Biomolecules & Therapeutics 2018; 26(5): 425-431  https://doi.org/10.4062/biomolther.2018.141
Cocaine- and Amphetamine-Regulated Transcript (CART) Peptide Plays Critical Role in Psychostimulant-Induced Depression
Qing Meng1, Hyoung-Chun Kim2, Seikwan Oh3, Yong-Moon Lee4, Zhenzhen Hu5,*, and Ki-Wan Oh4,*
1Queen Mary Institute, School of Medicine, Nanchang University, Nanchang, Jiangxi 33006, China, 2Neuropsychopharmacology and Toxicology Program, College of Pharmacy, Kangwon National University, Chuncheon 24341, Republic of Korea, 3Department of Molecular Medicine and TIDRC, School of Medicine, Ewha Womans University, Seoul 07985, Republic of Korea, 4Department of Pharmacy, College of Pharmacy, Chungbuk National University, Osong 28160, Republic of Korea, 5Department of Pathophysiology, College of Medicine, Nanchang University, Nanchang, Jiangxi 33006, China
*E-mail: kiwan@chungbuk.ac.kr (Oh KW), huzhenzhen@ncu.edu.cn (Hu Z) Tel: +82-43-261-2827 (Oh KW), +86-791-86360556 (Hu Z), Fax: +82-43-261-2827 (Oh KW), +86-791-86360556 (Hu Z)
Received: July 26, 2018; Revised: August 8, 2018; Accepted: August 8, 2018; Published online: September 1, 2018.
© The Korean Society of Applied Pharmacology. All rights reserved.

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract

Cocaine- and amphetamine-regulated transcript (CART) peptide is a widely distributed neurotransmitter expressed in the central nervous systems. Previously, several reports demonstrated that nucleus accumbal-injected CART peptide positively modulated behavioral sensitization induced by psychostimulants and regulated the mesocorticolimbic dopaminergic pathway. It is confirmed that CART peptide exerted inhibitory effect on psychostimulant-enhanced dopamine receptors signaling, Ca2+/calmodulin-dependent kinase signaling and crucial transcription factors expression. Besides modulation of dopamine receptors-related pathways, CART peptide also exhibited elaborated interactions with other neurotransmitter receptors, such as glutamate receptors and γ-aminobutyric acid receptors, which further account for attribution of CART peptide to inhibition of psychostimulant-potentiated locomotor activity. Recently, CART peptide has been shown to have anxiolytic functions on the aversive mood and uncontrolled drug-seeking behaviors following drug withdrawal. Moreover, microinjection of CART peptide has been shown to have an anti-depressant effect, which suggests its potential utility in the mood regulation and avoidance of depression-like behaviors. In this review, we discuss CART pathways in neural circuits and their interactions with neurotransmitters associated with psychostimulant-induced depression.

Keywords: CART peptide, Addiction, Psychostimulant, Depression
INTRODUCTION

Fragment of cocaine- and amphetamine-regulated transcript (CART) peptide was first discovered by Spiess et al. (1981) in the extraction of hypothalamus in 1981. Douglass et al. identified increased CART mRNA expression within the striatum of psychostimulant-exposed rats (Douglass et al., 1995; Douglass and Daoud, 1996), suggesting the role of CART peptide on the drug abuse. The complete sequences of CART gene were available and showed highly conservation across species (Kuhar et al., 2000; Dallvechia-Adams et al., 2002). The CART gene is composed of 3 exons and 2 introns with alternatively splicing in rat and mouse (Kuhar et al., 2000). And the mouse CART promoter contains series of transcription factor binding site, such as E-box, SP1, overlapped STAT/cyclic adenosine 5′-monophosphate (cAMP) response element (CRE)/AP1, SP2 sites (Kuhar et al., 2000), in which transcription factors including cAMP response element binding protein (CREB), cJUN, SP1 and AP2 may regulate expression of CART gene expression (Fig. 1). Surprisingly, expression of CART peptide dominates in the mesocorticolimbic dopaminergic (DA) system that extends from the ventral tegmental area (VTA) to the nucleus accumbens (NAc) and includes other limbic areas (amygdala, hippocampus, and frontal cortex), and is also widely distributed in the central nervous system (CNS) (Kuhar and Yoho, 1999; Kuhar et al., 2000). Compelling evidences also shows that repeated administration of psychostimulants enhances expression of CART peptide (Jaworski et al., 2003a; Hubert et al., 2008), which is supported by a study in which microinjections of CART peptide into NAc that effectively attenuated the rewarding properties of psychostimulants (Jaworski et al., 2003b; Yoon et al., 2007; Peng et al., 2014; Fu et al., 2016). These observations suggested CART peptide plays a positive role in the regulation of behavioral sensitization induced by psychostimulants and led to thorough investigations of the modes of action of CART peptide with the object of identifying its potential use for the treatment of drug addiction. For example, microinjection of CART peptide into rat NAc significantly blocked psychostimulant-induced up-regulation of dopamine receptor (DR) and activation of downstream cAMP/protein kinase A (PKA)/cAMP response element binding protein (CREB) pathway (Peng et al., 2014; Fu et al., 2016; Xiong et al., 2018). Psychostimulant-induced Ca2+ influx and phosphorylated calcium/calmodulin-dependent protein kinase IIα (pCaMKIIα) expression have also been attenuated by CART peptide. In addition, interactions between pCaMKIIα and D3R blocked the inhibitory effect of D3R on the cAMP/PKA/CREB pathway and behavioral sensitization (Xiong et al., 2018). Recently, CART peptide has been suggested to positively and allosterically modulate γ-aminobutyric acid B receptors (GABAB R), based on the observation that it inhibited drug-depressed GABAB R-G-protein-coupled inwardly rectifying K+-channel (GIRK) signaling. Thus, it has been suggested CART peptide modulates psychostimulant-induced hyperlo-comotion through DR-related calcium signaling and GABA-R-associated pathways (Moffett et al., 2011; Upadhya et al., 2012; Cai et al., 2014; Hu et al., 2015; Fu et al., 2016; Xiong et al., 2018). However, our understanding of CART pathways in neuronal circuits is lacking.

