QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Abstract Full Text (PDF) All Versions of this Article: jpet.105.091512v1 320/2/499    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Vicentic, A. Articles by Jones, D. C. Search for Related Content PubMed PubMed Citation Articles by Vicentic, A. Articles by Jones, D. C.

PERSPECTIVES IN PHARMACOLOGY

The CART (Cocaine- and Amphetamine-Regulated Transcript) System in Appetite and Drug Addiction

Division of Neuroscience, Yerkes National Primate Research Center, Emory University, Atlanta Georgia

Received June 2, 2006; accepted July 12, 2006.

	Abstract

Top Abstract Feeding and Obesity Drugs of Abuse Conclusions References

 
CART (cocaine- and amphetamine-regulated transcript) peptides are neuromodulators that are involved in feeding, drug reward, stress, cardiovascular function, and bone remodeling. CART peptides are abundant but discretely distributed in the brain, pituitary and adrenal glands, pancreas, and gut. High expression of CART in discrete hypothalamic nuclei associated with feeding has led to behavioral and pharmacological studies that strongly support an anorectic action of CART in feeding. Subsequent studies on humans and transgenic animals provide additional evidence that CART is important in the regulation of appetite as mutations in the CART gene are linked to eating disorders, including obesity and anorexia. The expression of CART in the mesolimbic dopamine circuit has lead to functional studies demonstrating CART's psychostimulant-like effects on locomotor activity and conditioned place preference in rats. These and other findings demonstrated that CART modulates mesolimbic dopamine systems and affects psychostimulant-induced reward and reinforcing behaviors. The link between CART and psychostimulants was substantiated by demonstrating alterations of the CART system in human cocaine addicts. CART seems to regulate the mesolimbic dopamine system, which serves as a common mechanism of action for both feeding and addiction. Indeed, recent studies that demonstrated CART projections from specific hypothalamic areas associated with feeding to specific mesolimbic areas linked to reward/motivation behaviors provide evidence that CART may be an important connection between food- and drug-related rewards. Given the enormous public health burden of both obesity and drug addiction, future studies exploring the pharmacotherapies targeting CART peptide represent an exciting and challenging research area.

	Feeding and Obesity

Top Abstract Feeding and Obesity Drugs of Abuse Conclusions References

 
Anatomical Evidence of CART's Role in Feeding
Douglass et al. (1995) observed that the distribution pattern of a novel mRNA up-regulated by cocaine and amphetamine was predominantly confined to hypothalamic neuroendocrine neurons and limbic circuits important in reward. Koylu et al. (1997) initially suggested that CART plays a role in food intake. Subsequent studies supported this contention as CART immunoreactivity was found in brain areas relevant to feeding (Elmquist et al., 1999), including the VMN, lateral hypothalamus (LH), arcuate nucleus (Arc), PVN, the nucleus of the solitary tract (NTS) (Koylu et al., 1998), and the nucleus accumbens (NAc) (Smith et al., 1999).

In addition to its distribution in feeding-associated brain regions, CART colocalizes with peptides that regulate feeding. For example, in the PVN, CART is coexpressed with thyrotropin-releasing hormone (Broberger, 1999) and corticotrophin-releasing factor (Sarkar et al., 2004), which suggests its involvement in the regulation of pituitary hormone secretion and/or energy metabolism. CART is coexpressed with melanin-concentrating hormone within the dorsomedial nucleus (DMN) and LH and pro-opiomelanocortin in the Arc (Vrang et al., 1999a). CART interacts with two most important mediators of feeding, NPY (Lambert et al., 1998) and leptin; however, it colocalizes only with c-fos in leptin-activated neurons (Elias et al., 1998) of the DMN and LH nuclei but not with NPY in the Arc nucleus (Vrang et al., 1999a).

Hypothalamic CART is also coexpressed with cannabinoid CB1 receptors that regulate feeding behavior and energy homeostasis (Cota et al., 2003). This interaction may be important for the regulation of appetite, because CB1 mice with a disrupted CB1 gene are lean and hypophagic and exhibit attenuated levels of CART mRNA. The findings that CART is colocalized with both orexigenic and anorexigenic peptides suggest that CART's role in appetite control and energy homeostasis is most probably modulatory.

View larger version (41K): [in this window] [in a new window]   Fig. 1. Anatomical distribution of CART mRNA and peptide in brain regions associated with feeding, appetite control, and the rewarding effects of psychostimulants. The four major regions/pathways are the mesolimbic DA system (VTA and NAc), several nuclei of the hypothalamus (PVN, DMN, VMN, and Arc), the pituitary, and the hindbrain (NTS). Regions in blue are associated with feeding and appetite regulation, and although the mesolimbic DA pathway (green) is strongly associated with the rewarding effects of psychostimulants, it also appears to play a role in appetite. Figure is adapted and modified from Hunter et al. (2004) with permission.

In addition to its widespread central localization, CART is abundantly present in peripheral areas associated with feeding. For example, CART is present in rat ileum (Couceyro et al., 1998) and numerous myenteric neurones throughout the gastrointestinal tract (Ekblad et al., 2003). CART is also expressed in several islet cell types during rat development and is up-regulated in -cells of diabetic rats, suggesting its importance for the regulation of islet hormonal secretion (Wierup et al., 2006). Finally, CART is selectively expressed in a population of sympathetic preganglionic neurons and adrenal glands, supporting its potential role as a signaling molecule in the sympatho-adrenal axis (Dun et al., 2000). The areas where CART may exert its anorectic properties are depicted in Fig. 1.

Functional Evidence of CART's Role in Feeding
Initial findings have demonstrated that i.c.v. administration of CART peptide profoundly inhibited feeding in rats, which was still apparent following NPY-stimulated feeding (Lambert et al., 1998). Administration of a CART antibody stimulated feeding, suggesting that endogenous CART peptide exerts an inhibitory tone on feeding (Kristensen et al., 1998; Lambert et al., 1998). Furthermore, administration of CART peptide activates an early gene, c-fos, in several hypothalamic and brain stem nuclei involved in feeding and metabolism, further implicating these regions in CART's anorectic action (Vrang et al., 1999b). Chronic central infusions of CART inhibited feeding and body weight gain in both lean and obese animals (Larsen et al., 2000). In addition, i.c.v administration of CART was accompanied by decreases in plasma insulin and leptin levels and increases in lipid oxidation, both of which limit fat storage (Rohner-Jeanrenaud et al., 2002).

