, which is associated with akinesia and bradykinesia symptoms in Parkinson's disease (Chesselet and Delfs, 1996). Furthermore, an increase in synchronized oscillatory burst firing in the globus pallidus could be responsible for resting tremors in Parkinson's disease (Plenz and Kital, 1999). Using advanced techniques such as cell-specific transgenic mice and optogenetics-based mapping, recent studies have revealed that the two types of globus pallidus neurons play different roles in normal motor control and

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Parkinson's disease. The selective activation of parvalbumin-positive neurons alleviates parkinsonian immobility and bradykinesia (Mastro et al., 2017), while the

chemogenetic activation of Npas1-expressing neurons suppresses movement (Glajch

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et al., 2016). In a mouse model of juvenile Huntington's disease, the number of

depolarization-induced spikes in the globus pallidus is reduced. In addition, changes

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in firing patterns, with increased variation in the inter-spike interval and burst firing,

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are observed in globus pallidus neurons in Huntington's disease (Akopian et al., 2016).

Morphological and functional studies have revealed that the globus pallidus

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integrates inhibitory GABAergic inputs from the striatum and excitatory glutamatergic inputs from the subthalamic nucleus, neocortex and thalamus (Naito A,

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Kita, 1994; Chesselet and Delfs, 1996). In addition to traditional neurotransmitters,

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neuropeptides and endocannabinoids, as endogenous active molecules, are also involved in various physiological functions in central nervous systems. Several neuropeptides, such as enkephalin, substance P, neurotensin, orexin, somatostatin, and pituitary adenylate cyclase-activating polypeptide, are widely distributed in the globus pallidus. Neuropeptides modulate the firing activities of globus pallidus neurons and, therefore, play a role in movement control. Endocannabinoids are typically lipophilic 4

molecules. Recently, endocannabinoid peptides (pepcans) were found to combine and modulate the activity of cannabinoid receptors as endogenous ligands (Rioli et al., 2003; Heimann et al., 2007). The globus pallidus has a particularly high density of cannabinoid receptors (Sciolino et al., 2010). Therefore, to fully understand the importance of the globus pallidus, we will discuss the morphology, electrophysiology and functions of several neuropeptides, together with endocannabinoids, in the globus pallidus. We will then describe the involvement of pallidal neuropeptides and

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endocannabinoids in neurological disorders. 2. Endocannabinoids in the globus pallidus

The endocannabinoid system participates in the regulation of a variety of

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physiological processes including learning and memory, mood, pain sensation,

locomotor activity, appetite and addiction (Aizpurua-Olaizola et al., 2017; Donvito et

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al., 2018). Endocannabinoids are usually released from postsynaptic neurons and

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retrogradely act on presynaptic receptors to modulate synaptic transmission. Two main types of cannabinoid receptors, cannabinoid type 1 (CB1) receptors and cannabinoid type 2 (CB2) receptors, are expressed in both central and peripheral

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nervous systems. Both CB1 and CB2 receptors form heteromers in which CB2 receptors negatively modulate CB1 receptor function (Callén et al., 2012).

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Particularly intense CB1 receptors are distributed in the globus pallidus

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(Herkenham et al., 1990, 1991; Mailleux and Vanderhaeghen, 1992; Wong et al., 2010; Lanciego et al., 2011; Coria et al., 2014). In a study using a novel positronemission tomography (PET) tracer, CB1 receptors were found to be expressed at the highest level in the human globus pallidus (Wong et al., 2010). The external globus pallidus of Macaca fascicularis also shows the highest level of CB2 receptor mRNA expression (Lanciego et al., 2011). Further morphological studies have demonstrated 5

that CB1 receptors are densely localized on presynaptic striatopallidal terminals in the globus pallidus (Freundt-Revilla et al., 2017; Davis et al., 2018). Both immunohistochemistry and in situ hybridization studies have revealed that the globus pallidus exhibits high levels of CB1 receptor protein expression but not CB1 receptor transcripts, while high levels of CB1 receptor transcripts are distributed in the striatum (Julian et al., 2003). The density of CB1 receptors in the globus pallidus declines with age in healthy adults (Wong et al., 2010).

