Cocaine- and amphetamine-regulated transcript peptide produces anxiety-like behavior in rodents

Chaki, Shigeyuki; Kawashima, Noritaka; Suzuki, Yoshiko; Shimazaki, Toshiharu; Okuyama, Shigeru

doi:10.1016/s0014-2999(03)01368-2

Cited by 89 publications

(49 citation statements)

References 26 publications

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“…In vitro, CART-(55-102) increases release of CRH from hypothalamic explants (Stanley et al 2001). Together, these data suggest that CART-(55-102) may activate the hypothalamus-pituitary-adrenal axis, possibly by interacting with the CRH system, thereby controlling emotional and stress responses (Chaki et al 2003). …”

Section: Introductionmentioning

confidence: 84%

Unique responses of midbrain CART neurons in macaques to ovarian steroids

et al. 2008

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CART (cocaine and amphetamine regulated transcript) is a neuropeptide involved in the control of several physiological processes, such as response to psychostimulants, food intake, depressive diseases and neuroprotection. It is robustly expressed in the brain, mainly in regions that control emotional and stress responses and it is regulated by estrogen in the hypothalamus. There is a distinct population of CART neurons located in the vicinity of the Edinger-Westphal nucleus of the midbrain that also colocalize urocortin-1. The aims of this study were 1) to determine the distribution of CART immunoreactive neurons in the monkey midbrain, 2) to examine the effects of estrogen (E) and progesterone (P) on midbrain CART mRNA and peptide expression and 3) to determine whether midbrain CART neurons contain steroid receptors. Adult female rhesus monkeys (Macaca mulatta) were spayed and either treated with placebo (OVX), estrogen alone (E), progesterone alone (P) or E + P. Animals were prepared (a) for RNA extraction followed by microarray analysis and quantitative (q) RT-PCR (n=3/group); (b) for immunohistochemical analysis of CART and CART +tryptophan hydroxylase (TPH), CART+estrogen receptors (ER) or CART+progesterone receptors (n=5/group) and (c) for western blots (n=3/group). Both E− and E+P-administration decreased CART gene expression on the microarray and with qRT-PCR. Stereological analysis of CART immunostaining at five levels of the Edinger-Westphal nucleus indicated little effect of E or E + P administration on the area of CART immunostaining. However, P administration increased CARTimmunopositive area in comparison to the OVX control group with Student's t-test, but not with ANOVA. CART 55-102 detection on western blot was unchanged by hormone administration. ERβand PR were detected in CART neurons and CART fibers appeared to innervate TPH-positive serotonin neurons in the dorsal raphe. In summary, E decreased CART mRNA, but this effect did not translate to the protein level. Moreover, P administration alone had a variable effect on CART mRNA, but it caused an increase in CART immunostaining. Together, the data suggest that CART neurons in the midbrain have a unique steroid response, which may be mediated by nuclear receptors, neuroactive steroids or interneurons.

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Section: Introductionmentioning

confidence: 84%

Unique responses of midbrain CART neurons in macaques to ovarian steroids

et al. 2008

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“…Several studies have suggested an important role of CART in anxiety-like behavior (Kask et al, 2000;Asakawa et al, 2001;Chaki et al, 2003). Administration of icv to rats results in a decreased ratio of open/total arm entries and reduces time spent in open part of the maze, thus suggesting increased anxiety-like behavior (Kask et al, 2000).…”

Section: Discussionmentioning

confidence: 99%

“…In support of this concept is the recent identification of a polymorphism in intron 1 of the CART gene that is associated with alcoholism in the Korean male population (Jung et al, 2004). CART also plays an important role in anxiety-like behavior and stress-related responses (Chaki et al, 2003;Stanek, 2006), and dosedependently enhances anxiety-like behavior in the elevated plus maze (EPM) test in both rats (Kask et al, 2000) and mice (Asakawa et al, 2001).…”

Section: Introductionmentioning

confidence: 95%

Importance of Cocaine- and Amphetamine-Regulated Transcript Peptide in the Central Nucleus of Amygdala in Anxiogenic Responses Induced by Ethanol Withdrawal