On the other hand, repeated psychostimulant intake may increase the risk of persistent drug-relapse accompanied by irritability, anxiety, and dysphoria (Koob and Le Moal, 1997; Koob et al., 1998). Furthermore, these addiction-related anxious and aversive emotions can lead to depression-like behaviors that may ultimately facilitate suicidal actions possibly mediated by GABAergic pathways (Stanek, 2006; Wiehager et al., 2009; Yoon et al., 2014). Interestingly, CART peptide has been closely linked with corticotropin-releasing factor (CRF) in the hypothalamic-pituitary-adrenal (HPA) axis and amygdala, the latter of which provides the interface between stress and addiction (Koob, 2008a). We hope this review of the role of CART in psychostimulants-induced anxiety-like behaviors will provide new avenues for the development of effective drugs for addiction and/or depression disorders based on understanding of CART pathways in neuronal circuits.

RELATIONS BETWEEN CART CONTAINING NEURAL CIRCUITS AND DEPRESSION

Drug addiction is considered as a psychiatric disorder that progresses from impulsivity to compulsivity, during which people undergo transformation from sense of pleasure or gratification in a positive reinforcement toward relief of anxiety or stress in negative reinforcement (Koob et al., 2004; Koob, 2008a, 2008b). On the other hand, drug cessation triggers protracted anxiety and depression-like symptoms due to counter-adaptive processes that include diminished functions of neurotransmitters in the neuro-circuits associated with acute drug reinforcing effects, such as, the dopamine signaling pathway. Chronic drug exposure results in within-system neuro-adaptations including decreased function of the same neurotransmitter in the same neuro-circuits involved in the acute reinforcing effect of the drug, such as the dopamine signaling pathway (Koob et al., 2004; Koob, 2008a, 2008b). According to the self-medication hypothesis, drug-addicted individuals suffer from deficits in self-esteem and emotion regulation, and cope with aversive and painful emotions by binging (Koob et al., 2004; Koob, 2008a, 2008b). This dysregulation may be a manifestation of altered information-processing, decision-making and behavioral motivation, all of which are associated with functional deficits in brain-stress and anti-stress systems (Koob et al., 2004; Koob, 2008a, 2008b). We later discuss the molecular mechanisms underlying disrupted mood regulation following psychostimulant abstinence and the effects of CART peptide on depressive-like emotions induced by drug withdrawal.

The Hypothalamic-Pituitary-Adrenal (HPA) axis

Pathophysiologic studies showed that quantities of CART immune-reactivity were synthesized and secreted from the anterior pituitary gland (Stanley et al., 2004) and hypothalamus (Smith et al., 2004). Stress regulates CART expression via CRF and glucocorticoids (Stanley et al., 2004). Conversely, the administration of CART peptide up-regulates cirrculating levels of ACTH and corticosterone in the HPA axis through the CRF-dependent mechanism (Vrang et al., 2000; Smith et al., 2004). Furthermore, multiple line of evidence shows that CART peptide plays a key role in the HPA-axis associated stress response (Vrang et al., 2000; Smith et al., 2004; Stanley et al., 2004; Job et al., 2011).

The HPA axis is composed of three major structures: the paraventricular nucleus of the hypothalamus, the anterior lobe of the pituitary gland, and the adrenal gland (Turnbull and Rivier, 1997; Zuloaga et al., 2015). CRF is synthesized and released by the medial parvocellular subdivision of the paraventricular nucleus to the portal blood vessels and then binds to the CRF 1 receptor on the pituitary corticotrophin to induce adrenocorticotropic hormone (ACTH) release into the systemic circulation, which in turn stimulates cortical secretion of glucocorticoid from the adrenal gland (Herman et al., 2005). And the HPA axis is finely tuned by negative feedback from glucocorticoid, which activates glucocorticoid receptor within the paraventricular nucleus and the hippocampus (Turnbull and Rivier, 1997). Acute psychostimulants exposure behaves like stressors that can elicit the activation of HPA axis (Chartoff and Carlezon, 2014), and thus, induce the release of the above-mentioned molecules, which then exert immediate or delayed effects on the mesocorticolimbic system. However, acute withdrawal from chronic psychostimulants induces allosteric load in HPA axis, elevates secretion of CRF and ACTH, and decreases cortisol levels, which are hallmarks of depressive and anxiety spectrum disorders in man (Li et al., 2013a; Zuloaga et al., 2015). However, in depressed patients, regulation of HPA axis is disrupted, which leads to low level of cortisol concentration in serum via stress reactivity (Peng et al., 2015). Surprisingly, hypercortisolemia is present in about 40%–60% of depressed adults (Carroll et al., 2007), which may explain the cause of disrupted hippocampal integrity and impaired memory function in the pathogenesis of depression. Several groups have reported intracerebroventricular or intraamygdalar injection of CRF1 receptor antagonists could effectively attenuate the aversive states and anxiogenic effects induced by drug abstinence, and thus, inhibit drug self-administration (George et al., 2007; Specio et al., 2008; Greenwell et al., 2009).