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As the receptors are located mainly on presynaptic terminals, endocannabinoids exert critical effects on the release of neurotransmitters in the globus pallidus. Many studies have revealed that activation of CB1 receptors inhibits striatopallidal

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GABAergic neurotransmission by reducing GABA release. Exogenous application of the synthetic cannabinoid receptor agonists WIN55212-2 or ACEA inhibits striatum

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stimulation-induced GABAergic inhibitory postsynaptic currents (IPSCs) in globus

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pallidus neurons (Engler et al., 2006; Caballero-Florán et al., 2016). Endogenously released cannabinoids from postsynaptic globus pallidus neurons also suppress synaptic GABAergic neurotransmission by acting on presynaptic CB1 receptors

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(Engler et al., 2006). The intravenous application of WIN55212-2 attenuates the inhibition of pallidal firing induced by the electrical stimulation of the striatum, which

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also suggests that cannabinoids inhibit striatopallidal GABAergic neurotransmission

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(Miller and Walker, 1996). Furthermore, the coactivation of CB1 receptors and D2 receptors converts the CB1 receptor-induced inhibition of striatopallidal GABAergic neurotransmission (Caballero-Florán et al., 2016). In addition to the disinhibition of striatum stimulation-induced firing activity, Miller and Walker (1996) also found that WIN55212-2 inhibits spontaneous firing activity in globus pallidus neurons, which is the opposite effect of that seen in evoked activity. Two possibilities may be involved 6

in the activation of the CB1 receptor-induced inhibition of spontaneous firing activity. On one way, in addition to reducing GABA release, WIN55212-2 also inhibits the subthalamo-pallidal glutamatergic neurotransmission through presynaptic CB1 receptors in the globus pallidus (Freiman and Szabo, 2005). On the other way, the local application of CB1 receptor agonists has been demonstrated to dose-dependently decrease GABA uptake in the globus pallidus (Maneuf et al., 1996). Moreover, chemically lesioning the globus pallidus abolishes the activation of the CB1 receptor-

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induced excitation of spontaneous firing in subthalamic neurons, indicating the CB1 receptor-induced presynaptic inhibition of GABA release from pallidal terminals

(Morera-Herreras et al., 2010a, 2010b). Recently, functional brain imaging has shown

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that chronic treatment with WIN 55212-2 induces hypermetabolism in the globus pallidus of mice (Mouro et al., 2018).

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Cannabinoid CB1 receptors have been demonstrated to be involved in several

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neurological disorders including Huntington's disease, Parkinson's disease, schizophrenia and depression. Previous studies have revealed a significant loss of CB1 receptors in all basal ganglia regions, including the globus pallidus, in

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Huntington's disease (Richfield and Herkenham, 1994; Glass et al., 2000, 2004; Lastres-Becker et al., 2002a, 2002b; Allen et al., 2009; Ooms et al., 2014). The

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dramatic loss of CB1 receptors in the globus pallidus appears in the very early stages

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of Huntington's disease in human post-mortem tissue (Glass et al., 2000), as well as in the early symptomatic phase of Huntington disease in a transgenic rat model (Casteels et al., 2011). In the late akinetic phase of Huntington's disease in a rat model, the loss of CB1 receptor binding is confined to the globus pallidus and striatum in the basal ganglia (Lastres-Becker et al., 2002b). The loss of CB1 receptors is accompanied by an upregulation of GABAA and GABAB receptors in the globus pallidus, which 7

suggests possible compensatory mechanisms in Huntington's disease (Allen et al., 2009). In addition to the decreased expression of CB1 receptors in the globus pallidus, the CB1 receptor agonist-induced activation of GTP-binding proteins is reduced in the globus pallidus of a transgenic model of Huntington's disease (Lastres-Becker et al., 2002a). However, the administration of an endocannabinoid uptake inhibitor attenuates motor hyperactivity in the early phase of Huntington's disease in a rat model (Lastres-Becker et al., 2002c). Moreover, in a transgenic mouse model of

receptors in the globus pallidus (Glass et al., 2004).

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Huntington's disease, exposure to an enriched environment delays the loss of CB1

In 6-OHDA parkinsonian rats, the expression of CB1 receptors displays

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structure-specific changes in different basal ganglia regions, with decreased CB1 receptor expression in the substantia nigra pars reticulata and the internal globus

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pallidus but increased CB1 receptor expression in the external globus pallidus

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(Chaves-Kirsten et al., 2013). However, the level of CB1 receptor mRNA expression is decreased in the globus pallidus in post-mortem parkinsonian human brain tissue (Hurley et al., 2003). In dopamine-denervated 6-OHDA parkinsonian rats, the

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activation of CB1 receptors decreases GABA release and blocks GABA uptake in the globus pallidus, while the coactivation of CB1 and dopamine D2 receptors increases

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GABA release. Consistently, behavioural tests further demonstrate that the