Dandekar

Singru

Kokare

et al. 2007

Neuropsychopharmacol

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We studied the involvement of cocaine-and amphetamine-regulated transcript peptide (CART) in the central nucleus of amygdala (CeA), lateral bed nucleus of the stria terminalis (BNSTl) and nucleus accumbens shell (AcbSh) in generation of ethanol withdrawal symptoms, with particular focus on anxiety-like behavior using a social interaction test. Administration of CART (54-102) into the lateral ventricle (50 and 100 ng) and bilaterally in the CeA (10 and 20 ng) caused a significant reduction in social interaction, suggesting an anxiogenic action of the peptide. Chronic ethanol treatment for 15 days followed by withdrawal precipitated an anxiogenic response at 24 h that was attenuated by intracerebroventricular (5 ml) and intra-CeA (1 ml) administration of antibodies against CART (1 : 500 dilution). An immunocytochemistry protocol was employed to study the response of the endogenous CART system in the CeA following chronic ethanol withdrawal. At 0 h ethanol withdrawal, CART immunoreactivity was apparent in few fibers and the profile was similar to that in the pair-fed control rats. Twenty-four hours following ethanol withdrawal, a highly significant increase (Po0.001) in CART immunoreactivity was noticed in the CeA, which returned to normal 48 and 72 h post-withdrawal. Similar doses of CART or CART antibody injected bilaterally into the BNSTl or AcbSh produced no response in the social interaction test. Furthermore, the CART immunoreactivity profile did not change at the post-withdrawal time points in each of these brain sites. We suggest that CART may mediate the early signs of anxiety-like behavior induced by ethanol withdrawal within the neuroanatomical framework of the CeA.

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“…The peptides are stored within the vesicles (Damaj et al 2003), and thus may act as a neuromodulator (Smith et al 1999). Physiologically, CART peptides produced hypophagia, hyperlocomotion and anxiety-like behavior (Chaki et al 2003;Kimmel et al 2000;Stanek 2006). At high doses, CART also induced analgesia and impaired locomotion (Damaj et al 2003 Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication.…”

mentioning

confidence: 99%

“…For instances, 5-HT 1A receptor agonist buspirone attenuated the anxiogenic response to CART (Chaki et al 2003). Increases in 5-hydroxytryptamine (5-HT; serotonin) turnover was implicated in the regulation of CART-induced hypophagia (Choi et al 2003).…”

mentioning

confidence: 99%

CART peptides increase 5-hydroxytryptamine in the dorsal raphe and nucleus accumbens of freely behaving rats

Ma¹,

Pearson²,

Tao³

2007

Neuroscience Letters

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Cocaine and amphetamine-regulated transcript peptides (CART) are implicated in the antidepressant effect. This may involve in 5-hydroxytryptamine (5-HT) in the CNS. The aim of the present studies was to investigate the effect of CART peptides on extracellular 5-HT in the dorsal raphe nucleus (DRN) and nucleus accumbens (NAcc) using a microdialysis approach in freely-behaving rats. Reverse infusion of CART in the DRN produced a concentration (10 µM-100 µM) -dependent increase in 5-HT in the DRN. Similarly, CART [62][63][64][65][66][67][68][69][70][71][72][73][74][75][76] (10 µM-100 µM) infused into the DRN and NAcc elevated 5-HT in the DRN and NAcc, respectively. Thus, CART increases extracellular 5-HT in both the DRN and NAcc. In addition, infusion of CART [62][63][64][65][66][67][68][69][70][71][72][73][74][75][76] (100 µM) in the DRN produced a significant increase in 5-HT in the NAcc, implying an existence of CART receptors responsible for the depolarization-dependent release. In summary, the results of the present studies suggest that CART peptides may have an antidepressant effect through increases in extracellular 5-HT. KeywordsCART peptides; antidepressant; dorsal raphe; nucleus accumbens; microdialysis; serotonin Cocaine-and amphetamine-regulated transcript peptides (CART) are a group of brainderived substances induced by the administration of cocaine and amphetamine, and they are widely distributed throughout the brain including the dorsal raphe nucleus (DRN) and nucleus accumbens (NAcc) (Douglass et al. 1995;Hurd and Fagergren 2000;Koylu et al. 1998). The peptides are stored within the vesicles (Damaj et al. 2003), and thus may act as a neuromodulator (Smith et al. 1999). Physiologically, CART peptides produced hypophagia, hyperlocomotion and anxiety-like behavior (Chaki et al. 2003;Kimmel et al. 2000;Stanek 2006). At high doses, CART also induced analgesia and impaired locomotion (Damaj et al. 2003 Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. CART (Chaki et al. 2003). Increases in 5-hydroxytryptamine (5-HT; serotonin) turnover was implicated in the regulation of CART-induced hypophagia (Choi et al. 2003). Recently, it was found that patients with CART mutation had high depression scores, supporting a speculation that CART may have an antidepressant effect, probably through 5-HT in the brain (Miraglia del Giudice et al. 2006;Pae et al. 2006). NIH Public AccessTo understand the role of CART in depression, the aim of the present studies was to determine extracellular 5-HT in response to CART administration in freely-behaving rats. The experiments were...

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Cocaine- and amphetamine-regulated transcript peptide produces anxiety-like behavior in rodents

Cited by 89 publications

References 26 publications

Unique responses of midbrain CART neurons in macaques to ovarian steroids

Unique responses of midbrain CART neurons in macaques to ovarian steroids

Importance of Cocaine- and Amphetamine-Regulated Transcript Peptide in the Central Nucleus of Amygdala in Anxiogenic Responses Induced by Ethanol Withdrawal

CART peptides increase 5-hydroxytryptamine in the dorsal raphe and nucleus accumbens of freely behaving rats

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