Serotonin (5-HT) neurotransmitter systems

5-HT is a widely distributed neurotransmitter in the CNS, and has been linked with arousal, anxiety, aversive affect and depressive disorders (Graeff et al., 1996; Pompili et al., 2010). The 5-HT pathway originates from the dorsal raphe nucleus (DRN) and it extends to the amygdala and frontal cortex to facilitate conditioned fear (Graeff et al., 1996). 5-HT synthesis is catalyzed by tyrosine hydroxylase and tryptophan hydroxylase, and synthesized 5-HT is stored in the presynaptic vesicles, where monoamine oxidase (MAO) metabolites can inhibit its release. 5-HT binds to guanine nucleotide triphosphate–binding protein–coupled receptors (GPCR) to activate (AC)/cAMP/PKA and PI/PLC/DAG/PKC signaling pathways, and ultimately promotes the expression of the CREB and induces profound antidepressant effects (Ruhe et al., 2007). Therefore, any abnormality that exists within the mechanisms of 5-HT secretion, receptor transportation and signal transduction may result in anxiogenic and depressive-like disorders. In particular, withdrawal from cocaine self-administration has been associated with a decrease in extracellular 5-HT in the NAc sub-regions (Parsons et al., 1996), whereas acute withdrawal from ethanol has been shown to increase in the sensitivity of 5-HT1A autoreceptor to modulate 5-HT synthesis (Esteban et al., 2002). Moreover, 5-HT2C receptor antagonist blocked the inhibitory dorsal raphe 5-HT2C receptor, and this potentially attenuated cocaine withdrawal exacerbated GABA activity, thereby prevented anxiety-like behaviors (Craige et al., 2015).

The serotonergic system interacts with CART system originated from the lateral hypothalamus to innervate other brain areas associated with stress (Ruhe et al., 2007). Light microscopic studies from Lee and Lee (2014) found reciprocal connections between CART-immunoreactive, hypothalamic paraventricular nucleus and the serotonergic dorsal raphe neurons. Ma et al. (2007) performed a microdialysis approach, which can increase 5-HT efflux made by infusions of CART peptide into the dorsal raphe nucleus and NAc. In addition, activation of 5-HT receptors by 5-HT might enhance dopaminergic signaling and further enhance anti-depressant effects. Interestingly, some studies also investigated that activation of 5-HT4 receptor upregulated CART mRNA expression in the NAc via cAMP/PKA signaling pathway (Jean et al., 2007; Jean et al., 2012) These observations support the protective role of CART peptide on the depression-deprived serotonin system during drug addiction (Ma et al., 2007).

GABA-ergic systems

Immunoblotting results show CART peptide co-localizes with GABA in the nerve terminals in the VTA and substantia nigra (SN) (Dallvechia-Adams et al., 2002), suggesting the intricate relationship between CART peptide and GABA. GABAA R is a ligand-gated ion channel mediating fast inhibitory synaptic transmission, especially in the dopaminergic brain areas such as VTA and substantia nigra compacta (Jiao et al., 2015). On the other hand, GABAB R is a G-protein-coupled receptor composed of 2 subunits, GABAB1(a,b) and GABAB2, which are responsible for agonist or antagonist binding and G-protein activation, respectively (Kulik et al., 2003; Pin and Bettler, 2016). In addition, presynaptic GABAB R inhibits Ca2+ influx whereas postsynaptic GABAB R activates GIRK, which may cause neuron hyperpolarization leading to slow inhibitory post-synaptic current (IPSC) and a reduced synaptic activity (Padgett et al., 2012). It has been reported that withdrawal from chronic morphine exposure increases GABA release in the VTA, resulted in a short-lived (1–3 days) GABAA-mediated inhibition, and up-regulation of cAMP-dependent proteins (Bonci and Williams, 1996; Bonci and Williams, 1997), all of which drive conditioned place aversion (Tan et al., 2012) and diminished GABAB-mediated inhibition (Bonci and Williams, 1996). Chronic methamphetamine and cocaine exposure can depress both GABAA R and GABAB R expression, and weaken GABAB R-GIRK signaling in VTA GABA neurons including glutamatergic neurons within the medial prefrontal cortex (mPFC) (Filip et al., 2015; Jiao et al., 2015). Previous studies indicated that injection of GABAB R agonist baclofen or GABAB R positive allosteric modulators can attenuate self-administration and drug craving in ethanol-dependent rats and human alcoholics (Addolorato et al., 2006; Knapp et al., 2007). Recently, we have shown the modulatory effect of intra-accumbally injected CART peptide on methamphetamine-induced depression of GABAB R-GIRK signaling and concomitant internalization and reduction of membrane GABAB R and GIRK receptors in the VTA and mPFC neurons (Hu et al., 2015), which suggests the regulatory targets of CART peptide are similar to those of the positive allosteric modulator GABAB R on GABAB1 R and GABAB2 R in the context of rescue from drug-depressed GABAB R-GIRK signaling (Fig. 2).

Glutamatergic pathway

The excitatory neurotransmitter glutamate is essential for the excitation propagation and neuronal transmission (Javitt et al., 2011). There are two main classes of glutamate receptors, that is, metabotropic glutamate receptors (mGluRs) and ionotropic glutamate receptors (iGluRs) (Javitt et al., 2011). mGluRs, are classified into group I, II and III subfamilies, and are seven transmembrane G-protein-coupled receptors (GP-CRs) associated with protein kinase B (PKB), nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB), CaM signaling cascades, or coupled Ca2+, K+ and Na+ channels (Javitt et al., 2011). Conversely, iGluRs are composed of N-methyl-D-aspartate (NMDA), a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and kainate receptors and share a voltage-gated ion channel function to enable cation influx (Javitt et al., 2011).