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coapplication of CB1 and D2 receptor agonists enhances motor asymmetry in 6OHDA parkinsonian rats (Muñoz-Arenas et al., 2015). The chronic application of an agonist of the GPR55 receptor, a third cannabinoid receptor, prevents MPTP-induced motor impairment (Celorrio et al., 2017). Cannabinoid receptors have been demonstrated to be involved in the treatment of motor complications in Parkinson's disease. A recent study found that the expression of CB1 receptors in the external 8

globus pallidus is upregulated during the active stage of levodopa-induced dyskinesia in parkinsonian monkeys (Rojo-Bustamante et al., 2018), suggesting that the pallidal CB1 receptors could be a potential target for the therapy of levodopa-induced abnormal involuntary movements. The coadministration of a cannabinoid receptor agonist significantly increases the duration of levodopa-induced antiparkinsonian action and alleviates levodopa-induced dyskinesia in a parkinsonian model (Fox et al., 2002; Ferrer et al., 2003; Gilgun-Sherki et al., 2003). However, a later study found

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that the systemic administration of a CB1 receptor antagonist has antiparkinsonian effects in MPTP parkinsonian marmosets and ameliorates levodopa treatment-induced dyskinesia (van der Stelt et al., 2005). The apparent paradox involving both CB1

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receptor agonists and antagonists in treating levodopa-induced dyskinesia may be due to the complex basal ganglia circuitry responsible for the dyskinesia.

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Clinical studies have shown high levels of CB1 receptors in the brains of

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schizophrenic patients (Verdurand et al., 2014). Polyriboinosinic-polyribocytidilic acid (poly I:C) is a synthetic analogue of double-stranded RNA that induces viral-like immune responses. The prenatal treatment of rodents with poly I:C leads to a variety

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of emotional and cognitive impairments implicated in schizophrenia. A positronemission tomography study revealed that prenatal application with poly I:C induces

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lower CB1 receptor expression in the globus pallidus in adolescent mice (Verdurand

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et al., 2014). However, the oral administration of antipsychotic haloperidol in rats increases levels of CB1 receptors in the basal ganglia including the globus pallidus, suggesting the involvement of pallidal CB1 receptors in schizophrenia (Delis et al., 2017). Chronic experimenter handling increases the cannabinoid receptor density in some brain regions, including the globus pallidus, which in turn attenuates anxietylike behaviour in socially isolated rats (Sciolino et al., 2010). In addition, the 9

ingestion of ethanol inhibits the CB1 receptor-mediated G protein pathway in the globus pallidus (Molet et al., 2012). In summary, particularly high levels of CB1 receptors are localized on presynaptic terminals in the globus pallidus. The activation of CB1 receptors inhibits both striatopallidal GABA release and subthalamo-pallidal glutamate release. Pallidal cannabinoid receptors are involved in Huntington's disease, Parkinson's disease and schizophrenia. A dramatic loss of pallidal CB1 receptors appears in the early stages of

levodopa-induced dyskinesia in a parkinsonian model. 3. Enkephalin in the globus pallidus

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Huntington's disease. The application of a cannabinoid receptor agonist alleviates

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On the basis of projection areas, expressed dopamine receptors and released

neurotransmitters, medium spiny striatal GABAergic neurons can be divided into two

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major populations. One population projects to the substantia nigra pars reticulata with

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expression of substance P and dopamine D1 receptors, and the other population projects to the globus pallidus with expression of enkephalin and dopamine D2 receptors (Wilson and Phelan, 1982; Gerfen and Young, 1988; Back and Gorenstein,

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1989; Smith and Bolam, 1990). Enkephalin is a pentapeptide that is further classified into two structurally different enkephalin peptides: met-enkephalin and leu-

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enkephalin. Met-enkephalin immunoreactive cell bodies are observed in the globus

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pallidus (Chen et al., 2008). Early studies by Hoover and Marshall (1999; 2002) showed that 42% of globus pallidus neurons expressing preproenkephalin mRNA preferentially project to the striatum. Using poste-mbedment-staining electron microscopic immunocytochemistry, an early morphological study showed the vesicular localization of immunoreactive met-enkephalin in the globus pallidus (Coulter, 1988). Immunohistochemical, ligand binding and in situ hybridization 10

studies indicate the presence of both presynaptic and postsynaptic μ, δ and κ opioid receptors within the globus pallidus (Abou-Khalil et al., 1984; Delfs et al., 1994a; Mansour et al, 1994; Bausch et al., 1995; Peckys and Landwehrmeyer, 1999). A progressive age-related loss of δ opioid receptors is observed in the globus pallidus of senescent guinea pigs (Hiller et al., 1993). Earlier functional studies revealed that both morphine and met-enkephalin inhibit neuronal activity in the majority of globus pallidus neurons, while excitation occurs in

