Activity of various CART peptides in changing locomotor activity in the rat

doi:10.1054/npep.2002.0884

Neuropeptides

Volume 36, Issue 1, February 2002, Pages 9-12

https://doi.org/10.1054/npep.2002.0884 Get rights and content

Abstract

Several CART (cocaine- and amphetamine-regulated transcript) peptides have been identified in the brain. One peptide, rlCART 55–102, has been previously characterized in locomotor and feeding assays in rodents. The present study characterized the locomotor-stimulating effect of several additional CART peptides after intra-VTA administration in rats. The results confirm earlier findings that intra-VTA administration of rlCART 55–102 dose-dependently increased locomotor activity. Intra-VTA administration of rlCART 62–102 increased activity comparable with that produced by rlCART 55–102. However, intra-VTA administration of rsCART 10–89 and rlCART 55–59 did not increase motor activity. These results suggest that the portion of rlCART 55–102 responsible for increasing motor activity must reside within the portion of the protein also encompassed by rlCART 61–102, as the initial 5-amino acidsequence of rlCART 55–102 did not increase motor activity. In summary, rlCART 55–102 and rlCART 62–102 arebehaviorally active in this locomotor assay, while rsCART 10–89 and rlCART 55–59 are not.

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Cited by (39)

CART modulates the effects of levodopa in rat model of Parkinson's disease
2016, Behavioural Brain Research
Parkinson’s disease (PD) is an age-related disorder characterized by a progressive degeneration of dopaminergic neurons of substantia nigra (SN). The neuropeptide cocaine- and amphetamine-regulated transcript (CART) is known to closely interact with the dopamine system and regulate psychomotor activity. We screened the effectiveness of CART in reversing the symptoms of PD in a rat model. PD like condition was induced by administering 6-hydroxydopamine (6-OHDA) directly in the SN of the right side. Fifteen days later, intraperitoneal (IP) treatment with apomorphine hydrochloride to these rats, resulted in contralateral rotations in the rotation test chamber suggesting induction of PD-like symptoms. This action of apomorphine was significantly attenuated by intracerebroventricular (ICV) treatment with CART and potentiated by CART antibody. IP treatment with levodopa also produced contralateral rotation in PD induced rats, and showed anti-Parkinson-like action. Prior treatment with CART via ICV route potentiated the anti-Parkinsonian effects of levodopa, while CART antibody produced opposite effects. CART treatment per se, to PD induced rats produced ipsilateral rotations, suggesting that the peptide may promote the endogenous release of dopamine from intact neurons. While CART-immunoreactivity in arcuate nucleus, paraventricular nucleus, striatum, substantia nigra, ventral tegmental area and locus coeruleus was reduced in the PD induced rats, levodopa treatment restored the expression of CART-immunoreactivity in these nuclei. These results suggest that endogenous CART might closely interact with the dopamine containing SN-striatal pathway which is known to profoundly influence the motor system. The study underscores the importance of CART as a potential therapeutic agent in the treatment of PD.
Involvement of oxidative stress in the regulation of NPY/CART-mediated appetite control in amphetamine-treated rats
2015, NeuroToxicology
Citation Excerpt :
In addition, CART peptide is a modulator of dopamine and psychostimulants because CART tends to oppose large increases in dopamine signaling (Hubert et al., 2008) and prevent the oxidative stress in the brain (Balkan et al., 2012; Sha et al., 2014). There are two active CART peptide fragments, i.e. CART (55–102) and CART (62–102), that exhibit different relative activities in different testing paradigms (Kimmel et al., 2002). CART (55–102) is five-fold more potent than CART (62–102) in the inhibition of food intake (Rohner-Jeanrenaud et al., 2002; Vicentic et al., 2006).
