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

Abstract

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...

Sex-specific differences in the dynamics of cocaine- and amphetamine-regulated transcript and nesfatin-1 expressions in the midbrain of depressed suicide victims vs. controls

“…The notion that CART may play a role in the pathogenesis of major depression is further corroborated by the fact that it can modulate signal transduction pathways of neurotrophic factors such as brain-derived neurotrophic factor, and directly control the expression of genes coding for key enzymes in the biosynthesis of serotonin, factors all assumed to be involved in depression (for reviews see: Ma et al, 2007;Pae et al, 2007;Rogge et al, 2008). More specifically, CART markedly enhances hypothalamic and cortical serotonin release in the rat (Vaarmann and Kask, 2001), but the neuronal circuitry underpinning this phenomenon is not fully understood.…”

Cocaine- and Amphetamine-Regulated Transcript Peptide Plays a Role in the Manifestation of Depression: Social Isolation and Olfactory Bulbectomy Models Reveal Unifying Principles

“…Pae et al (2007) commented on the therapeutic usefulness of CART in the treatment of depression. In recent years, Ma et al (2007) observed that increased the extracellular 5-HT, and speculated that the effect may be responsible for antidepressant-like action of CART. Furthermore, CART influences the expression of a range of neurotransmitters such as g-aminobutyric acid, 5-HT, noradrenaline (NA), and dopamine that directly regulate affective disorders including depression Figure 3 Photomicrographs showing cocaine-and amphetamine-regulated transcript peptide immunoreactive (CART-ir) cells (arrows) and fibers (arrowheads) in the hypothalamic paraventricular nucleus (PVN) of shamoperated (sham, (a)), olfactory bulbectomy (OBX, (b)), group housed (paired, (c)), and social isolated for 6 weeks (socially isolated, (d)) rats.…”

“…Scale bar ¼ 200 mm. (Vaarmann and Kask, 2001;Choi et al, 2003;Yang et al, 2004;Hunter et al, 2006;Jaworski et al, 2007;Ma et al, 2007), and it is possible that antidepressant action of CART may be mediated via some of these neurotransmitters.…”

“…Preliminary results suggest that, CART directly controls the expression of several important neurotransmitters, which are instrumental in processing neuropsychological behaviors (Vaarmann and Kask, 2001;Yang et al, 2004;Jaworski et al, 2007). Ma et al (2007) have suggested that an increase in 5-hydroxytryptamine (5-HT) may contribute to the antidepressant-like effect of CART. Moreover, therapeutic efficacy of CART has been suggested in the treatment of depression and neurodegenerative disorders (Lakatos et al, 2005;Wu et al, 2006;Pae et al, 2007;Orsetti et al, 2008).…”

Unique responses of midbrain CART neurons in macaques to ovarian steroids

“…It has been reported in rats that CART may have an antidepressant effect through increases in extracellular serotonin (Ma et al 2007). Specifically, a CART infusion in the dorsal raphe nucleus leads to a significant increase of serotonin efflux in the nucleus accumbens, a major target of dorsal raphe serotonergic projections.…”