Cocaine and amphetamine regulated transcript (CART) and the stress response

doi:10.1016/j.peptides.2006.03.032

Peptides

Volume 27, Issue 8, August 2006, Pages 1956-1969

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Abstract

CART is expressed abundantly in the hypothalamic paraventricular nucleus and locus coeruleus, major corticotropin releasing factor (CRF) and noradrenaline sources, respectively. There is a bidirectional relation between CART and hypothalamo–pituitary–adrenal axis activity. CART stimulates CRF, adrenocorticotropic hormone and glucocorticoid secretion, whereas CRF and glucocorticoids increase the transcriptional activity of the CART gene; adrenalectomy declines CART expression in the hypothalamus. Stress exposure modulates CART expression in hypothalamus and amygdala in rat brain in a region and sex specific manner. CART may be a mediator peptide in the interaction between stress, drug abuse, and feeding. The review discusses the established role of CART as it relates to the stress response.

Section snippets

The stress response

The adaptive capacity of an organism is directly proportional to its ability to survive despite changes in external environment. Claude Bernard (1813–1878) introduced the term “internal milieu” and anticipated that all physiologic systems evolved to buffer the internal environment from perturbations. Subsequently Walter Cannon (1871–1945) used the term “homeostasis” to describe the fine tuning of the internal environment by various physiologic arrangements to maintain equilibrium despite

Functional implications of CART localization in the HPA axis

Distribution of CART mRNA and peptides has been demonstrated by in situ hybridization, immunocytochemistry and RIA experiments [13], [25], [27], [29], [33], [41], [43], [46], [73], [81], [82], [83], [132], [133], [152]. These experiments show that CART has a wide distribution throughout the nervous system including sensory processing areas (i.e., olfactory bulb, sensory cortex, midbrain, and thalamic nuclei), central autonomic control areas (i.e., nucleus tractus solitarius, ambiguous,

The interaction between stress, drug addiction and feeding

In many cases, the peptides inhibiting food intake facilitate fear reactions, whereas the majority of the agents reducing anxiety responses stimulate appetite (e.g., [75]) Feeding is regulated through complex neuroanatomical networks and neurochemical mechanisms. In the 1940s, following the demonstration of hyperphagia and weight gain following lesions of the ventromedial nucleus of hypothalamus [12], [64], this region was proposed as the satiety center [137]. However later, this effect was

Sex differences

Sex differences transcend reproductive functions, are evident in the structural and functional organization of the brain, and are reflected in group differences in cognitive abilities, addiction and stress responsively [115]. Sex differences in the structure of the amygdala and the integration by the amygdala of the hormonal environment to modulate the stress response, have been documented [107], [130]. CART mRNA expression has been studied in mesolimbic brain areas of male and female

CART and glucocorticoids

CART peptides exhibit a diurnal variation and CART levels are correlated positively with glucocorticoid hormone levels in rat and monkey blood [143]. In accordance with the diurnal rhythm, in the rat, CART levels are low in the morning and high during evening hours while in the monkey, the opposite pattern is observed: higher CART levels in the morning and lower levels at night. Acute intraperitoneal CORT administration in the morning increases low CART peptide levels in rat blood whereas

CART acts centrally through CRF to increase ACTH and CORT

ICV CART administration induces c-Fos expression in the parvocellular subdivision of PVN [150], [152]. Many of these c-Fos positive neurons also co-express CRF-IR [150]. Vrang et al. reported that CART-IR fibers closely appose these c-Fos positive CRF neurons [150]. According to Wittmann et al. [160] most of the CART-IR axons terminating on CRF neurons in PVN also express phenylethanolamine-N-methyl-tranferase and originates in medulla. Some of these CART-IR fibers co-express alpha-melanocyte

CART peptides in fear and anxiety

In rats, CART (62–76) (CART 89–103, with the leader sequence) injection into the lateral cerebral ventricle causes a dose-dependent increase in anxiety-related behaviors in the elevated plus maze test in addition to inhibiting food intake. Water intake and spontaneous locomotor activity in the open field test were not affected, ruling out unspecific effects of the peptide [75]. In mice, ICV injection of CART (55–102) fragment also reduced the time spent in the open arms of the elevated

Effects of systemic stressors on CART peptide expression

The involvement of CART in response to various systemic stressors including hemodynamic stress, inflammation, and cold stress has been established. Hypotension induced by a nitric oxide generator, sodium nitroprusside, increased CART-IR in the hypothalamohypophysial portal blood [94]. CART may have a role in hemodynamic stress with a possible impact on anterior pituitary function. First-order parasympathetic sensory afferent neurons reside in the nodose ganglion and project to the nucleus of