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very few globus pallidus neurons (Frey and Huffman, 1985). The unilateral microinjection of a κ opioid receptor agonist into the globus pallidus induces

ipsilateral rotation behaviours, while μ and δ opioid receptor agonists induce no

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circling behaviours (Dewar et al., 1985). Opioid receptor agonists induce the

presynaptic inhibition of GABA release from striatopallidal terminals (Dewar et al.,

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1987; Maneuf et al., 1994). Using whole-cell patch-clamp recordings, Stanford and

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Cooper (1999) reported that presynaptic μ opioid receptors are located on both striatopallidal and pallidopallidal terminals of spontaneously firing globus pallidus neurons, whereas presynaptic δ opioid receptors are preferentially located on

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terminals of quiescent globus pallidus neurons. The activation of both receptor subtypes by enkephalin inhibits GABA transmission in the globus pallidus (Maneuf et

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al., 1994; Stanford and Cooper, 1999), suggesting that enkephalin may be involved in

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maintaining the inhibitory function of the globus pallidus. The activation of κ, μ and δ opioid receptors inhibits Ca2+ currents preferentially in type I globus pallidus neurons (Spadoni et al., 2004). In addition to modulating GABA release, the activation of μ and δ opioid receptors enhances enkephalin release in the globus pallidus of freely moving rats (Olive and Maidment, 1998).

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There is a functional relationship between enkephalin and dopamine in the globus pallidus. The blockade of dopamine D1 receptors prevents amphetamineinduced enkephalin release in the globus pallidus and suppresses hyperlocomotion, while the blockade of opioid receptors in the globus pallidus inhibits dopamine release and attenuates amphetamine-induced locomotor activation (Mabrouk et al., 2011). The globus pallidus contains a large number of neurons expressing dopamine D1 and D2 receptor heteromers that are selective dynorphin/enkephalin neurons. In

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schizophrenia patients, the sensitivity of the D1-D2 heteromer in the globus pallidus is significantly increased (Perreault et al., 2010).

In addition to the interaction with GABA and dopamine, enkephalin is also

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closely related to other neurotransmitters or neuromodulators. The application of a δ opioid receptor agonist inhibits K+-induced acetylcholine release in the globus

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pallidus (Ruzicka and Jhamandas, 1991). Activation of 5-HT1B receptors reduces the

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expression of met-enkephalin in the globus pallidus, and blockade of opioid receptors by naloxone suppresses 5-HT1B receptor-induced increases in locomotor activity (Compan et al., 2003). High levels of corticotropin-releasing factor type 1 receptor

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(CRFR1) are expressed in the globus pallidus. The specific knockdown or blockade of CRFR1 in the globus pallidus increases anxiety-like behaviour through a reduction in

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enkephalin in the globus pallidus (Sztainberg et al., 2011).

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There is evidence showing complex changes in enkephalin expression in the globus pallidus during parkinsonian states. Early studies revealed that unilateral 6OHDA lesions can increase enkephalin and/or met-enkephalin levels in the striatum (Gerfen et al., 1990; Salin et al., 1996) but decrease expression levels in the globus pallidus (Salin et al., 1996). Similarly low levels of enkephalin and met-enkephalin are observed in the globus pallidus of marmosets prenatally treated with MPTP 12

(Pérez-Otaño et al., 1995) and in MPTP mice (Bissonnette et al., 2014). In addition to low levels of enkephalin and/or met-enkephalin in the globus pallidus in parkinsonian states, other studies have shown increased levels of enkephalin in the globus pallidus (Dacko and Schneider, 1991; Martorana et al., 2003; Betarbet and Greenamyre, 2004; Bourdenx et al., 2014). Bourdenx et al. (2014) reported that the levels of metenkephalin, C-terminally extended met-enkephalin and leu-enkephalin are increased in MPTP parkinsonian monkeys, and levodopa treatment induces a strong decrease in

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the expression of met-enkephalin and leu-enkephalin. The conflict, in terms of the change in enkephalin and/or met-enkephalin levels seen in parkinsonian states, may reflect a compensatory mechanism or the complex interconnection between the two

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hemispheres. For example, the overexpression of pre-enkephalin in the striatum

resumes the decreased density of enkephalin-positive fibers and lower concentrations

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of dopamine in the globus pallidus, and alleviates locomotor activity in MPTP mice

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(Bissonnette et al., 2014). Furthermore, no major differences in the expression of pallidal met-enkephalin are exhibitied after bilateral lesions, while unilateral lesions decrease the expression of pallidal met-enkephalin, suggesting complex

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interhemispheric adaptive mechanisms (Salin et al., 1996). Another possible reason for the dissimilar reports about enkephalin expression is the modulation of different