In addition to inhibiting feeding, i.c.v. administration of CART peptide produced disruption of locomotor activity, raising questions about the specificity of its anorectic effects (Abbott et al., 2001; Aja et al., 2002). For instance, administration of CART peptide into either the third or fourth ventricle decreased intake of a liquid sucrose diet, altered licking patterns, and produced movement-associated tremors in rats. The rapidity by which CART caused these hypophagic and motor effects suggests a periventricular site of action, possibly via sites in the caudal hindbrain (Aja et al., 2001). Injections of CART peptide into the fourth ventricle also produced conditioned taste aversion (CTA) accompanied by reduced ingestion of both water and sweet liquid diets (Aja et al., 2002). This suggests that the ability of CART to reduce food intake when administered into the fourth ventricle may be secondary to the production of an aversive state. The mechanisms of CART-induced CTA are not clear; CART could mimic signals of gastrointestinal malaise, or alternatively, it may be a signal that is integral in developing CTA (Aja et al., 2002). Another mechanism for CART's anorectic effect may be via activation of the sympathoadrenal system as administration of CART peptide increases blood glucose levels (Vrang et al., 2000) and blood pressure (Matsumura et al., 2001). Elucidation of the exact mechanisms involved in CART's anorectic effects and resolving these issues will have a significant impact on the development of the CART system as a pharmacological target for appetite control and body weight.

Whereas numerous studies have reported attenuation of feeding following i.c.v. injections of CART, studies investigating the impact of intranuclear CART injections on feeding have been inconclusive. For example, direct administration of CART peptide into the NAc shell inhibits feeding without affecting motor behavior (Yang et al., 2005). In contrast, direct administration of high doses of CART into several discrete hypothalamic nuclei increased food intake (Abbott et al., 2001). This effect was not apparent until 1 to 2 h following administration and was accompanied by a significant decrease in feeding that occurred 4 to 24 h postinjection, perhaps suggesting either i) a compensatory decrease in feeding or ii) a delayed anorectic effect following the initial stimulation of feeding. Likewise, after gene transfer that elevated CART peptide levels in the Arc, animals consumed more food and their body weight increased (Kong et al., 2003). Moreover, this study showed a strong correlation between CART levels and thermogenesis; overexpression of the CART gene in the rat Arc combined with sustained exposure to cold increased CART mRNA levels and weight loss, suggesting an increase in energy expenditure and a potential role of CART in cold adaptation and cold-induced hyperphagia in rodents. These studies received support from a report showing that self-starved anorexic (anx/anx) mice display low body weight and marked behavioral alterations, including abnormal movement and hyperactivity (Johansen et al., 2000). These abnormalities were accompanied by down-regulated CART mRNA and peptide levels in the Arc, which could be interpreted as a protective mechanism of suppressing the anorexigenic state in catabolic animals (Johansen et al., 2000). In conclusion, CART-mediated regulation of appetite in the hypothalamus is a complex process, and it is plausible that the hypothalamic CART system is differentially regulated. Differential responses to i.c.v. versus intranuclear administration of CART suggests that CART may be activating two independent appetite circuits within the hypothalamus, one that is anorexigenic and the other that is orexigenic.

It is currently unknown whether peripheral CART plays a role in feeding. Fasting alters CART blood levels and abolishes its diurnal rhythm (Vicentic, 2006), suggesting that peripheral CART levels are sensitive to fuel availability. However, direct evidence of the involvement of peripheral CART in feeding behavior is still lacking; intraperitoneal administration of CART peptide did not affect feeding (Jensen et al., 1999), whereas mice lacking the CART gene displayed increased body weight and impaired glucose elimination and insulin secretion but no difference in food intake (Wierup et al., 2006).

Functional Responses of CART to Different Metabolic and Feeding States
The effects of centrally administered CART peptide on metabolism and associated behaviors are not limited to feeding. For example, i.c.v. administration of CART reduces gastric motility, emptying, and secretion (Asakawa et al., 2001). Research conducted in mutant animals also supports the role of CART as a mediator of metabolic regulation. Compared with wild type, CART knockout mice are prone to being obese and are susceptible to high-fat diet-induced obesity (Asnicar et al., 2001). Genetic deletion of CART impairs glucose-stimulated insulin secretion, suggesting that CART is needed for normal pancreatic function. Furthermore, CART peptide levels were shown to respond to changes in the metabolic state of normal, wild-type animals. Fasting-induced decreases in CART levels were also observed in several studies (Bertile et al., 2003; Yang et al., 2005; Vicentic, 2006). These studies suggest that CART-producing neurons are involved in energy homeostasis and that decreases in CART levels following acute dietary restriction may reflect a compensatory mechanism to reduce caloric expenditure. In contrast, a high-energy diet acutely up-regulated hypothalamic CART mRNA (Wortley et al., 2004), which was positively correlated with a reduction in lipid storage, promotion of fat utilization, and circulating leptin levels. Obese mice with hyperleptinemia also display up-regulation of CART expression (Tsuruta et al., 2002). These findings suggest that activation of CART neurons stimulates catabolic pathways that may minimize excessive accumulation of body fat under conditions of positive energy balance.

Contradictory results have been reported following chronic exposure to high-fat diets. CART mRNA and peptide expression was decreased in the Arc according to one report (Tian et al., 2004) and increased in another (Wortley et al., 2004). Moreover, hyperthyroidism, which is accompanied by increased food intake, decreases CART expression in the PVN (Lopez et al., 2002). Discrepancies in findings may be due to different paradigms used, different diets, and/or different periods of exposure to each diet. Indeed, neurons of the hypothalamic regulatory system controlling body weight differentially react to CART (Davidowa et al., 2005). This effect is dependent on the nutritional state of the animal (i.e., overweight, fed, or short-term fasting), suggesting that increased inhibitory responses to CART may reflect a general mechanism in adaptation of neuronal regulatory systems to the nutritional state.

Interaction of CART with Leptin
CART's anorectic action is strongly associated with that of peripheral adiposity signal and one of the most important regulators of food intake, leptin. CART mRNA levels are low in various hypothalamic nuclei of rodents with a disrupted leptin system (Murphy, 2005). Leptin replacement subsequently restores CART transcript levels in ob/ob mice that lack functional leptin receptors (Kristensen et al., 1998), and chronic leptin injections decrease body weight and adiposity and increase CART expression in mice (Ahima and Hileman, 2000). In a mouse model of anorexia (anx/anx) with disrupted leptin signaling and reduced food intake, CART levels are markedly decreased (Johansen et al., 2000). Furthermore, in a polygenic model of high-fat diet/energy-induced obesity accompanied by hyperleptinemia and diabetes, CART levels are attenuated in the Arc nucleus because of a defect in central leptin signaling and receptors (Tian et al., 2004). These results are not surprising because CART proximal promoter has a signal transducer and activator of transcription binding site that may be relevant for the effects of leptin on CART expression (Dominguez et al., 2002).

