Paraventricular nucleus anandamide signaling alters eating and substrate oxidation.

In the central nervous system, the endocannabinoid anandamide [N-arachidonoylethanolamine (AEA)] is believed to increase food intake through on-demand activation of hypothalamic circuits. The present study examined the effects of hypothalamic paraventricular nucleus (PVN) injections of AEA (25-400 pmol) on food intake and energy substrate oxidation [respiratory quotient (RQ)]. PVN administration of AEA increased eating behavior and RQ, indicating enhanced carbohydrate oxidation. Further, PVN administration of the cannabinoid type 1 receptor inverse agonist AM251 (5-10 µg) attenuated both the eating and the RQ responses elicited by AEA (100 pmol). AM251 administered alone did not alter food intake or RQ. Overall, these findings are consistent with a role for PVN cannabinoid type 1 receptors in the regulation of eating and energy homeostasis.

Ghrelin is an orexigenic peptide and elicits anxiety-like behaviors following administration into discrete regions of the hypothalamus.

Previous evidence indicates that peripherally administered ghrelin significantly increases corticotropin releasing hormone (CRH) mRNA and serum corticosterone. In addition, intraventricular administration of ghrelin has been reported to elicit anxiety-like behaviors suggesting that the peptide plays a role in mediating neuroendocrine and behavioral responses to stress. In the present study, we characterized the orexigenic, metabolic, and anxiogenic actions of ghrelin following microinjection into the arcuate nucleus (ARN), paraventricular nucleus (PVN), perifornical hypothalamus (PFH), and ventromedial nucleus (VMN). To assess ghrelin's role in anxiogenic behavior, rats were injected with vehicle or 50-800pmol of ghrelin and then placed in an elevated plus maze (EPM) for 10min. Each test was performed as a single trial per animal. In separate behavioral testing we measured the induction of stereotypic behaviors. Doses of 200pmol or higher administered into the ARN and PVN elicited anxiety-like behaviors, including an increased avoidance of the open arms of the EPM. However, in the PFH and VMN, higher doses of ghrelin (400-800pmol) were required to induce anxiety. Ghrelin doses as low as 50pmol stimulated eating and altered energy substrate oxidation (respiratory quotient; RQ) when injected into the ARN and PVN. Injections into the PFH and VMN elicited more modest effects on eating and RQ at doses of 400pmol or greater. Our findings indicate that regions of the hypothalamus appear to be differentially sensitive and responsive to the feeding-stimulant, metabolic, and anxiogenic actions of ghrelin and that the ARN and PVN, in particular, exert a primary role in mediating these effects.

The cannabinoid receptor CB1 inverse agonist AM251 potentiates the anxiogenic activity of urocortin I in the basolateral amygdala.

The basolateral amygdala is reported to play an important role in the neural bases of emotional processing. Previous studies have shown that injections of urocortin I (UcnI) into the basolateral amygdala (BLA) elicit anxiety-like behaviors in animal models. The present study examined the anxiogenic effects of UcnI administered directly into the BLA of male Sprague-Dawley rats. UcnI was administered at doses of 0.1-10.0 pmol and rats were then placed in an elevated plus maze for 10 min. UcnI reliably decreased the percent time spent in the open arms of the elevated plus maze (EPM) as well as open arm entries. This effect was observed across all doses tested, indicating the induction of anxiety-like behavior. In separate groups of rats, the CB(1) inverse agonist AM251 was administered systemically (0.03-3.0 mg/kg IP) or directly into the BLA (0.25-25.0 pmol) and EPM performance assessed. Both routes of AM251 administration produced a reduction in open arm entries and in time spent in the open arms. Moreover, when rats were pretreated with AM251 either systemically or directly into the BLA, the anxiogenic effect of UcnI was potentiated. That is, co-administration of AM251 and UcnI produced a greater suppression of percent time spent in the open arms and open arm entries as compared to UcnI alone. Based on these findings, we propose that urocortin and endocannabinoid signaling are part of an integrated neural axis modulating anxiety states within the basolateral amygdala. This article is part of a Special Issue entitled 'Anxiety and Depression'.

Anorexigenic action of nitric oxide synthase inhibition in the raphe nuclei.

The present report examined the effects of midbrain raphe nuclei injections of nitric oxide synthase inhibitors NG-nitro-L-arginine methyl ester (L-NAME) and 7-nitroindazole (7-NI) on eating behavior. L-NAME (5-500 pmol) and 7-NI (2-200 pmol) were administered into either the dorsal or median raphe nucleus. Both nitric oxide synthase inhibitors decreased food intake in adult male Sprague-Dawley rats when injected into either raphe site. Further, eating elicited by dorsal and median raphe injections of the 5-HT1A agonist 8-OH-DPAT (0.8 nmol) was attenuated by L-NAME or 7-NI pretreatment. Our findings indicate that nitric oxide acts within the raphe to alter food intake. The inhibitory effects of L-NAME and 7-NI on eating elicited by 8-OH-DPAT further suggest that nitric oxide and 5-HT systems interact in the control of food intake.