Amphetamine (AMPH) treatment can suppress appetite and increase oxidative stress in the brain. AMPH-induced appetite suppression is associated with the regulation of neuropeptide Y (NPY) and cocaine- and amphetamine-regulated transcript (CART) in the hypothalamus. The present study explored whether antioxidants, including glutathione S-transferase (GST) and glutathione peroxidase (GP), were involved in this NPY/CART-mediated appetite control. Rats were treated daily with AMPH for four days. Changes in food intake and expression levels of hypothalamic NPY, CART, GST, and GP were examined and compared. Results showed that, in AMPH-treated rats, (1) food intake and NPY expression decreased, while CART, GST, and GP expression increased; (2) NPY knockdown in the brain enhanced the decrease in NPY and the increases in CART, GST, and GP expression; and (3) central inhibition of reactive oxygen species production decreased GST and GP and modulated AMPH anorexia and the expression levels of NPY and CART. The present results suggest that oxidative stress in the brain participates in regulating NPY/CART-mediated appetite control in AMPH-treated rats. These results may advance the knowledge regarding the molecular mechanism of AMPH-evoked or NPY/CART-mediated appetite suppression.
Regulation of the mesolimbic dopamine circuit by feeding peptides
2015, Neuroscience
Citation Excerpt :
However, a few studies have implicated CART action in the VTA for its anorexigenic effects. Intra-VTA injection of CART dose-dependently increases locomotor activity and induces a CPP (Kimmel et al., 2000, 2002). However, intra-VTA CART55–102 reduces locomotor activating effects of systemic cocaine (Jaworski et al., 2003, 2007).
Polypeptides produced in the gastrointestinal tract, stomach, adipocytes, pancreas and brain that influence food intake are referred to as ‘feeding-related’ peptides. Most peptides that influence feeding exert an inhibitory effect (anorexigenic peptides). In contrast, only a few exert a stimulating effect (orexigenic peptides), such as ghrelin. Homeostatic feeding refers to when food consumed matches energy deficits. However, in western society where access to palatable energy-dense food is nearly unlimited, food is mostly consumed for non-homeostatic reasons. Emerging evidence implicates the mesocorticolimbic circuitry, including dopamine neurons of the ventral tegmental area (VTA), as a key substrate for non-homeostatic feeding. VTA dopamine neurons encode cues that predict rewards and phasic release of dopamine in the ventral striatum motivates animals to forage for food. To elucidate how feeding-related peptides regulate reward pathways is of importance to reveal the mechanisms underlying non-homeostatic or hedonic feeding. Here, we review the current knowledge of how anorexigenic peptides and orexigenic peptides act within the VTA.
Both neuropeptide Y knockdown and Y1 receptor inhibition modulate CART-mediated appetite control
2015, Hormones and Behavior
Citation Excerpt :
Thus, it is possible that CART may participate in regulating NPY- and POMC-mediated appetite control in AMPH-treated rats. There are two active CART peptide fragments, CART (55–102) and CART (62–102), that exhibit different relative activities in different testing paradigms (Kimmel et al., 2002). CART (55–102) is five-fold more potent than CART (62–102) in the inhibition of food intake (Vicentic et al., 2006).
Amphetamine (AMPH)-induced appetite suppression has been attributed to its inhibition of neuropeptide Y (NPY)-containing neurons in the hypothalamus. This study examined whether hypothalamic cocaine- and amphetamine-regulated transcript (CART)-containing neurons and NPY Y1 receptor (Y1R) were involved in the action of AMPH. Rats were treated daily with AMPH for four days, and changes in feeding behavior and expression levels of NPY, CART, and POMC were assessed and compared. The results showed that both feeding behavior and NPY expression decreased during AMPH treatment, with the biggest reduction occurring on Day 2. By contrast, the expression of CART and melanocortin 3 receptor (MC3R), a member of the POMC neurotransmission, increased with the maximum response on Day 2, directly opposite to the NPY expression results. The intracerebroventricular infusion of NPY antisense or Y1R inhibitor both modulated AMPH-induced anorexia and the expression levels of MC3R and CART. The results suggest that in the hypothalamus both POMC- and CART-containing neurons participate in regulating NPY-mediated appetite control during AMPH treatment. These results may advance the knowledge of molecular mechanism of anorectic drugs.