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neuronal populations in the globus pallidus. It has been demonstrated that the

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expression of pallidal enkephalin decreases in parvalbumin-negative neurons and increases in parvalbumin-positive neurons from the early to the chronic stages of the disease in 6-OHDA parkinsonian rats (Martorana et al., 2003). The expression of the μ opioid receptor is decreased in the globus pallidus in both symptomatic and spontaneously recovered cats with Parkinson's disease (Schroeder and Schneider, 2002a). A functional study revealed that enkephalin attenuates GABA release in the 13

globus pallidus of MPTP parkinsonian cats but not in that of normal cats (Schroeder and Schneider, 2002b). In addition to Parkinson's disease, enkephalin immunoreactivity is significantly lower in the external segment of the globus pallidus in Huntington's disease (Sapp et al., 1995; Allen et al., 2009). The overexpression of striatal pre-enkephalin improves behavioural dysfunction in a mouse model of Huntington's disease, which is associated with increased levels of enkephalin in the globus pallidus as well as the

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striatum and substantia nigra (Bissonnette et al., 2013). The expression of enkephalin and opioid receptors may be involved in chronic neuroleptic-induced tardive

dyskinesia. The μ receptor expression in the globus pallidus is reduced in haloperidol-

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treated animals (Delfs et al., 1994b; Bower et al., 2000). A high level of enkephalin in the stiratopallidal pathway contributes to tardive dyskinesia, which could be

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attenuated by the non-specific opioid receptor antagonist naloxone (McCormick and

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Stoessl, 2002).

In summary, the globus pallidus receives GABA-enkephalin projections from a discrete population of striatal neurons. The μ, δ and κ opioid receptors are expressed

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in the globus pallidus. The activation of opioid receptors by enkephalin modulates GABA, dopamine and acetylcholine release in the globus pallidus. In a parkinsonian

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state, levels of enkephalin and the expression of the μ opioid receptor change in the

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globus pallidus. Low levels of pallidal enkephalin are observed in the globus pallidus in Huntington's disease. Finally, the expression of enkephalin and opioid receptors in the globus pallidus may be involved in neuroleptic-induced tardive dyskinesia. 4. Substance P in the globus pallidus The globus pallidus receives substance P innervation presumably from axon collaterals of the population of striatal neurons that project to the substantia nigra pars 14

reticulata and express substance P and dopamine D1 receptors (Smith and Bolam, 1990). Substance P binds to neurokinin-1 receptors and modulates the activity of globus pallidus neurons. Neurokinin-1 receptors are expressed in the globus pallidus (Hietala et al., 2005; Lévesque et al., 2006; Chen et al., 2009). At the electron microscopic level, neurokinin-1 receptors are mainly located at intracellular sites or at the extrasynaptic membrane, and are occasionally distributed at presynaptic terminals forming both symmetric and asymmetric synapses in the globus pallidus. This

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morphological distribution indicates that substance P may exert effects at both postsynaptic and presynaptic sites in the globus pallidus (Lévesque et al., 2006).

There are two major subpopulations of GABAergic projection neurons in the globus

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pallidus of rodents. Recent morphological studies have revealed that neurokinin-1 receptors are expressed on pallidal neurons projecting to the subthalamic nucleus

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(namely, prototypic neurons, immunopositive to parvalbumin and/or Lhx6) but not

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arkypallidal neurons (Mizutani et al., 2017).

Both in vivo and in vitro patch clamp recordings have revealed that the activation of neurokinin-1 receptors depolarizes globus pallidus neurons and increases the firing

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rate directly through postsynaptic effects (Cui et al., 2007; 2008; Chen et al., 2009). The suppression of potassium conductance may be the predominant ionic mechanism

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of substance P-induced excitation (Chen et al., 2009). Consistent with morphological

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studies, it has been reported that substance P induces electrophysiological effects only on prototypic neurons but not arkypallidal neurons (Mizutani et al., 2017). Lesioning of striatal interneurons expressing substance P receptors has been shown to decrease the activity in the external segment of the globus pallidus suggesting that the striatopallidal projection neurons exert enhanced inhibitory influence on pallidal neurons without striatal substance P receptor-expressing interneurons (Chiken et al., 15

2003). Substance P does not clearly modulate neurotransmitter release presynaptically. Patch clamp recordings in brain slices show that neurokinin-1 receptor agonists significantly increase the frequency of spontaneous inhibitory postsynaptic currents, but only induce a transient increase in the frequency of miniature inhibitory postsynaptic currents. No change is observed in either spontaneous or miniature excitatory postsynaptic currents (Chen et al., 2009). The microinjection of a low concentration of substance P into the globus pallidus