Interaction of CART with Glucocorticoids
It is well known that an excess of glucocorticoids is associated with obesity in humans and animals, especially with abdominal obesity (Dallman et al., 2004). A regulatory effect of glucocorticoids on CART expression was demonstrated in several central and peripheral tissues (Vicentic, 2006). CART induced c-fos expression in corticotrophine-releasing peptide neurons in the PVN may induce corticosterone secretion, thus potentially contributing to the inhibitory effects of CART on feeding (Larsen et al., 2000). The effect of glucocorticoids on CART may be direct because corticosterone increases CART levels, whereas metyrapone abolishes the evening peak in CART levels (Vicentic, 2006). It is also of interest that CART levels in blood exhibit a circadian rhythm that is similar to that of glucocorticoids and that it is altered by adrenalectomy (Vicentic, 2006). These results suggest that CART peptide plays a role in the function of hypothalamic-pituitary-adrenal axis activity, which may be relevant to its action in feeding.

CART and Human Obesity
The human CART gene is ideally positioned as a candidate for obesity, because it maps to chromosome 5q13-14, which is a susceptibility locus for obesity (Hager et al., 1998; Echwald et al., 1999). Polymorphisms of the CART gene, as well as differences in CART peptide levels, have been implicated in hereditary obesity, variations in energy expenditure, hip-to-waste size ratio, overindulgent forms of ingestive behavior, and anorexia nervosa (Challis et al., 2000; del Giudice et al., 2001; Yamada et al., 2002; Guerardel et al., 2005).

Some of the most convincing evidence supporting a role for CART in human obesity was described in a study on an obese Italian family (del Giudice et al., 2001). A missense mutation in CART gene resulted in a substitution of Leu with Phe and was linked to severe early-onset obesity over three generations. Interestingly, the same mutation in a CART cDNA construct was found to alter CART peptide levels in AtT20 cells, possibly through CART processing, sorting, and trafficking (Dominguez et al., 2004). The mutation and phenotype described indicate that the CART system plays an important role in the regulation of human body weight and possibly carry further health implications. Indeed, members of the same Italian family carrying the L34F mutation exhibited higher depression and anxiety scores compared with controls, thus suggesting that CART may link feeding and emotion (Yanik et al., 2006). Another finding linking CART to human obesity demonstrated six polymorphisms in the CART gene promoter region in thirty obese Japanese men (Yamada et al., 2002). In addition, a deletion mutation in exon 3 of the CART gene may be linked to augmented total cholesterol levels in a population of patients suffering from type 2 diabetes (Fu et al., 2002). Future studies examining CART gene polymorphisms would contribute to the understanding of obesity and may potentially lead to the use of CART peptide as a therapeutic target for appetite, affective disorders, and any related secondary complications, including cardiovascular disease. Table 1 summarizes possible mechanisms of CART's regulation of body weight.

	Drugs of Abuse

Top Abstract Feeding and Obesity Drugs of Abuse Conclusions References

 
Neuroanatomical Evidence for CART's Role in the Actions of Psychostimulants
A role for CART in modulating the reward and reinforcing effects of psychostimulants is suggested by a variety of studies. First, CART mRNA and peptide are distributed in the majority of reward-associated regions. Second, CART-containing neurons form synapses with neurons containing neurotransmitters associated with addiction, including dopamine (DA) and GABA. Finally, colocalization studies indicate that CART is expressed in neurons that synthesize a variety of neurochemicals implicated in the pharmacological actions of psychostimulants. Perhaps two of the most important regions pertinent to CART's role in drug-mediated reward, reinforcement, and behavior are part of the mesolimbic DA pathway, the ventral tegmental area (VTA), and NAc. In the VTA, nerve terminals containing CART mRNA and peptide are associated with both DA- and GABA-synthesizing neurons (Koylu et al., 1999; Dallvechia-Adams et al., 2002), whereas in the NAc, CART is preferentially localized to the shell region of the accumbens, which is highly sensitive to the effects of drugs of abuse (Hurd and Fagergren, 2000). Two other regions, the amygdala and cortex, play important roles in both the acute reinforcing effects and long-term consequences of drug use. CART mRNA is expressed in several regions of the extended amygdala (Hurd and Fagergren, 2000). Moreover, in a functional sense, binge cocaine administration up-regulates CART mRNA in the amygdalae, suggesting that the rewarding effects of cocaine may be mediated via this CART system (Fagergren and Hurd, 1999). Because of the role of amygdala in mediating environmental stressors, CART may associate otherwise neutral environmental stimuli with the presence of drugs. The cortex is activated by environmental cues that motivate drug intake and is strongly associated with the cognitive effects of long-term drug abuse. CART mRNA and peptide expression vary dramatically throughout the cortex (Couceyro et al., 1998), with significant differences noted in cortical CART mRNA expression between rats and humans. In humans, the highest levels of CART mRNA are found in discreet regions of the cortex (Couceyro et al., 1997) associated with the motivational process of drug use, which supports a potential role for CART in the reward. In contrast, rat expression of cortical CART mRNA is mostly limited to discreet areas in the primary somatosensory cortex (Couceyro et al., 1997), which is more indicative for a role of CART in sensory processing.

Neurons containing CART mRNA and/or peptide synapse with other neurons containing neurochemicals were involved in drug addiction (Vrang et al., 2000; Dallvechia-Adams et al., 2002), perhaps most importantly DA and GABA. Specifically, CART nerve terminals in the VTA contact both dopaminergic neurons, which project to the accumbens and GABAergic interneurons (Dallvechia-Adams et al., 2002). Thus, CART may modulate DA activity in the VTA through either i) the direct stimulation of dopaminergic neurons or ii) the indirect disinhibition of DA neurons via CART-mediated inhibition of GABA release. Conversely, in the NAc shell, dopaminergic terminals synapse with CART peptide-containing GABAergic medium spiny output neurons, suggesting that accumbal DA may modulate CART peptide activity (Koylu et al., 1999). Therefore, a functional relationship among CART peptide, DA, and GABA can be envisioned in the reinforcing effects of psychostimulants.

Colocalization studies also support a role for CART in the actions of psychostimulants. For instance, in the NAc, CART peptide colocalizes with dynorphin and GABA (Dallvechia-Adams et al., 2002), which have been linked to drugs of abuse (Fagergren and Hurd, 1999; Roberts, 2005). The majority of CART peptide-immunoreactive terminals identified in the NAc appear to be axon collaterals of striatal projection neurons that express GABA (Smith et al., 1999). Furthermore, CART colocalizes with GABA in axon terminals of the VTA (Dallvechia-Adams et al., 2002), suggesting that CART and GABA may act as cotransmitters in accumbal projection neurons involved in the modulation of the effects of psychostimulants. CART also colocalizes with tyrosine hydroxylase in axon terminals of VTA neurons (Koylu et al., 1999), indicating a probable modulatory relationship between CART and DA. Taken together, the anatomical evidence demonstrates that CART plays an important role in modulating the brain circuitry involved in psychostimulant addiction, including the acute reinforcing actions and the body's long-term response to psychostimulants.