The lateral habenula (LHb) has recently attracted attention due to its modulatory role on depressive behaviors and drug abuse (Lecca et al., 2014). Anatomical studies indicated that LHb, which is positioned near the midline and surrounded by the thalamus, receives prominent glutamatergic afferents from the lateral hypothalamus, and cortical inputs, for example, from the high AMPA-R but low synaptic NMDA-R expressing neurons in medial prefrontal cortex (Lecca et al., 2014). Investigators have reported that aberrant LHb activity over-activates βCaMKII and contributes to aversive and depressive disorders (Li et al., 2013b), whereas the co-release of GABA and glutamate controls LHb activity and can be used to treat depression (Shabel et al., 2014). Cui et al. (2018) found the upregulation of astroglial Kir4.1 in the LHb depressed neuronal bursts in a rat model of depression, and Yang et al. (2018) found LHb burst required both NMDARs and low-voltage-sensitive T-type calcium channels (T-VSCCs) and that blockade of NMDAR or T-VSCCs by ketamine (a NMDAR antagonist) in the LHb induced a rapid antidepressant effect.

Previous reports on CART peptide showed similar pathways to those associated with glutamate receptors. Intra-accumbally injected CART peptide decreased the expression of αCaMKII (Fu et al., 2016; Xiong et al., 2018), which after Ca2+ channel activation couples with NMDAR to enhance neuronal excitability (Liu and Murray, 2012). As discussed above, our recent experiments showed CART peptide has a significant positive effect on GIRK signaling pathways, whereby GIRK channels exert modulatory effects on depressive-like behaviors (Hu et al., unpublished data). In addition, NMDA receptors also activate GIRK channels. Taken together, it is apparent more efforts are required to identify the role of CART peptide on the depression-related LHb area and to determine whether the glutamatergic system is a key target for the inhibitory effect of CART peptide on rewarding properties and anxiety-like behaviors.

CART PEPTIDE AND DEPRESSION THERAPY

Interest in the pathophysiological mechanisms of depression and treatment strategies is increasing, and in view of the many addiction and depression patterns exhibited, the anxiolytic effects of CART peptide might be useful in this context. Currently, the treatment of depression involves the prolonged use of high doses of antidepressants, such as, selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs) or monoamine oxidase inhibitors (MAOIs), or electroconvulsive therapy (ECT) (Kupfer et al., 2012). Furthermore, evidence indicates the effects of these drugs might be augmented by CART peptide (Job et al., 2011; Mao, 2011). It has been reported CART peptide levels are low in the cerebrospinal fluid of major depression disease patients, which suggests a close relationship between CART peptide and depression (Yoon et al., 2018), which is supported by marked reductions of CART-immunoreactive fibers in the paraventricular thalamic nucleus and locus coeruleus of socially isolated rats (Dandekar et al., 2009; Choudhary et al., 2018). Recently, it was reported CART-ergic neurons in the lateral hypothalamus innervated neurons of the paraventricular nucleus communicated with glutamatergic fibers in the NAc shell to modulate psychostimulant-induced reward behaviors, whereas intra-paraventricular hypothalamus infusions of CART antibody or intra-accumbal NMDA receptor antagonist (MK-801) injection blunted the modulatory effect of CART peptide (Choudhary et al., 2018). We have observed pretreatment of basal CaMKIIα-overexpressing NAc neurons with CART peptide injection decreased cocaine or amphetamine (stress)-enhanced pCaMKIIα expression (Fu et al., 2016; Xiong et al., 2018) and that these reductions were coupled with the activations of NMDA receptors, which suggests the inhibitory and modulatory effects of CART peptide on the glutamate receptor-Ca2+/CAM-pCaMKII signaling pathway influences learning and memory formation. Furthermore, we previously showed CART peptide can promote hippocampal neuron survival by upregulating BDNF (Wu et al., 2006; Pae et al., 2007). In addition, some reports have demonstrated the availability of CART-specific binding sites within brain stress regions, suggesting selective CART peptide receptors can induce anxiolytic and antidepressant effects (Nagelova et al., 2014). These findings and their implications indicate more efforts are required to identify other regions influenced by the anxiolytic and antidepressant CART pathways.

CONCLUSION

Recent experimental findings and reports of associations between neural circuits and disrupted neurotransmissions and psychostimulant addiction and depression suggest CART peptide might be therapeutically useful for the treatment of addiction and depression (Job et al., 2011; Mao et al., 2012). Briefly, we summarize the pathways involved in CART peptide-induced amelioration of anxiety-like behaviors during drug withdrawal as follows: (1) CRF-dependent up-regulation of a disrupted HPA axis, (2) CART-induced increase 5HT efflux in the dorsal raphe nucleus and NAc and the subsequent activations of 5-HT autoreceptors and dopaminergic signaling, and (3) CART-induced rescue of the psychostimulant-depressed GABA R signaling pathway within the VTA. (4) CART peptide-induced modulation of glutamate pathways in LHb.

However, some studies have reported adverse side effects when CART peptide was used to alleviate anxious and depressive-related behaviors (Stanek, 2006; Job et al., 2011; Mao et al., 2012). Therefore, we suggest CART related pathways should be further investigated to elucidate the molecular mechanisms responsible for the anxiolytic and antidepressant effects of CART during drug withdrawal.

CONFLICT OF INTEREST

All authors declare no conflict of interest.

ACKNOWLEDGMENTS

This work was supported by grants from the Natural Science Foundation of Jiangxi Province (Grant no. 20161BBG70065 to Z. Hu) and the National Research Foundation (NRF) of Korea funded by the Ministry of Science, ICT & Future Planning (MRC 2010-0029355 to S. Oh).