Microinjection of CART (cocaine- and amphetamine-regulated transcript) peptide into the nucleus accumbens inhibits the cocaine-induced upregulation of dopamine receptors and locomotor sensitization
2014, Neurochemistry International
Repeated exposure to addictive drugs enhances dopamine receptor (DR) signaling and the ultimate phosphorylation of the cyclic adenosine 5′-monophosphate (cAMP)-response element-binding protein (CREB)-regulated cocaine- and amphetamine-regulated transcript (CART) expression in the nucleus accumbens (NAcc). These effects are known to contribute to the expression of behavioral sensitization. CART peptides are neuropeptides that modulate drug reward and reinforcement. The present experiments investigated the effects of CART 55–102 microinjection into the NAcc on (1) the phosphorylation of CREB, (2) cAMP/protein kinase A (PKA) signaling and (3) extracellular signal-regulated kinase (ERK) phosphorylated kinase signaling. Here, we show that repeated microinjections into the NAcc of CART 55–102 peptides (1.0 or 2.5 μg, 0.5 μl/side) attenuates cocaine-induced enhancements of D1R, D2R and D3R phosphorylation in this sites. Furthermore, the microinjection of CART 55–102 followed by repeated injections of cocaine (15 mg/kg) dose-dependently blocked the enhancement of cAMP levels, PKA activity and pERK and pCREB levels on the fifth day of cocaine administration. The cocaine-induced locomotor activity and behavioral sensitization in rats were also inhibited by the 5-day-microinjection of CART peptides. These results suggest that the phosphorylation of CREB by cocaine in the NAcc was blocked by the CART 55–102 peptide via the inhibition of D1R and D2R stimulation, D3R phosphorylation, cAMP/PKA signaling and ERK phosphorylated kinase signaling. These effects may have played a compensatory inhibitory role in the behavioral sensitization of rats that received microinjections of CART 55–102.
CART in the brain of vertebrates: Circuits, functions and evolution
2014, Peptides
Citation Excerpt :
However, no such effect was observed by Couceyro et al. [71]. CART 55–102, as well as 62–102, stereotaxically injected in the ventral tegmental area (VTA) stimulated locomotor activity with immediate effect, while some other fragments were ineffective [169,170]. The intra-accumbal administration of shRNAs against CART peptides caused about 2.5-fold increase in cocaine-mediated locomotion [153].
Cocaine- and amphetamine-regulated transcript peptide (CART) with its wide distribution in the brain of mammals has been the focus of considerable research in recent years. Last two decades have witnessed a steady rise in the information on the genes that encode this neuropeptide and regulation of its transcription and translation. CART is highly enriched in the hypothalamic nuclei and its relevance to energy homeostasis and neuroendocrine control has been understood in great details. However, the occurrence of this peptide in a range of diverse circuitries for sensory, motor, vegetative, limbic and higher cortical areas has been confounding. Evidence that CART peptide may have role in addiction, pain, reward, learning and memory, cognition, sleep, reproduction and development, modulation of behavior and regulation of autonomic nervous system are accumulating, but an integration has been missing. A steady stream of papers has been pointing at the therapeutic potentials of CART. The current review is an attempt at piecing together the fragments of available information, and seeks meaning out of the CART elements in their anatomical niche. We try to put together the CART containing neuronal circuitries that have been conclusively demonstrated as well as those which have been proposed, but need confirmation. With a view to finding out the evolutionary antecedents, we visit the CART systems in sub-mammalian vertebrates and seek the answer why the system is shaped the way it is. We enquire into the conservation of the CART system and appreciate its functional diversity across the phyla.

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REGULAR ARTICLEActivity of various CART peptides in changing locomotor activity in the rat

Abstract

Brain Res

Eur J Pharmacol

Brain Res

Trends Neurosci

Reg Peptides

Eur J Pharmacol

Brain Res

FEBS Lett

Int J Biochem Cell Biol

Brain Res

Brain Res

REGULAR ARTICLE
Activity of various CART peptides in changing locomotor activity in the rat