Neuropharmacological Evidence of a Role for CART in Psychostimulant Addiction
The relationship between CART and other neurotransmitters linked to the actions of psychostimulants is complex. For instance, i) under certain conditions, CART mRNA and peptide levels are directly affected by cocaine and amphetamine, ii) CART peptide has an affect on (and is affected by) DA and GABA, and iii) the regulation of the CART gene involves CREB, which has been implicated in psychostimulant addiction (Table 1).

CART's involvement in the actions of psychostimulants was first noted in a study demonstrating that acute cocaine and amphetamine up-regulated CART mRNA in the rat brain (Douglass et al., 1995). This report has proven controversial as this finding has been difficult to replicate (Vrang et al., 2002; Marie-Claire et al., 2003; Hunter et al., 2005). It now appears that a binge-dosing regime, rather than acute administration of cocaine, reliably increases CART expression (Fagergren and Hurd, 1999; Hunter et al., 2005). However, there seems to be at least two physiological conditions in which CART mRNA levels are increased by acute cocaine. First, cocaine seems to affect the regulation of the CART gene under conditions of enhanced cAMP signaling (Jones and Kuhar, 2006). Second, CART mRNA and peptide levels are sensitive to stress as corticosterone increases accumbal CART mRNA, whereas pretreatment with metyrapone decreases CART peptide levels (Vicentic, 2006). Glucocorticoids also seem to be involved in the modulation of rewarding behaviors, including food and drug intake (Goeders, 2002). Interestingly, CART's diurnal rhythm correlates with daily variations in glucocorticoids levels (Vicentic, 2006); consequently, CART may influence the diurnal variation in cocaine sensitization and reward. Therefore, under certain conditions involving stress or increased cAMP, psychostimulants may alter CART mRNA and peptide levels.

The CART system modulates mesolimbic dopaminergic activity and attenuates the behavioral effects of cocaine and amphetamine (Jaworski et al., 2003; Kim et al., 2003), suggesting a complex relationship between CART, DA, and psychostimulants and the brain's reward/reinforcement pathways. Increasing evidence suggests that CART affects brain DA levels, and vice versa, DA seems to regulate CART peptide levels. For instance, CART peptide inhibits DA release in vitro (Brunetti et al., 2000). In contrast, central administration of CART increases DA turnover (Yang et al., 2005), whereas direct intra-VTA injections of CART moderately increase extracellular DA levels in the NAc (Kuhar et al., 2005). That being said, although central injections of CART increase the activity of the nigrostriatal and mesolimbic DA systems in the rat, this treatment does not alter dopaminergic activity in the prefrontal cortex (Shieh, 2003). This is important because humans and rodents have different patterns of cortical CART expression (Koylu et al., 1998). Consequently, potential differences in CART's function in the cortex, which could include effects related to psychostimulant abuse, may exist.

In addition to its effects on brain dopamine turnover, CART expression may be regulated via DA D3 receptors (Beaudry et al., 2004; Hunter et al., 2006). First, CART and DA receptor transcripts colocalize (Beaudry et al., 2004). Second, dopaminergic nerve terminals in the NAc synapse on CART-containing neurons (Koylu et al., 1999), hence providing the proximity required for neurotransmitter signaling. These studies suggest that DA plays a role in regulating CART gene expression possibly via the activation of CREB. Indeed, CART gene expression is regulated via cAMP signaling and pCREB in vivo as centrally administered forskolin activated cAMP, phosphorylated CREB, and increased CART mRNA and peptide levels (Jones and Kuhar, 2006). Moreover, cocaine potentiated forskolin-induced CART mRNA expression. In support, cocaine overdose victims have both increased pCREB and CART levels (Tang et al., 2003), suggesting an association between the drug, the transcription factor, and the neuropeptide. Thus, perhaps CART peptide levels are regulated by cocaine in a chronic abuser, whose basal cAMP signaling is enhanced because of constant cocaine use. Because CART peptide seems to oppose some of the effects of cocaine, the stimulatory effect of cocaine on CART gene expression suggests the existence of an endogenous feedback mechanism to attenuate the behavioral effects of cocaine. Therefore, the pharmacological evidence suggesting a role for CART peptide in the rewarding and reinforcing effects of psychostimulants is consistent with both anatomical and behavioral studies.

Behavioral Evidence Supporting a Role for CART in Psychostimulant Addiction
Central administration of CART peptide into the rat VTA mimics the stimulatory effects of psychostimulants by causing an increase in locomotor activity (LMA) and conditioned place preference (Kimmel et al., 2000). The CART-induced increase in activity was attenuated in a dose-dependent manner by the DA receptor antagonist haloperidol, supporting a dopaminergic-mediated mechanism. In contrast, injection of CART peptide into the accumbens had no effect on LMA; however, intra-accumbal CART administration attenuated LMA produced by systemically administered cocaine and amphetamine (Jaworski et al., 2003). Consistent with its effects on cocaine-induced LMA, CART peptide dose-dependently attenuated locomotion produced by intra-accumbal infusions of DA, thus indicating a direct modulation of mesolimbic DA (Jaworski et al., 2003). Because of CART peptide's dual role in the VTA (stimulatory) and NAc (attenuation of cocaine- and DA-induced behaviors), it is plausible that CART peptide modulates responses to reward and reinforcement. This hypothesis is supported by a recent study demonstrating that, after behavioral conditioning, exposure to cues associated with cocaine increased CART-immunoreactive neurons in the NAc (Mattson and Morrell, 2005), suggesting that, not only does cocaine itself affect CART levels, the conditioning and environmental cues associated with cocaine also increase CART peptide levels. This study suggests that the CART may mediate the cognitive effects of drug addiction and play an important role in long-term conditioning of drug-related cues.