Figures
Fig. 1. Overview of CART gene structure and CART peptide 3D structure. (A) The schematic diagram of CART gene and its proximal promoter transcription factor binding sites. The diagram shown here is based on the genomic structure of mouse CART genes and adapted from works of Dominguez et al. The CART gene is composed of 3 exons and 2 introns, in which several transcription binding sites are presented, and the transcription initiation site is shown as +1. The diagram is not to scale. (B) The 3D structure of human CART peptide chain A, extending from residues 76–116 of C-terminal domain. The structure is downloaded from protein data bank (PBD, id: 1hy9).
Fig. 2. Outline of key CART-containing neural circuits underlying the pathogenesis of depression. The role of CART in the brain regions such as frontal cortex, striatum, nucleus accumbens, amygdala, and hypothalmus are involved in the development of neuro-pathogenesis. DA and CART peptide could increase the hippocampal BDNF secretion, which may rescue the disrupted function of hippocampus. Additionally, GABAergic and glutaminergic pathways are also associated with reward process, anxiety and dysphoria. The stress-depressed interaction between the amygdala and hippocampus was also augmented by CART peptide, which may play an important role in the modulation of the anxious and depressive-like behaviors.
References
  1. Addolorato, G, Leggio, L, Agabio, R, Colombo, G, and Gasbarrini, G (2006). Baclofen: a new drug for the treatment of alcohol dependence. Int J Clin Pract. 60, 1003-1008.
    Pubmed CrossRef
  2. Anacker, C, Zunszain, PA, Cattaneo, A, Carvalho, LA, Garabedian, MJ, Thuret, S, and Pariante, CM (2011). Antidepressants increase human hippocampal neurogenesis by activating the glucocorticoid receptor. Molecular Psychiatry. 16, 738-750.
    Pubmed KoreaMed CrossRef
  3. Avalos-Fuentes, A, Albarrán-Bravo, S, Loya-Lopéz, S, Cortés, H, Recillas-Morales, S, and Magaña, JJ (2015). Dopaminergic denervation switches dopamine D3 receptor signaling and disrupts its ca(2+) dependent modulation by camkii and calmodulin in striatonigral projections of the rat. Neurobiology of Disease. 74, 336-346.
    CrossRef
  4. Bonci, A, and Williams, JT (1996). A common mechanism mediates long-term changes in synaptic transmission after chronic cocaine and morphine. Neuron. 16, 631-639.
    Pubmed CrossRef
  5. Bonci, A, and Williams, JT (1997). Increased probability of GABA release during withdrawal from morphine. J Neurosci. 17, 796-803.
    Pubmed CrossRef
  6. Cai, Z, Zhang, D, Ying, Y, Yan, M, Yang, J, Xu, F, Oh, K, and Hu, Z (2014). Inhibitory modulation of CART peptides in accumbal neuron through decreasing interaction of CaMKIIalpha with dopamine D3 receptors. Brain Res. 1557, 101-110.
    Pubmed CrossRef
  7. Carroll, BJ, Cassidy, F, Naftolowitz, D, Tatham, NE, Wilson, WH, Iranmanesh, A, Liu, PY, and Veldhuis, JD (2007). Pathophysiology of hypercortisolism in depression. Acta Psychiatr Scand Suppl., 90-103.
    Pubmed CrossRef
  8. Chartoff, EH, and Carlezon, WA (2014). Drug withdrawal conceptualized as a stressor. Behav Pharmacol. 25, 473-492.
    Pubmed KoreaMed
  9. Choudhary, AG, Somalwar, AR, Sagarkar, S, Rale, A, Sakharkar, A, Subhedar, NK, and Kokare, DM (2018). CART neurons in the lateral hypothalamus communicate with the nucleus accumbens shell via glutamatergic neurons in paraventricular thalamic nucleus to modulate reward behavior. Brain Struct Funct. 223, 1313-1328.
  10. Craige, CP, Lewandowski, S, Kirby, LG, and Unterwald, EM (2015). Dorsal raphe 5-HT(2C) receptor and GABA networks regulate anxiety produced by cocaine withdrawal. Neuropharmacology. 93, 41-51.
    Pubmed KoreaMed CrossRef
  11. Cui, Y, Yang, Y, Ni, Z, Dong, Y, Cai, G, Foncelle, A, Ma, S, Sang, K, Tang, S, Li, Y, Shen, Y, Berry, H, Wu, S, and Hu, H (2018). Astroglial Kir4.1 in the lateral habenula drives neuronal bursts in depression. Nature. 554, 323-327.
    Pubmed CrossRef
  12. Dallvechia-Adams, S, Kuhar, MJ, and Smith, Y (2002). Cocaine- and amphetamine-regulated transcript peptide projections in the ventral midbrain: colocalization with gamma-aminobutyric acid, melanin-concentrating hormone, dynorphin, and synaptic interactions with dopamine neurons. J Comp Neurol. 448, 360-372.
    Pubmed CrossRef
  13. Dandekar, MP, Singru, PS, Kokare, DM, and Subhedar, NK (2009). Cocaine- and amphetamine-regulated transcript peptide plays a role in the manifestation of depression: social isolation and olfactory bulbectomy models reveal unifying principles. Neuropsychopharmacology. 34, 1288-1300.
    CrossRef
  14. Douglass, J, and Daoud, S (1996). Characterization of the human cDNA and genomic DNA encoding CART: a cocaine- and amphetamine-regulated transcript. Gene. 169, 241-245.
    Pubmed CrossRef