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significantly enhances passive avoidance learning, as well as positive reinforcement, through the neurokinin-1 receptor (Kertes et al., 2009; 2010). Early studies indicate that, in the parkinsonian brain, the levels of substance P-like immunoreactivity

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(Mauborgne et al., 1983) and substance P receptors (Fernandez et al., 1994) decrease significantly in the globus pallidus. However, other studies revealed no change in

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substance P levels in the basal ganglia of Parkinson's disease brains (Jenner et al.,

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1986; Clevens and Beal, 1989). A functional study revealed that the activation of neurokinin-1 receptors induces a weaker excitation of globus pallidus neurons in 6OHDA parkinsonian rats, which implies the involvement of the pallidal substance P

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system in the aetiology of Parkinson's disease (Cui et al., 2008). In summary, the globus pallidus receives substance P innervation from axon

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collaterals of striatal neurons projecting to the substantia nigra pars reticulata.

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Neurokinin-1 receptors are expressed on the subpopulation of globus pallidus neurons which project to the subthalamic nucleus. The activation of the neurokinin-1 receptors by substance P increases the neuronal excitability of pallidal neurons mainly through the suppression of potassium conductance. The levels of substance P and substance P receptors decrease in the globus pallidus of brains of Parkinson's disease. 5. Neurotensin in the globus pallidus 16

Striatal neurotensin-immunoreactive neurons project predominantly to the globus pallidus (Sugimoto and Mizuno, 1987; Brog and Zahm, 1996). Extremely dense networks of neurotensin-containing fibers are observed in the globus pallidus (Atoji et al., 1995). Neurotensin receptors are expressed on both parvalbumin-positive and negative neurons in the globus pallidus (Fassio et al., 2000; Martorana et al., 2006). Both in vitro and in vivo electrophysiological recordings showed that neurotensin modulates the firing activity of globus pallidus neurons through neurotensin-1

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receptors (Chen et al., 2004; Martorana et al., 2006; Xue et al., 2007). Several ionic mechanisms, including N-type calcium channels, potassium channels and non-

selective cation channels, are involved in neurotensin-induced electrophysiological

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effects (Chen et al., 2004; Martorana et al., 2006).

There is a close interaction between neurotensin and dopamine in the globus

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pallidus. Enhancing dopaminergic neurotransmission increases neurotensin content in

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the globus pallidus (Frankel et al., 2005; Hanson et al., 2013; German et al., 2014). The application of methylphenidate, a psychostimulant, significantly increases levels of neurotensin in the globus pallidus, and this effect is blocked by both dopamine D1

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and D2 receptor antagonists (Alburges et al., 2011). However, dopamine D2 receptors exert an opposite effect on the level of neurotensin. Blockade of dopamine D2

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receptors increases neurotensin-like immunoreactivity in the globus pallidus,

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indicating the involvement of D2 receptors in the modulation of the striatopallidal neurotensin pathway (Castel et al., 1994). Furthermore, microinjection of neurotensin into the substantia nigra pars compacta increases dopamine release in the globus pallidus (Napier et al., 1985), while pretreatment with neurotensin 1 receptor antagonist reduces the number of dopamine D1/D2 like receptor-induced Fos immunoreactive cells in the globus pallidus (Alonso et al., 1999). 17

In addition to its relationship with dopamine, neurotensin modulates the release of GABA and glutamate in the globus pallidus. The intrastriatal application of neurotensin significantly increases GABA and glutamate release in the globus pallidus through neurotensin 1 receptors (Ferraro et al., 1997; 1998; 2012). In vitro patch clamp recordings demonstrate that neurotensin increases glutamate-medicated excitatory postsynaptic currents in the globus pallidus (Chen et al., 2006), suggesting the presynaptic facilitation on glutamate release. Finally, nicotine self-administration

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increases levels of neurotensin in the globus pallidus (Pittenger et al., 2016). Neurotensin levels are closely related to neurological diseases including

Parkinson’s disease. For example, levels of neurotensin increase significantly in both

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the substantia nigra pars compacta and pars reticulata in parkinsonian patients

(Fernandez et al., 1995). Levels of neurotensin in the globus pallidus are unaltered

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(Fernandez et al., 1995), but the density of neurotensin receptors in both the lateral

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and medial segments of the globus pallidus decreases (Fernandez et al., 1994). Early studies showed that in rats receiving unilateral 6-OHDA injections in the ventral tegmental area, the neurotensin immunoreactivity territory in the globus pallidus on

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the lesioned side is significantly larger than that on the non-lesioned side (Zahm and Johnson, 1989). In normal rats, neurotensin immunoreactivity is poorly localized in