CART knockout (KO) mice have been generated and used in studies examining the behavioral effects of psychostimulants. Unfortunately, the results have been contradictory. For instance, a decreased response to amphetamine and cocaine was observed in CART KO mice versus wild-type mice (Couceyro et al., 2005). Despite an increased ambulatory effect in response to high doses of amphetamine, the data suggest attenuation of psychostimulant-induced LMA in CART KO mice. In addition, unpublished studies from our laboratory demonstrated that CART KO mice are less sensitive to the reinforcing effects of cocaine because cocaine-induced LMA was blunted in CART KO mice. In contrast to these studies suggesting differences in drug-influenced behavior between wild-type and KO mice, a recent report (Steiner et al., 2006) indicated that there were no significant differences in cocaine-induced LMA or cocaine self-administration. The authors suggest that, although CART may serve a modulatory role in the effects of psychostimulants in intact animals, it is not essential if lacking throughout development. Reasons underlying the discrepancy in results are unclear; however, differences in both the strain of mouse and the way in which the KO mice were generated should be considered as possible explanations. Although the data and subsequent interpretations of the relationship between psychostimulants and the CART system may differ, it is apparent that CART modulates the reinforcing behavioral effects of psychostimulants.

The Role of CART Peptide in the Effects of Nonpsychostimulant Drugs of Abuse
CART also seems to be involved in modulating the actions of nonstimulant drugs of abuse. For instance, alcoholism in a Korean population is associated with a mutation in the CART gene (Jung et al., 2004). DA receptor-sensitive increases in CART mRNA and peptide in the rat NAc was noted following ethanol administration (Salinas et al., 2006). CART peptides also act on µ-opioid receptors (Rothman et al., 2003) and enhance the spinal analgesic actions of morphine (Damaj et al., 2004). Finally, a cannabinoid CB1 antagonist, rimonabant, inhibited drug-induced food intake in wild-type but not CART-deficient mice (Osei-Hyiaman et al., 2005).

	Conclusions

Top Abstract Feeding and Obesity Drugs of Abuse Conclusions References

 
Despite some ambiguous reports, the majority of studies support the hypothesis that CART is an important regulator of appetite and psychostimulant addiction. Anatomically, CART peptides and/or mRNA are found in several brain regions associated with both feeding and reward/reinforcement, and there is a strong anatomical association between CART and other systems associated with feeding and the rewarding properties of psychostimulants. CART has been linked to leptin and glucocorticoids, two important regulators of feeding, as well as DA and GABA, which are involved in the rewarding effect produced by psychostimulants. In addition, several different lines of pharmacological and behavioral evidence suggest that CART peptides modulate the mesocorticolimbic dopaminergic system. Because of CART's interactions with mesolimbic dopamine system, although speculative, the CART system may have implications for other neurological disorders involving dopaminergic transmission. Indeed, obesity and drug abuse is highly prevalent among patients suffering from mental disorders such as schizophrenia. There is a great potential for CART as a therapeutic target for i) the treatment of human eating disorders, including obesity and anorexia nervosa, and ii) the treatment of psychostimulant addiction (Hunter and Kuhar, 2003). Despite advances in understanding CART's role in the central nervous and peripheral systems, much work is yet to be done in the CART field. One of the major challenges in the field has been the absence of an identifiable CART receptor; however, recent advances (Vicentic et al., 2006) could greatly facilitate understanding of pharmacological and behavioral effects of CART. These studies demonstrated for the first time signaling mechanisms and specific binding of CART peptide in a cell line supporting the existence of a specific CART receptor that is G-protein-coupled and functions via Gi/o mechanisms. These novel findings open a possibility for the future cloning of a CART receptor and the development of drugs that would target CART as a potential treatment of eating and drug abuse-related disorders.

	Footnotes

 
This work was supported by National Institutes of Health Grants RR00165, DA00418, DA10732, HD37583, and DA15513.

A.V. and D.C.J. contributed equally to this work.

Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

doi:10.1124/jpet.105.091512.

ABBREVIATIONS: CART, cocaine- and amphetamine-regulated transcript; VMN, ventromedial hypothalamic nucleus; LH, lateral hypothalamus; Arc, arcuate nucleus; PVN, paraventricular nucleus; NTS, the nucleus of the solitary tract; CRF, corticotrophin-releasing factor; DMN, dorsomedial nucleus of the hypothalamus; NPY, neuropeptide Y; CTA, conditioned taste aversion; DA, dopamine; VTA, ventral tegmental area; NAc, nucleus accumbens; GABA, -aminobutyric acid; LMA, locomotor activity; CREB, cAMP-response element-binding protein; KO, knockout.

Address correspondence to: Dr. Aleksandra Vicentic, Yerkes National Primate Research Center of Emory University, 954 Gatewood Rd, N.E., Atlanta, GA 30329. E-mail: avicen2{at}emory.edu

	References

Top Abstract Feeding and Obesity Drugs of Abuse Conclusions References

 

Abbott CR, Rossi M, Wren AM, Murphy KG, Kennedy AR, Stanley SA, Zollner AN, Morgan DG, Morgan I, Ghatei MA, et al. (2001) Evidence of an orexigenic role for cocaine- and amphetamine-regulated transcript after administration into discrete hypothalamic nuclei. Endocrinology 142: 3457–3463.[Abstract/Free Full Text]

Ahima RS and Hileman SM (2000) Postnatal regulation of hypothalamic neuropeptide expression by leptin: implications for energy balance and body weight regulation. Regul Pept 92: 1–7.[CrossRef][Medline]

Aja S, Robinson BM, Mills KJ, Ladenheim EE, and Moran TH (2002) Fourth ventricular CART reduces food and water intake and produces a conditioned taste aversion in rats. Behav Neurosci 116: 918–921.[CrossRef][Medline]

Aja S, Schwartz GJ, Kuhar MJ, and Moran TH (2001) Intracerebroventricular CART peptide reduces rat ingestive behavior and alters licking microstructure. Am J Physiol 280: R1613–R1619.

Asakawa A, Inui A, Yuzuriha H, Nagata T, Kaga T, Ueno N, Fujino MA, and Kasuga M (2001) Cocaine-amphetamine-regulated transcript influences energy metabolism, anxiety and gastric emptying in mice. Horm Metab Res 33: 554–558.[CrossRef][Medline]

Asnicar MA, Smith DP, Yang DD, Heiman ML, Fox N, Chen YF, Hsiung HM, and Koster A (2001) Absence of cocaine- and amphetamine-regulated transcript results in obesity in mice fed a high caloric diet. Endocrinology 142: 4394–4400.[Abstract/Free Full Text]

Beaudry G, Zekki H, Rouillard C, and Levesque D (2004) Clozapine and dopamine D3 receptor antisense reduce cocaine- and amphetamine-regulated transcript expression in the rat nucleus accumbens shell. Synapse 51: 233–240.[CrossRef][Medline]

Bertile F, Oudart H, Criscuolo F, Maho YL, and Raclot T (2003) Hypothalamic gene expression in long-term fasted rats: relationship with body fat. Biochem Biophys Res Commun 303: 1106–1113.[CrossRef][Medline]