  15. Douglass, J, McKinzie, AA, and Couceyro, P (1995). PCR differential display identifies a rat brain mRNA that is transcriptionally regulated by cocaine and amphetamine. J Neurosci. 15, 2471-2481.
    Pubmed CrossRef
  16. Esteban, S, Moranta, D, Sastre-Coll, A, Miralles, A, and Garcia-Sevilla, JA (2002). Withdrawal from chronic ethanol increases the sensitivity of presynaptic 5-HT(1A) receptors modulating serotonin and dopamine synthesis in rat brain in vivo. Neurosci Lett. 326, 121-124.
    Pubmed CrossRef
  17. Filip, M, Frankowska, M, Sadakierska-Chudy, A, Suder, A, Szumiec, L, Mierzejewski, P, Bienkowski, P, Przegalinski, E, and Cryan, JF (2015). GABAB receptors as a therapeutic strategy in substance use disorders: focus on positive allosteric modulators. Neuropharmacology. 88, 36-47.
    CrossRef
  18. Fu, Q, Zhou, X, Dong, Y, Huang, Y, Yang, J, Oh, KW, and Hu, Z (2016). Decreased caffeine-induced locomotor activity via microinjection of CART peptide into the nucleus accumbens is linked to inhibition of the pCaMKIIa-D3R interaction. PLoS ONE. 11, e0159104.
    Pubmed KoreaMed CrossRef
  19. George, O, Ghozland, S, Azar, MR, Cottone, P, Zorrilla, EP, Parsons, LH, O’Dell, LE, Richardson, HN, and Koob, GF (2007). CRF-CRF1 system activation mediates withdrawal-induced increases in nicotine self-administration in nicotine-dependent rats. Proc Natl Acad Sci USA. 104, 17198-17203.
    Pubmed KoreaMed CrossRef
  20. Graeff, FG, Guimaraes, FS, De Andrade, TG, and Deakin, JF (1996). Role of 5-HT in stress, anxiety, and depression. Pharmacol Biochem Behav. 54, 129-141.
    Pubmed CrossRef
  21. Greenwell, TN, Funk, CK, Cottone, P, Richardson, HN, Chen, SA, Rice, KC, Zorrilla, EP, and Koob, GF (2009). Corticotropin-releasing factor-1 receptor antagonists decrease heroin self-administration in long- but not short-access rats. Addict Biol. 14, 130-143.
    Pubmed KoreaMed CrossRef
  22. Herman, JP, Ostrander, MM, Mueller, NK, and Figueiredo, H (2005). Limbic system mechanisms of stress regulation: hypothalamo-pituitary-adrenocortical axis.. Prog. Neuropsychopharmacol. Biol Psychiatry. 29, 1201-1213.
    Pubmed CrossRef
  23. Hu, Z, Oh, EH, Chung, YB, Hong, JT, and Oh, KW (2015). Predominant D1 receptors involvement in the over-expression of CART peptides after repeated cocaine administration. Korean J Physiol Pharmacol. 19, 89-97.
    Pubmed KoreaMed CrossRef
  24. Hubert, GW, Jones, DC, Moffett, MC, Rogge, G, and Kuhar, MJ (2008). CART peptides as modulators of dopamine and psychostimulants and interactions with the mesolimbic dopaminergic system. Biochem Pharmacol. 75, 57-62.
    CrossRef
  25. Javitt, DC, Schoepp, D, Kalivas, PW, Volkow, ND, Zarate, C, Merchant, K, Bear, MF, Umbricht, D, Hajos, M, Potter, WZ, and Lee, CM (2011). Translating glutamate: from pathophysiology to treatment. Sci Transl Med. 3, 102mr2.
    Pubmed KoreaMed CrossRef
  26. Jaworski, JN, Kozel, MA, Philpot, KB, and Kuhar, MJ (2003a). Intra-accumbal injection of CART (cocaine-amphetamine regulated transcript) peptide reduces cocaine-induced locomotor activity. J Pharmacol Exp Ther. 307, 1038-1044.
    CrossRef
  27. Jaworski, JN, Vicentic, A, Hunter, RG, Kimmel, HL, and Kuhar, MJ (2003b). CART peptides are modulators of mesolimbic dopamine and psychostimulants. Life Sci. 73, 741-747.
    CrossRef
  28. Jean, A, Conductier, G, Manrique, C, Bouras, C, Berta, P, Hen, R, Charnay, Y, Bockaert, J, and Compan, V (2007). Anorexia induced by activation of serotonin 5-HT4 receptors is mediated by increases in CART in the nucleus accumbens. Proc Natl Acad Sci USA. 104, 16335-16340.
    Pubmed KoreaMed CrossRef
  29. Jean, A, Laurent, L, Bockaert, J, Charnay, Y, Dusticier, N, Nieoullon, A, Barrot, M, Neve, R, and Compan, V (2012). The nucleus accumbens 5-HTR(4)-CART pathway ties anorexia to hyperactivity.. Transl Psychiatry. 2, e203.
    CrossRef
  30. Jiao, D, Liu, Y, Li, X, Liu, J, and Zhao, M (2015). The role of the GABA system in amphetamine-type stimulant use disorders. Front Cell Neurosci. 9, 162.
    Pubmed KoreaMed CrossRef
  31. Job, MO, McNamara, IM, and Kuhar, MJ (2011). cart peptides regulate psychostimulants and may be endogenous antidepressants. Curr Neuropharmacol. 9, 12-16.
    Pubmed KoreaMed CrossRef
  32. Knapp, DJ, Overstreet, DH, and Breese, GR (2007). Baclofen blocks expression and sensitization of anxiety-like behavior in an animal model of repeated stress and ethanol withdrawal. Alcohol Clin Exp Res. 31, 582-595.
    Pubmed KoreaMed
  33. Koob, GF (2008a). Hedonic homeostatic dysregulation as a driver of drug-seeking behavior.. Drug Discov. Today Dis Models. 5, 207-215.
    CrossRef
  34. Koob, GF (2008b). A role for brain stress systems in addiction. Neuron. 59, 11-34.
    CrossRef
  35. Koob, GF, and Le Moal, M (1997). Drug abuse: hedonic homeostatic dysregulation. Science. 278, 52-58.