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fibers but not expressed in the cell bodies of neurons in the globus pallidus. However,

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after nigrostriatal pathway lesioning, neurotensin immunoreactivity is found in both fibers and cell bodies in more rostral dorsal-lateral region of the globus pallidus (Martorana et al., 2003). In vivo extracellular electrophysiological recordings have demonstrated that neurotensin exerts stronger excitatory effects on the non-lesioned side than that on the lesioned side or in normal rats (Chen et al., 2009; Xue et al., 2009). In haloperidol-induced parkinsonian rats, microinjecting neurotensin into the 18

globus pallidus ameliorates catalepsy (Xue et al., 2007; Xue and Chen, 2010). In addition to Parkinson's disease, the intrapallidal administration of a neurotensin receptor antagonist attenuates neuroleptic-induced vacuous chewing movements in a rodent model of tardive dyskinesia (McCormick and Stoess, 2003). In summary, the globus pallidus receives neurotensin innervation from the striatum and expresses neurotensin receptors. The activation of neurotensin-1 receptors increases firing activity in pallidal neurons through multiple ionic

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mechanisms. The enhancement of dopaminergic neurotransmission increases neurotensin levels in the globus pallidus. In addition, neurotensin increases glutamate release presynaptically in the globus pallidus. The neurotensin immunopositive

6. Other neuropeptides in the globus pallidus

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territory in the globus pallidus is enlarged during parkinsonian states.

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Orexin is a neuropeptide that was first identified in the hypothalamus (de Lecea et al.,

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1998). Both orexin-A and orexin-B are produced from the prepro-orexin precursor in the posterior lateral hypothalamus. Orexins bind two types of G protein-coupled receptors, orexin 1 (OX1) and orexin 2 (OX2) receptors (Marcus et al., 2001;

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Langmead et al., 2004). Substantial evidence indicates that central orexinergic systems play numerous roles in physiological functions, including sleep/wakefulness,

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motivational behaviours, body weight regulation, neuroendocrine regulation,

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sympathetic activation and somatic motor control (Chemelli et al., 1999; Li et al., 2014; Hu et al., 2015). The globus pallidus receives orexinergic innervation from the hypothalamus (Cutler et al., 1999; Nambu et al., 1999; Schmitt et al., 2012). Both OX1 and OX2 receptors are expressed in the globus pallidus (Hervieu et al., 2001; Ch'ng and Lawrence, 2015). It is known that narcolepsy is a neurological disease that is mainly caused by the loss of orexinergic cells in the hypothalamus. Primary 19

antibodies from narcolepsy patients could stain multipolar neurons in the globus pallidus suggesting the possible involvement of pallidal orexins in sleep (Bergman et al., 2014). Central orexinergic systems are also closely related to Parkinson's disease. The number of orexinergic neurons and the concentration of orexin in cerebrospinal fluid decrease significantly in Parkinson's disease patients (Yasui et al., 2006; Fronczek et al., 2007; Thannickal et al., 2007; Wienecke et al., 2012). Both exogenous and endogenous orexins increase spontaneous firing activity of pallidal

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neurons through OX1 and OX2 receptors (Xue et al., 2016; Wang et al., 2019). The influx of Ca2+ through L-type Ca2+ channels is involved in orexin-induced excitation

(Wang et al., 2019). The intrapallidal application of orexins ameliorates parkinsonian

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motor deficits by increasing the spontaneous firing rate of globus pallidus neurons in 6-OHDA and MPTP parkinsonian animals (Xue et al., 2016; Wang et al., 2019).

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Somatostatin is synthesized and released by some local GABAergic interneurons

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in the striatum and is involved in the feedforward inhibitory circuit (López-Huerta et al., 2012). Striatal somatostatin nerve fibers may originate from somatostatincontaining neurons in the globus pallidus (Widmann et al., 1987). Somatostatin and its

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receptors are expressed in the globus pallidus. The intrapallidal microinjection of somatostatin dose-dependently increases rat locomotor activity and dopamine release

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in the striatum (Marazioti et al., 2008).