Broberger C (1999) Hypothalamic cocaine- and amphetamine-regulated transcript (CART) neurons: histochemical relationship to thyrotropin-releasing hormone, melanin-concentrating hormone, orexin/hypocretin and neuropeptide Y. Brain Res 848: 101–113.[CrossRef][Medline]

Broberger C, Holmberg K, Kuhar MJ, and Hokfelt T (1999) Cocaine- and amphetamine-regulated transcript in the rat vagus nerve: a putative mediator of cholecystokinin-induced satiety. Proc Natl Acad Sci USA 96: 13506–13511.[Abstract/Free Full Text]

Brunetti L, Orlando G, Michelotto B, Recinella L, and Vacca M (2000) Cocaine- and amphetamine-regulated transcript peptide-(55–102) and thyrotropin releasing hormone inhibit hypothalamic dopamine release. Eur J Pharmacol 409: 103–107.[CrossRef][Medline]

Challis BG, Yeo GS, Farooqi IS, Luan J, Aminian S, Halsall DJ, Keogh JM, Wareham NJ, and O'Rahilly S (2000) The CART gene and human obesity: mutational analysis and population genetics. Diabetes 49: 872–875.[Abstract]

Cota D, Marsicano G, Tschop M, Grubler Y, Flachskamm C, Schubert M, Auer D, Yassouridis A, Thone-Reineke C, Ortmann S, et al. (2003) The endogenous cannabinoid system affects energy balance via central orexigenic drive and peripheral lipogenesis. J Clin Investig 112: 423–431.[CrossRef][Medline]

Couceyro P, Paquet M, Koylu E, Kuhar MJ, and Smith Y (1998) Cocaine- and amphetamine-regulated transcript (CART) peptide immunoreactivity in myenteric plexus neurons of the rat ileum and co-localization with choline acetyltransferase. Synapse 30: 1–8.[CrossRef][Medline]

Couceyro PR, Evans C, McKinzie A, Mitchell D, Dube M, Hagshenas L, White FJ, Douglass J, Richards WG, and Bannon AW (2005) Cocaine- and amphetamine-regulated transcript (CART) peptides modulate the locomotor and motivational properties of psychostimulants. J Pharmacol Exp Ther 315: 1091–1100.[Abstract/Free Full Text]

Couceyro PR, Koylu EO, and Kuhar MJ (1997) Further studies on the anatomical distribution of CART by in situ hybridization. J Chem Neuroanat 12: 229–241.[CrossRef][Medline]

Dallman MF, la Fleur SE, Pecoraro NC, Gomez F, Houshyar H, and Akana SF (2004) Minireview: glucocorticoids—food intake, abdominal obesity, and wealthy nations in 2004. Endocrinology 145: 2633–2638.[Abstract/Free Full Text]

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.[CrossRef][Medline]

Damaj MI, Hunter RG, Martin BR, and Kuhar MJ (2004) Intrathecal CART (55–102) enhances the spinal analgesic actions of morphine in mice. Brain Res 1024: 146–149.[CrossRef][Medline]

Davidowa H, Li Y, and Plagemann A (2005) The main effect of cocaine- and amphetamine-regulated transcript (CART) peptide on hypothalamic neuronal activity depends on the nutritional state of rats. Neuro Endocrinol Lett 26: 29–34.[Medline]

del Giudice EM, Santoro N, Cirillo G, D'Urso L, Di Toro R, and Perrone L (2001) Mutational screening of the CART gene in obese children: identifying a mutation (Leu34Phe) associated with reduced resting energy expenditure and cosegregating with obesity phenotype in a large family. Diabetes 50: 2157–2160.[Abstract/Free Full Text]

Dominguez G, del Giudice EM, and Kuhar MJ (2004) CART peptide levels are altered by a mutation associated with obesity at codon 34. Mol Psychiatry 9: 1065–1066.[CrossRef][Medline]

Dominguez G, Lakatos A, and Kuhar MJ (2002) Characterization of the cocaine- and amphetamine-regulated transcript (CART) peptide gene promoter and its activation by a cyclic AMP-dependent signaling pathway in GH3 cells. J Neurochem 80: 885–893.[CrossRef][Medline]

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.[Abstract]

Dun SL, Chianca DA Jr, Dun NJ, Yang J, and Chang JK (2000) Differential expression of cocaine- and amphetamine-regulated transcript-immunoreactivity in the rat spinal preganglionic nuclei. Neurosci Lett 294: 143–146.[CrossRef][Medline]

Echwald SM, Sorensen TI, Andersen T, Hansen C, Tommerup N, and Pedersen O (1999) Sequence variants in the human cocaine and amphetamine-regulated transcript (CART) gene in subjects with early onset obesity. Obes Res 7: 532–536.[Medline]

Ekblad E, Kuhar M, Wierup N, and Sundler F (2003) Cocaine- and amphetamine-regulated transcript: distribution and function in rat gastrointestinal tract. Neurogastroenterol Motil 15: 545–557.[CrossRef][Medline]

Elias CF, Lee C, Kelly J, Aschkenasi C, Ahima RS, Couceyro PR, Kuhar MJ, Saper CB, and Elmquist JK (1998) Leptin activates hypothalamic CART neurons projecting to the spinal cord. Neuron 21: 1375–1385.[CrossRef][Medline]

Elmquist JK, Elias CF, and Saper CB (1999) From lesions to leptin: hypothalamic control of food intake and body weight. Neuron 22: 221–232.[CrossRef][Medline]

Fagergren P and Hurd YL (1999) Mesolimbic gender differences in peptide CART mRNA expression: effects of cocaine. Neuroreport 10: 3449–3452.[Medline]

Fu M, Cheng H, Chen L, Wu B, Cai M, Xie D, and Fu Z (2002) Association of the cocaine and amphetamine-regulated transcript gene with type 2 diabetes mellitus. Zhonghua Nei Ke Za Zhi 41: 805–808.[Medline]

Goeders NE (2002) The HPA axis and cocaine reinforcement. Psychoneuroendocrinology 27: 13–33.[CrossRef][Medline]

Guerardel A, Barat-Houari M, Vasseur F, Dina C, Vatin V, Clement K, Eberle D, Vasseur-Delannoy V, Bell CG, Galan P, et al. (2005) Analysis of sequence variability in the CART gene in relation to obesity in a Caucasian population. BMC Genet 6: 19.[CrossRef][Medline]

Hager J, Dina C, Francke S, Dubois S, Houari M, Vatin V, Vaillant E, Lorentz N, Basdevant A, Clement K, et al. (1998) A genome-wide scan for human obesity genes reveals a major susceptibility locus on chromosome 10. Nat Genet 20: 304–308.[CrossRef][Medline]

Hsun Lin H, Chiu HY, and Lai CC (2005) Potentiation of spinal N-methyl-D-aspartate-mediated nociceptive transmission by cocaine-regulated and amphetamine-regulated transcript peptide in rats. Neuroreport 16: 253–257.[CrossRef][Medline]

Hunter RG, Jones D, Vicentic A, Hue G, Rye D, and Kuhar MJ (2006) Regulation of CART mRNA in the rat nucleus accumbens via D3 dopamine receptors. Neuropharmacology.