    Pubmed CrossRef
  36. Koob, GF, Sanna, PP, and Bloom, FE (1998). Neuroscience of addiction. Neuron. 21, 467-476.
    Pubmed CrossRef
  37. Koob, GF, Ahmed, SH, Boutrel, B, Chen, SA, Kenny, PJ, Markou, A, O’Dell, LE, Parsons, LH, and Sanna, PP (2004). Neurobiological mechanisms in the transition from drug use to drug dependence. Neurosci Biobehav Rev. 27, 739-749.
    Pubmed CrossRef
  38. Kuhar, MJ, and Yoho, LL (1999). CART peptide analysis by Western blotting. Synapse. 33, 163-171.
    Pubmed CrossRef
  39. Kuhar, MJ, Adams, LD, Hunter, RG, Vechia, SD, and Smith, Y (2000). CART peptides. Regul Pept. 89, 1-6.
    Pubmed CrossRef
  40. Kulik, A, Vida, I, Lujan, R, Haas, CA, Lopez-Bendito, G, Shigemoto, R, and Frotscher, M (2003). Subcellular localization of metabotropic GABA(B) receptor subunits GABA(B1a/b) and GABA(B2) in the rat hippocampus. J Neurosci. 23, 11026-11035.
    Pubmed CrossRef
  41. Kupfer, DJ, Frank, E, and Phillips, ML (2012). Major depressive disorder: new clinical, neurobiological, and treatment perspectives. Lancet. 379, 1045-1055.
    KoreaMed CrossRef
  42. Lecca, S, Meye, FJ, and Mameli, M (2014). The lateral habenula in addiction and depression: an anatomical, synaptic and behavioral overview. Eur J Neurosci. 39, 1170-1178.
    Pubmed CrossRef
  43. Lee, JS, and Lee, HS (2014). Reciprocal connections between CART-immunoreactive, hypothalamic paraventricular neurons and serotonergic dorsal raphe cells in the rat: light microscopic study. Brain Res. 1560, 46-59.
    Pubmed CrossRef
  44. Li, K, Zhou, T, Liao, L, Yang, Z, Wong, C, Henn, F, Malinow, R, Yates, JR, and Hu, H (2013a). betaCaMKII in lateral habenula mediates core symptoms of depression. Science. 341, 1016-1020.
    CrossRef
  45. Li, SX, Yan, SY, Bao, YP, Lian, Z, Qu, Z, Wu, YP, and Liu, ZM (2013b). Depression and alterations in hypothalamic-pituitary-adrenal and hypothalamic-pituitary-thyroid axis function in male abstinent methamphetamine abusers. Hum Psychopharmacol. 28, 477-483.
    CrossRef
  46. Liu, XB, and Murray, KD (2012). Neuronal excitability and calcium/calmodulin-dependent protein kinase type II: location, location, location. Epilepsia. 53, 45-52.
    Pubmed CrossRef
  47. Ma, Z, Pearson, E, and Tao, R (2007). CART peptides increase 5-hydroxytryptamine in the dorsal raphe and nucleus accumbens of freely behaving rats. Neurosci Lett. 417, 303-307.
    Pubmed KoreaMed CrossRef
  48. Mao, P (2011). Potential antidepressant role of neurotransmitter CART: implications for mental disorders. Depress Res Treat. 2011, 762139.
    Pubmed KoreaMed
  49. Mao, PZ, Meshul, CK, Thuillier, P, Goldberg, NRS, and Reddy, PH (2012). CART Peptide Is a Potential Endogenous Antioxidant and Preferentially Localized in Mitochondria. PLoS ONE. 7, e29343.
    Pubmed KoreaMed CrossRef
  50. Moffett, MC, Song, J, and Kuhar, MJ (2011). CART peptide inhibits locomotor activity induced by simultaneous stimulation of D1 and D2 receptors, but not by stimulation of individual dopamine receptors. Synapse. 65, 1-7.
    CrossRef
  51. Nagelova, V, Pirnik, Z, Zelezna, B, and Maletinska, L (2014). CART (cocaine- and amphetamine-regulated transcript) peptide specific binding sites in PC12 cells have characteristics of CART peptide receptors. Brain Res. 1547, 16-24.
    Pubmed CrossRef
  52. Padgett, CL, Lalive, AL, Tan, KR, Terunuma, M, Munoz, MB, Pangalos, MN, Martinez-Hernandez, J, Watanabe, M, Moss, SJ, Lujan, R, Luscher, C, and Slesinger, PA (2012). Methamphetamine-evoked depression of GABA(B) receptor signaling in GABA neurons of the VTA. Neuron. 73, 978-989.
    Pubmed KoreaMed CrossRef
  53. Pae, CU, Lee, C, and Paik, IH (2007). Therapeutic implication of cocaine- and amphetamine-regulated transcript (CART) in the treatment of depression.. Med Hypotheses. 69, 132-135.
    CrossRef
  54. Parsons, LH, Koob, GF, and Weiss, F (1996). Extracellular serotonin is decreased in the nucleus accumbens during withdrawal from cocaine self-administration. Behav Brain Res. 73, 225-228.
    Pubmed CrossRef
  55. Peng, GJ, Tian, JS, Gao, XX, Zhou, YZ, and Qin, XM (2015). Research on the pathological mechanism and drug treatment mechanism of depression. Curr Neuropharmacol. 13, 514-523.
    Pubmed KoreaMed CrossRef
  56. Peng, Q, Sun, X, Liu, Z, Yang, J, Oh, KW, and Hu, Z (2014). Micro-injection of CART (cocaine- and amphetamine-regulated transcript) peptide into the nucleus accumbens inhibits the cocaine-induced upregulation of dopamine receptors and locomotor sensitization. Neurochem Int. 75, 105-111.
    Pubmed CrossRef
  57. Pin, JP, and Bettler, B (2016). Organization and functions of mGlu and GABAB receptor complexes. Nature. 540, 60-68.
    Pubmed CrossRef
