Interaction of cholecystokinin and cannabinoid agonist CP55,940 in the nucleus of solitary tract (NTS) and area postrema (AP) in regulation of food intake
Gaddam, Dhanunjaya Reddy
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The nucleus of the solitary tract (NTS), and area postrema (AP) located in the dorso-medial brain stem are major regions of the hindbrain important in the short term regulation of food intake. Cholecystokinin (CCK) is a well-studied satiety signal that plays important roles in the regulation of short-term food intake.Cannabinoids have been known for ages to increase the consumption of highly palatable foods. Studies from our lab have earlier have shown that intracerebroventricular (ICV) administration of cannabinoid agonist, CP55,940 into the 4th ventricle increased the consumption of sweetened condensed milk. Neurons in the NTS and AP are shown to express c-Fos protein following intraperitoneal (IP) injection of CCK. Our hypothesis is that cannabinoids decrease the activation of c-Fos in the neurons of NTS and AP by CCK and this effect involves catecholaminergic neurons. Cannulated rats were given CP55,940 (0.5[mu]g/5[mu]l/animal) via the 4th ventricle and were administered CCK (5[mu]g/kgB.Wt, IP), 15 minutes after CP55,940 injection. Our results from this study showed that CP55,940 suppresses the c-Fos expression activated by CCK. The c-Fos counts in the CP/CCK treated rats, (NTS 69 ± 19, AP 30 ± 6; mean±SEM) were significantly lower than the counts in the saline/CCK treated group (NTS 371 ± 94; AP 150 ± 47; mean±SEM) (P<0.05). Results using the cannabinoid 1 receptor (CB1 receptor) antagonist SR141716, CP55,940 and CCK showed that the inhibitory effect of CP55,940 on c-Fos activation of CCK was effectively blocked using the SR141716. The c-Fos counts in the SR/CP/CCK treated rats were significantly higher than those from rats treated with saline/CP/CCK (104.3±40.12 vs 24.29±6.08). Double labeling studies using c-Fos and TH antibodies showed c-Fos expression activated by CCK in TH positive cells but there was no statistically significant difference in the number of TH positive neurons showing the c-Fos immunoreactivity between the different treatment groups. The number of TH positive neurons showing c-Fos immunoreactivity in CP/CCK treated rats, (NTS 39 ± 6; mean±SEM) were not significantly different than the counts in the saline/CCK treated rats (NTS 42 ± 9; mean±SEM) (P>0.05). Similarly the counts of TH positive neurons showing c-Fos immunoreactivity in the NTS of SR/CP/CCK treated rats (13±1) were not significantly different from the rats treated with saline/CP/CCK (7±1), SR/saline/CCK (13±1), saline/saline CCK (15±4). These studies indicate that CCK induced c-Fos like immunoreactivity in the NTS and the activation of NTS neurons by CCK is inhibited by CP55,940. Our study also showed that cannabinoid antagonist SR141716 decreased the inhibitory effect of CP55,940 on neuronal activation of CCK suggesting that this effect is mediated through the CB1 receptor. Doublelabling immunohistochemistry shows that this interaction of CCK and CP55,940 seems not to involve the catecholaminergic neurons in NTS.