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Pituitary adenylate cyclase-activating polypeptide (PACAP) is a neuropeptide that exerts strong neurotrophic and neuroprotective effects. There are three G proteincoupled PACAP receptors: the specific Pac1 receptor (Pac1R) and the Vpac1/Vpac2 receptors. In the MPTP parkinsonian macaque model, the Pac1R immunoreactivity is markedly reduced in the external segment of the globus pallidus (Feher et al., 2018). 7. Conclusion 20

In this review article, we provide a research advance of neuropeptides including enkephalin, substance P, neurotensin, orexin, somatostatin, pituitary adenylate cyclase-activating polypeptide, and endocannabinoids in the globus pallidus. Based on current studies, these neuropeptides and endocannabinoids significantly modulate the activity of globus pallidus neurons through presynaptic and/or postsynaptic receptors (Figure 1). Levels of the neuropeptides and endocannabinoids and their receptors change in some neurological disorders, such as Parkinson's disease,

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Huntington's disease and schizophrenia (Table 1). Neuropeptides and endocannabinoids in the globus pallidus may function as potential targets of treatment

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for some neurological diseases.

Author contributions

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X-YC wrote the original draft. YX edited the reference and worked on the table. HC

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worked on the figure and revised the manuscript. LC contributed to the conception, design and revision of the manuscript.

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Disclosure and conflicts of interest

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The authors declare no conflict interest.

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Acknowledgement

This work was supported by grants from National Natural Science Foundation of China (31671076, 81200872), Natural Science Foundation of Shandong Province (ZR2019MH110).

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catalepsy: behavioral and electrophysiological studies. Neurosci Bull. 2010;26:345-54. https://doi.org/10.1007/s12264-010-0518-y. Xue Y, Yang YT, Liu HY, Chen WF, Chen AQ, Sheng Q, Chen XY, Wang Y, Chen

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Figure legends

Figure 1. A schematic diagram describing the major cellular functions of four neuropeptides and endocannabinoids on globus pallidus neurons via presynaptic and/or postsynaptic receptors. Endocannabinoids bind to presynaptic CB1 receptors and inhibit both GABA and glutamate release. The activation of CB1 receptors also inhibits GABA uptake. Enkephalin acts on both μ and δ opioid

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receptors presynaptically and reduces GABA release through the inhibition of the Ca2+ current in the globus pallidus. The activation of the postsynaptic

neurokinin-1 receptors by substance P enhances the firing activity of prototypic

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globus pallidus neurons via the suppression of the K+ conductance. Neurotensin activates postsynaptic neurotensin receptors and increases the firing activity of

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globus pallidus neurons. Several ionic mechanisms, including the activation of

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the N-type Ca2+ channels and non-selective cation channels and the inhibition of the K+ channels, may be involved in neurotensin-induced excitation. Neurotensin also increases glutamate release by activating the presynaptic neurotensin

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receptors. Orexin combines with postsynaptic orexin receptors to increase the firing activity of pallidal neurons probably through L-type Ca2+ channels. CB1R:

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cannabinoid type 1 receptor; δR: δ receptor; EC: endocannabinoids; ENK:

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enkephalin; GABA: γ-aminobutyric acid; Glu: glutamate; μR: μ receptor; NK1R: neurokinin-1 receptor; NT: neurotensin; NTR: neurotensin receptor; OXR: orexin receptor; SP: substance P.

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Table 1 Changes in the level of neuropeptides and endocannabinoids and their receptors in the globus pallidus of neurological diseases Recept ors

Endoca nnabino id

CB1

Neurological diseases PD Hu ma n

Reference

HD

Ani mal

Hu ma n

Ani mal

Hu ma n

Schizophrenia Ani Halope mal ridol treatm ent

↓

Richfield and Herkenham, 1994; Glass et al., 2000; Allen et al., 2009 Lastres-Becker et al., 2002a, 2002b; Glass et al., 2004; Casteels et al., 2011; Ooms et al., 2014 Chaves-Kirsten et al., 2013

↓ ↑ ↓

Verdurand et al., 2014

↑ ↓

Enkeph alin and/or metenkepha lin

↓ ↓

na

NK1

(-)

↓

Bower et al., 2000; Delfs et al., 1994b Mauborgne et al., 1983 Fernandez et al., 1994 Jenner et al., 1986; Clevens and Beal, 1989 Zahm and Johnson, 1989; Martorana et al., 2003 Fernandez et al., 1994

↑

ur

Neurote nsin

Dacko and Schneider, 1991; Martorana et al., 2003; Betarbet and Greenamyre, 2004; Bourdenx et al., 2014 Sapp et al., 1995; Allen et al., 2009 Schroeder and Schneider, 2002a

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lP

↓

re

↓

Substan ce P

Delis et al., 2017

Pérez-Otaño et al., 1995; Salin et al., 1996; Bissonnette et al., 2014

↑

μ

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Neurop eptides/ endocan nabinoi ds

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NT ↓ recepto r CB1: cannabinoid type 1 receptor HD: Huntington's disease NK1: neurokinin-1 receptor NT: neurotensin

PD: Parkinson's disease (-): no change

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