  58. Pompili, M, Serafini, G, Innamorati, M, Moller-Leimkuhler, AM, Giupponi, G, Girardi, P, Tatarelli, R, and Lester, D (2010). The hypothalamic-pituitary-adrenal axis and serotonin abnormalities: a selective overview for the implications of suicide prevention. Eur Arch Psychiatry Clin Neurosci. 260, 583-600.
    Pubmed CrossRef
  59. Ruhe, HG, Mason, NS, and Schene, AH (2007). Mood is indirectly related to serotonin, norepinephrine and dopamine levels in humans: a meta-analysis of monoamine depletion studies. Mol. Psychiatry. 12, 331-359.
  60. Shabel, SJ, Proulx, CD, Piriz, J, and Malinow, R (2014). Mood regulation. GABA/glutamate co-release controls habenula output and is modified by antidepressant treatment. Science. 345, 1494-1498.
    Pubmed KoreaMed CrossRef
  61. Smith, SM, Vaughan, JM, Donaldson, CJ, Rivier, J, Li, C, Chen, A, and Vale, WW (2004). Cocaine- and amphetamine-regulated transcript activates the hypothalamic-pituitary-adrenal axis through a corticotropin-releasing factor receptor-dependent mechanism. Endocrinology. 145, 5202-5209.
    Pubmed CrossRef
  62. Specio, SE, Wee, S, O’Dell, LE, Boutrel, B, Zorrilla, EP, and Koob, GF (2008). CRF(1) receptor antagonists attenuate escalated cocaine self-administration in rats. Psychopharmacology. 196, 473-482.
    CrossRef
  63. Spiess, J, Villarreal, J, and Vale, W (1981). Isolation and sequence analysis of a somatostatin-like polypeptide from ovine hypothalamus. Biochemistry. 20, 1982-1988.
    Pubmed CrossRef
  64. Stanek, LM (2006). Cocaine- and amphetamine related transcript (CART) and anxiety. Peptides. 27, 2005-2011.
    Pubmed CrossRef
  65. Stanley, SA, Murphy, KG, Bewick, GA, Kong, WM, Opacka-Juffry, J, Gardiner, JV, Ghatei, M, Small, CJ, and Bloom, SR (2004). Regulation of rat pituitary cocaine- and amphetamine-regulated transcript (CART) by CRH and glucocorticoids. Am J Physiol Endocrinol Metab. 287, E583-E590.
    Pubmed CrossRef
  66. Tan, KR, Yvon, C, Turiault, M, Mirzabekov, JJ, Doehner, J, Labouebe, G, Deisseroth, K, Tye, KM, and Luscher, C (2012). GABA neurons of the VTA drive conditioned place aversion. Neuron. 73, 1173-1183.
    Pubmed CrossRef
  67. Turnbull, AV, and Rivier, C (1997). Corticotropin-releasing factor (CRF) and endocrine responses to stress: CRF receptors, binding protein, and related peptides. Proc Soc Exp Biol Med. 215, 1-10.
    Pubmed CrossRef
  68. Upadhya, MA, Nakhate, KT, Kokare, DM, Singh, U, Singru, PS, and Subhedar, NK (2012). CART peptide in the nucleus accumbens shell acts downstream to dopamine and mediates the reward and reinforcement actions of morphine. Neuropharmacology. 62, 1823-1833.
    CrossRef
  69. Vrang, N, Larsen, PJ, Kristensen, P, and Tang-Christensen, M (2000). Central administration of cocaine-amphetamine-regulated transcript activates hypothalamic neuroendocrine neurons in the rat. Endocrinology. 141, 794-801.
    Pubmed CrossRef
  70. Wiehager, S, Beiderbeck, DI, Gruber, SH, El-Khoury, A, Wamsteeker, J, Neumann, ID, Petersen, A, and Mathe, AA (2009). Increased levels of cocaine and amphetamine regulated transcript in two animal models of depression and anxiety. Neurobiol Dis. 34, 375-380.
    Pubmed CrossRef
  71. Wu, B, Hu, S, Yang, M, Pan, H, and Zhu, S (2006). CART peptide promotes the survival of hippocampal neurons by upregulating brain-derived neurotrophic factor. Biochem Biophys Res Commun. 347, 656-661.
    Pubmed CrossRef
  72. Xiong, L, Meng, Q, Sun, X, Lu, X, Fu, Q, Peng, Q, Yang, J, Oh, KW, and Hu, ZZ (2018). CART peptide in the nucleus accumbens shell inhibits cocaine-induced locomotor sensitization to transient overexpression of alpha-Ca2+/Calmodulin-dependent Protein Kinase II. J Neurochem.
    CrossRef
  73. Yang, Y, Cui, Y, Sang, K, Dong, Y, Ni, Z, Ma, S, and Hu, H (2018). Ketamine blocks bursting in the lateral habenula to rapidly relieve depression. Nature. 554, 317-322.
    Pubmed CrossRef
  74. Yoon, HS, Adachi, N, and Kunugi, H (2014). Microinjection of cocaine- and amphetamine-regulated transcript 55–102 peptide into the nucleus accumbens could modulate anxiety-related behavior in rats. Neuropeptides. 48, 319-325.
    Pubmed CrossRef
  75. Yoon, HS, Kim, S, Park, HK, and Kim, JH (2007). Microinjection of CART peptide 55–102 into the nucleus accumbens blocks both the expression of behavioral sensitization and ERK phosphorylation by cocaine. Neuropharmacology. 53, 344-351.
    Pubmed CrossRef
  76. Yoon, HS, Hattori, K, Sasayama, D, and Kunugi, H (2018). Low cocaine- and amphetamine-regulated transcript (CART) peptide levels in human cerebrospinal fluid of major depressive disorder (MDD) patients. J Affect Disord. 232, 134-138.
    Pubmed CrossRef
  77. Zuloaga, DG, Jacobskind, JS, and Raber, J (2015). Methamphetamine and the hypothalamic-pituitary-adrenal axis. Front Neurosci. 9, 178.
    Pubmed KoreaMed CrossRef

This Article


Cited By Articles

Funding Information

Services
Social Network Service

e-submission

Archives