Nicotine administration effects on feeding and cocaine–amphetamine-regulated transcript (CART) expression in the hypothalamus
Introduction
Using a model of intermittent nicotine administration during the rat's normal activity period, previous studies have shown that nicotine results in decreased food intake and decreased meal size [3]. However, after nine days of continued nicotine administration a significant compensatory increase in meal number results in an increase in food intake to control levels, but body weight continues to be reduced [3]. Currently, the mechanism by which this model of nicotine administration affects feeding and body weight is unknown.
To address the mechanism of nicotine action on feeding and body weight the expression of several genes was quantitated in the hypothalamus during the course of nicotine administration. Genes that nicotine could utilize to regulate feeding and body weight are agouti related protein (AGRP) with known orexigenic action [51] and cocaine–amphetamine-regulated transcript (CART), with known anorexigenic effects [33]. CART is found in several hypothalamic areas including the ARC, DMN, PVN and PE [11], [30] and AGRP is known to be expressed in the ARC [45]. AGRP is a natural antagonist of the melanocortin receptors 3 and 4 (MC3R and MC4R), which modulates the effects of the anorexigenic peptide alpha-melanocyte stimulating hormone (α-MSH) [16], [21], [28], [29], [39], [45]. α-MSH is derived from the precursor molecule pro-opiomelanocortin (POMC). A previous study in our lab showed that administration of nicotine attenuated the ability of the MC3R/4 receptor agonist, MTII, to suppress food intake [2] suggesting an involvement of AGRP, MC3R/4 receptors and the α-MSH pathway in modulating nicotine's effects on feeding. Corticotropin releasing hormone receptor-1 (CRH-R1) or often called corticotropin releasing factor receptor-1 (CRF-R1) mRNA has been localized to the PVN [42], [52]. CRH-R1 has been shown to modulate feeding behavior in experiments using pharmacological agents and knockout mice [37], [43]. Another gene, NPY has been shown to be modulated during nicotine administration at the transcript and protein level [18], [34]. Infusion of neuropeptide Y (NPY) in the PVN has been shown to increase meal size and number [10]. NPY stimulation of feeding can occur through the Y5 receptor [19], [22]. However, the Y1 receptor is also thought to be involved in NPY's stimulation of ingestion [15], [25], [27]. NPY is produced in the ARC and there is also NPY mRNA present in both the DMN [5] and PVN [12], [26], [32], [36].
To begin to understand the mechanisms by which nicotine induced changes in feeding behavior and body weight we studied the transcript levels of multiple genes in the ARC, DMN and PVN plus PE. Often a correlation between transcript and neuropeptide levels can be detected in the hypothalamic nuclei suggesting that measurement of transcript levels reveals changes in gene expression [17], [23], [35], [44], [53] although this correlation is not always observed [14]. Gene expression was analyzed at time points where critical changes in meal patterns had occurred. One critical time point was at two days, where continued nicotine administration suppressed food intake by decreasing meal size and the second time point was at nine days where increased meal number led to normalized daily food intake [3].
Section snippets
Animals and nicotine injections
The present study was reviewed and approved by the Baylor College of Dentistry Institutional Animal Care and Use Committee and complied with the principles of laboratory animal care.
Sprague–Dawley out-bred male (250 g) rats (Harlan Industries, Houston, TX) were housed individually in a constant room temperature at 23 °C with standard food pellets (Harland Industries, Rodent diet 7002) and water available ad libitum. All animals were maintained on a 12:12 light/dark cycle (lights out at 0800 h).
Nicotine effects on food intake and body weight
Consistent with previous results [3] food intake was significantly suppressed on the first and second day of nicotine treatment, but food intake attained control levels (i.e., saline) on the ninth day of nicotine administration (Fig. 1).
Body weight was significantly attenuated on the first and second day of nicotine treatment. After the first day of nicotine injection the nicotine group was on average 3.5 ± 0.9 g, lighter than the saline injected group (P < 0.01). After the second day of nicotine
Discussion
Nicotine injections utilizing 4 mg/kg/day nicotine tartrate, given in four equal doses during the rat's normal activity period (i.e., dark phase) model smoking behavior, in that nicotine is administered intermittently. Nicotine administered using this model decreased food intake by decreasing meal size and also reduced body weight [3]. Concomitant with this nicotine induced decrease in food intake and meal size was an increase in hypothalamic CART mRNA levels, specifically in the PVN and/or PE.
Conclusions
Our results reveal that an increase in CART transcript in the PVN and/or PE occurs after two days of continued nicotine administration and that this increase correlates with reduced food intake, meal size and body weight supporting the anorectic role of this molecule. Nine days after continued nicotine injection food intake normalizes by a compensatory increase in meal size and a decrease in the DMN CART levels is observed. Together the data are consistent with CART functioning, in part, to
Acknowledgements
We would like to thank Connie Tillberg, Priscilla Gillaspie and Gerald Hill for their expertise and assistance on this work. This work was supported by the Tobacco Settlement Proceeds (TEF 2000-22).
References (53)
- et al.
Prog Brain Res
(1992) - et al.
Am J Physiol Regul Integr Comp Physiol
(2001) - et al.
Life Sci
(2003) - et al.
Pharmacol Biochem Behav
(2003) - et al.
- et al.
Physiol Behav
(2002) - et al.
Physiol Behav
(1997) - et al.
Am J Physiol
(1995) - et al.
Physiol Behav
(1986) - et al.
Clin Pharmacol Ther
(1984)
Neuroendocrinology
J Chem Neuroanat
Am J Physiol Regul Integr Comp Physiol
J Clin Invest.
Diabetes
J Comp Neurol
Nature
Am J Physiol Endocrinol Metab
Am J Physiol Regul Integr Comp Physiol
J Biol Chem
J Neuroendocrinol
Am J Physiol Endocrinol Metab
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