Hunter RG and Kuhar MJ (2003) CART peptides as targets for CNS drug development. Curr Drug Target CNS Neurol Disord 2: 201–205.[CrossRef][Medline]

Hunter RG, Lim MM, Philpot KB, Young LJ, and Kuhar MJ (2005) Species differences in brain distribution of CART mRNA and CART peptide between prairie and meadow voles. Brain Res 1048: 12–23.[CrossRef][Medline]

Hunter RG, Philpot K, Vicentic A, Dominguez G, Hubert GW, and Kuhar MJ (2004) CART in feeding and obesity. Trends Endocrinol Metab 15: 454–459.[CrossRef][Medline]

Hurd YL and Fagergren P (2000) Human cocaine- and amphetamine-regulated transcript (CART) mRNA is highly expressed in limbic- and sensory-related brain regions. J Comp Neurol 425: 583–598.[CrossRef][Medline]

Jaworski JN, Kozel MA, Philpot KB, and Kuhar MJ (2003) Intra-accumbal injection of CART (cocaine-amphetamine-regulated transcript) peptide reduces cocaine-induced locomotor activity. J Pharmacol Exp Ther 307: 1038–1044.[Abstract/Free Full Text]

Jensen PB, Kristensen P, Clausen JT, Judge ME, Hastrup S, Thim L, Wulff BS, Foged C, Jensen J, Holst JJ, et al. (1999) The hypothalamic satiety peptide CART is expressed in anorectic and non-anorectic pancreatic islet tumors and in the normal islet of Langerhans. FEBS Lett 447: 139–143.[CrossRef][Medline]

Johansen JE, Broberger C, Lavebratt C, Johansson C, Kuhar MJ, Hokfelt T, and Schalling M (2000) Hypothalamic CART and serum leptin levels are reduced in the anorectic (anx/anx) mouse. Brain Res Mol Brain Res 84: 97–105.[Medline]

Jones DC and Kuhar MJ (2006) Cocaine-amphetamine-regulated transcript expression in the rat nucleus accumbens is regulated by adenylyl cyclase and the cyclic-adenosine 5'-monophosphate/protein kinase A second messenger system. J Pharmacol Exp Ther 317: 454–461.[Abstract/Free Full Text]

Jung SK, Hong MS, Suh GJ, Jin SY, Lee HJ, Kim BS, Lim YJ, Kim MK, Park HK, Chung JH, et al. (2004) Association between polymorphism in intron 1 of cocaine- and amphetamine-regulated transcript gene with alcoholism, but not with bipolar disorder and schizophrenia in Korean population. Neurosci Lett 365: 54–57.[CrossRef][Medline]

Kim JH, Creekmore E, and Vezina P (2003) Microinjection of CART peptide 55–102 into the nucleus accumbens blocks amphetamine-induced locomotion. Neuropeptides 37: 369–373.[CrossRef][Medline]

Kimmel HL, Gong W, Vechia SD, Hunter RG, and Kuhar MJ (2000) Intra-ventral tegmental area injection of rat cocaine and amphetamine-regulated transcript peptide 55–102 induces locomotor activity and promotes conditioned place preference. J Pharmacol Exp Ther 294: 784–792.[Abstract/Free Full Text]

Kong WM, Stanley S, Gardiner J, Abbott C, Murphy K, Seth A, Connoley I, Ghatei M, Stephens D, and Bloom S (2003) A role for arcuate cocaine and amphetamine-regulated transcript in hyperphagia, thermogenesis, and cold adaptation. FASEB J 17: 1688–1690.[Abstract/Free Full Text]

Koylu EO, Couceyro PR, Lambert PD, and Kuhar MJ (1998) Cocaine- and amphetamine-regulated transcript peptide immunohistochemical localization in the rat brain. J Comp Neurol 391: 115–132.[CrossRef][Medline]

Koylu EO, Couceyro PR, Lambert PD, Ling NC, DeSouza EB, and Kuhar MJ (1997) Immunohistochemical localization of novel CART peptides in rat hypothalamus, pituitary and adrenal gland. J Neuroendocrinol 9: 823–833.[CrossRef][Medline]

Koylu EO, Smith Y, Couceyro PR, and Kuhar MJ (1999) CART peptides colocalize with tyrosine hydroxylase neurons in rat locus coeruleus. Synapse 31: 309–311.[CrossRef][Medline]

Kristensen P, Judge ME, Thim L, Ribel U, Christjansen KN, Wulff BS, Clausen JT, Jensen PB, Madsen OD, Vrang N, et al. (1998) Hypothalamic CART is a new anorectic peptide regulated by leptin. Nature (Lond) 393: 72–76.[CrossRef][Medline]

Kuhar MJ, Adams LD, Hunter RG, Vechia SD, and Smith Y (2000) CART peptides. Regul Pept 89: 1–6.[CrossRef][Medline]

Kuhar MJ, Jaworski JN, Hubert GW, Philpot KB, and Dominguez G (2005) Cocaine- and amphetamine-regulated transcript peptides play a role in drug abuse and are potential therapeutic targets. AAPS J 7: E259–E265.[CrossRef][Medline]

Lambert PD, Couceyro PR, McGirr KM, Dall Vechia SE, Smith Y, and Kuhar MJ (1998) CART peptides in the central control of feeding and interactions with neuropeptide Y. Synapse 29: 293–298.[CrossRef][Medline]

Larsen PJ, Vrang N, Petersen PC, and Kristensen P (2000) Chronic intracerebroventricular administration of recombinant CART(42–89) peptide inhibits and causes weight loss in lean and obese Zucker (fa/fa) rats. Obes Res 8: 590–596.[Medline]

Lopez M, Seoane L, Tovar S, Senaris RM, and Dieguez C (2002) Thyroid status regulates CART but not AgRP mRNA levels in the rat hypothalamus. Neuroreport 13: 1775–1779.[CrossRef][Medline]

Marie-Claire C, Laurendeau I, Canestrelli C, Courtin C, Vidaud M, Roques B, and Noble F (2003) Fos but not Cart (cocaine and amphetamine regulated transcript) is overexpressed by several drugs of abuse: a comparative study using real-time quantitative polymerase chain reaction in rat brain. Neurosci Lett 345: 77–80.[CrossRef][Medline]