CART: a neuropeptide acting systemically through the hypothalamic–pituitary portal circulation

CART is synthesized in neuroendocrine cells of parvocellular hypothalamus. Immunocytochemistry studies show co-localization with thyrotrophin releasing hormone, somatostatin and POMC in PVN, periventricular nucleus and ARC, respectively [13], [47], [149]. Also systemic fluorogold injection shows a similar co-localization in fluorogold-labeled neuroendocrine cells of hypothalamus [94]. Co-localization with CRF is reported in only one paper [99] while the majority of studies report none or minor

CART: localization and function in the autonomic nervous system

There are CART-IR neurons in the ARC which directly innervate the intermediolateral cell column of the thoracic spinal cord and are activated by leptin [46]. CART may be mediating leptin's actions on thermogenesis and energy expenditure. ICV CART increases CREB phosphorylation in the ventral parvocellular subdivision of PVN [120]. This region of PVN involves neurons projecting to sympathetic preganglionic neurons of the brain stem and spinal cord.

Rostral ventrolateral medulla contains

Acknowledgements

Supported by NIH Grant no. 3 R01 DA010732-05S1, RR00165, DA00418 and Ege University Research Fund grant 2000-TIP-003.

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Citation Excerpt :
It is noteworthy that there is a bidirectional relationship between hypothalamic pituitary adrenal HPA axis and CART activity [119]. CART stimulated glucocorticoid, CRF and adrenocorticotropic hormone (ACTH) secretion, whereas glucocorticoid and CRF increase the transcriptional activity of the CART gene [119]. For instance, intracerebroventricular injection of the CART peptides resulted in c-fos elevation in CRF containing neurons [79,218].
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ReviewCocaine and amphetamine regulated transcript (CART) and the stress response

Abstract

Section snippets

The stress response

Functional implications of CART localization in the HPA axis

The interaction between stress, drug addiction and feeding

Sex differences

CART and glucocorticoids

CART acts centrally through CRF to increase ACTH and CORT

CART peptides in fear and anxiety

Effects of systemic stressors on CART peptide expression

CART: a neuropeptide acting systemically through the hypothalamic–pituitary portal circulation

CART: localization and function in the autonomic nervous system

Acknowledgements

Brain Res Bull

Physiol Behav

Brain Res Bull

Brain Res

J Steroid Biochem Mol Biol

Brain Res

Eur J Pharmacol

Brain Res

J Steroid Biochem Mol Biol

Biol Psychiatry

J Chem Neuroanat

Front Neuroendocrinol

Kidney Int

Brain Res Mol Brain Res

Neuroscience

Neurosci Lett

Neurosci Lett

J Chem Neuroanat

Neuron

Pharmacol Biochem Behav

Neurosci Lett

Psychoneuroendocrinology

Neuroscience

Physiol Behav

Neurosci Res

Trends Endocrinol Metab

Eur J Pharmacol

Neuropeptides

J Pharmacol Toxicol Methods

Life Sci

FEBS Lett

Psychoneuroendocrinology

Brain Res

Neuropsychopharmacology

Brain Res

Regul Pept

Behav Brain Res

Trends Neurosci

Pharmacol Biochem Behav

Neurosci Lett

Cocaine- but not food-seeking behavior is reinstated by stress after extinction

Psychopharmacology (Berl)

The modulation of cocaine and amphetamine regulated transcript (CART) expression in the arcuate and paraventricular nuclei of the rat following restraint and forced swim stress

Effects of adrenalectomy on CART expression in the rat arcuate nucleus

Synapse

CART gene promoter transcription is regulated by a cyclic adenosine monophosphate response element

Obes Res

Hypothalamic–pituitary–adrenal axis activation by experimental periodontal disease in rats

J Periodont Res

Experimental hypothalamic hyperphagia in the albino rat

Yale J Biol Med

Effect of l-NAME, a specific nitric oxide synthase inhibitor, on corticotropin-releasing hormone-elicited ACTH and corticosterone secretion

J Physiol Pharmacol

Cocaine- and amphetamine-regulated transcript in catecholamine and noncatecholamine presympathetic vasomotor neurons of rat rostral ventrolateral medulla

J Comp Neurol

Distribution of cocaine- and amphetamine-regulated transcript peptide in the guinea pig intrinsic cardiac nervous system and colocalization with neuropeptides or transmitter synthetic enzymes

J Comp Neurol

Review
Cocaine and amphetamine regulated transcript (CART) and the stress response