Matsumura K, Tsuchihashi T, and Abe I (2001) Central human cocaine- and amphetamine-regulated transcript peptide 55–102 increases arterial pressure in conscious rabbits. Hypertension 38: 1096–1100.[Abstract/Free Full Text]

Mattson BJ and Morrell JI (2005) Preference for cocaine- versus pup-associated cues differentially activates neurons expressing either Fos or cocaine- and amphetamine-regulated transcript in lactating, maternal rodents. Neuroscience 135: 315–328.[CrossRef][Medline]

Murphy KG (2005) Dissecting the role of cocaine- and amphetamine-regulated transcript (CART) in the control of appetite. Brief Funct Genomic Proteomic 4: 95–111.[Abstract/Free Full Text]

Osei-Hyiaman D, Depetrillo M, Harvey-White J, Bannon AW, Cravatt BF, Kuhar MJ, Mackie K, Palkovits M, and Kunos G (2005) Cocaine- and amphetamine-related transcript is involved in the orexigenic effect of endogenous anandamide. Neuroendocrinology 81: 273–282.[CrossRef][Medline]

Roberts DC (2005) Preclinical evidence for GABA_B agonists as a pharmacotherapy for cocaine addiction. Physiol Behav 86: 18–20.[CrossRef][Medline]

Rohner-Jeanrenaud F, Craft LS, Bridwell J, Suter TM, Tinsley FC, Smiley DL, Burkhart DR, Statnick MA, Heiman ML, Ravussin E, et al. (2002) Chronic central infusion of cocaine- and amphetamine-regulated transcript (CART 55–102): effects on body weight homeostasis in lean and high-fat-fed obese rats. Int J Obes Relat Metab Disord 26: 143–149.[CrossRef][Medline]

Rothman RB, Vu N, Wang X, and Xu H (2003) Endogenous CART peptide regulates mu opioid and serotonin 5-HT(2A) receptors. Peptides 24: 413–417.[CrossRef][Medline]

Salinas A, Wilde JD, and Maldve RE (2006) Ethanol enhancement of cocaine- and amphetamine-regulated transcript mRNA and peptide expression in the nucleus accumbens. J Neurochem, 97: 408–415.[CrossRef][Medline]

Sarkar S, Wittmann G, Fekete C, and Lechan RM (2004) Central administration of cocaine- and amphetamine-regulated transcript increases phosphorylation of cAMP response element binding protein in corticotropin-releasing hormone-producing neurons but not in prothyrotropin-releasing hormone-producing neurons in the hypothalamic paraventricular nucleus. Brain Res 999: 181–192.[CrossRef][Medline]

Shieh K (2003) Effects of the cocaine- and amphetamine-regulated transcript peptide on the turnover of central dopaminergic neurons. Neuropharmacology 44: 940–948.[CrossRef][Medline]

Smith Y, Kieval J, Couceyro PR, and Kuhar MJ (1999) CART peptide-immunoreactive neurones in the nucleus accumbens in monkeys: ultrastructural analysis, colocalization studies, and synaptic interactions with dopaminergic afferents. J Comp Neurol 407: 491–511.[CrossRef][Medline]

Spiess J and Vale W (1980) Multiple forms of somatostatin-like activity in rat hypothalamus. Biochemistry 19: 2861–2866.[CrossRef][Medline]

Steiner RC, Hsiung HM, and Picciotto MR (2006) Cocaine self-administration and locomotor sensitization are not altered in CART knockout mice. Behav Brain Res 171: 56–62.[CrossRef][Medline]

Tang WX, Fasulo WH, Mash DC, and Hemby SE (2003) Molecular profiling of midbrain dopamine regions in cocaine overdose victims. J Neurochem 85: 911–924.[Medline]

Tian DR, Li XD, Shi YS, Wan Y, Wang XM, Chang JK, Yang J, and Han JS (2004) Changes of hypothalamic alpha-MSH and CART peptide expression in diet-induced obese rats. Peptides 25: 2147–2153.[CrossRef][Medline]

Tsuruta Y, Yoshimatsu H, Hidaka S, Kondou S, Okamoto K, and Sakata T (2002) Hyperleptinemia in A(y)/a mice upregulates arcuate cocaine- and amphetamine-regulated transcript expression. Am J Physiol 282: E967–E973.

Vicentic A (2006) CART peptide diurnal variations in blood and brain. Peptides, in press.

Vicentic A, Lakatos A, and Jones D (2006) The CART receptors: Background and recent advances. Peptides, in press.

Vrang N, Larsen PJ, Clausen JT, and Kristensen P (1999a) Neurochemical characterization of hypothalamic cocaine-amphetamine-regulated transcript neurons. J Neurosci 19: RC5.[Abstract/Free Full Text]

Vrang N, Larsen PJ, and Kristensen P (2002) Cocaine-amphetamine regulated transcript (CART) expression is not regulated by amphetamine. Neuroreport 13: 1215–1218.[CrossRef][Medline]

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.[Abstract/Free Full Text]

Vrang N, Tang-Christensen M, Larsen PJ, and Kristensen P (1999b) Recombinant CART peptide induces c-Fos expression in central areas involved in control of feeding behaviour. Brain Res 818: 499–509.[CrossRef][Medline]

Wierup N, Bjorkqvist M, Kuhar MJ, Mulder H, and Sundler F (2006) CART regulates islet hormone secretion and is expressed in the beta-cells of type 2 diabetic rats. Diabetes 55: 305–311.[Abstract/Free Full Text]

Wortley KE, Chang GQ, Davydova Z, Fried SK, and Leibowitz SF (2004) Cocaine- and amphetamine-regulated transcript in the arcuate nucleus stimulates lipid metabolism to control body fat accrual on a high-fat diet. Regul Pept 117: 89–99.[CrossRef][Medline]

Yamada K, Yuan X, Otabe S, Koyanagi A, Koyama W, and Makita Z (2002) Sequencing of the putative promoter region of the cocaine- and amphetamine-regulated-transcript gene and identification of polymorphic sites associated with obesity. Int J Obes Relat Metab Disord 26: 132–136.[CrossRef][Medline]

Yang SC, Shieh KR, and Li HY (2005) Cocaine- and amphetamine-regulated transcript in the nucleus accumbens participates in the regulation of feeding behavior in rats. Neuroscience 133: 841–851.[CrossRef][Medline]

Yanik T, Dominguez G, Kuhar MJ, Del Giudice EM, and Loh YP (2006) The Leu34Phe ProCART mutation leads to cocaine- and amphetamine-regulated transcript (CART) deficiency: a possible cause for obesity in humans. Endocrinology 147: 39–43.[Abstract/Free Full Text]

This Article Abstract Full Text (PDF) All Versions of this Article: jpet.105.091512v1 320/2/499    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services