Stimulation of lateral septum CRF2 receptors promotes anorexia and stress-like behaviors: functional homology to CRF1 receptors in basolateral amygdala

Abstract

The corticotropin-releasing factor (CRF) system is the primary central mediator of stress-like states, coordinating behavioral, endocrine, and autonomic responses to stress. Although induction of anorexia is a well documented effect of CRF receptor agonist administration, the central sites and behavioral processes underlying this phenomenon are poorly understood. The present studies addressed this question by examining the neuroanatomical, behavioral, and pharmacological mechanisms mediating decreases in feeding produced by the CRF1/CRF2 receptor agonist urocortin. Separate groups of food-restricted male Sprague Dawley rats were given infusions of urocortin (0, 50, 125, 250 ng/0.5 microl) into the lateral septum (LS) and immediately afterward were rated on a wide array of behaviors (locomotion, rearing, grooming, stereotypies) including a microstructural analysis of ingestive behavior. Intra-LS urocortin infusion dose-dependently reduced feeding and drinking while concomitantly increasing grooming, stereotypies, and ethological plus traditional measures of anxiety-like responses in the elevated plus-maze. Urocortin infusion into neighboring sites (lateral ventricle, medial caudate) had no effects. Coinfusion into the LS of the mixed CRF1/CRF2 receptor antagonist D-Phe-CRF(12-41) (0, 100, 1000 ng/0.5 microl) or the novel selective CRF2 receptor antagonist Astressin2B (0, 500, 1000 ng/0.5 microl) blocked urocortin-induced effects, but the CRF1-selective antagonist NBI27914 (0, 500, 1000 ng/0.5 microl) had no effect, although it completely reversed the behavioral sequelae of CRF when infused into the basolateral amygdala. These results indicate that one of the modes through which the CRF system promotes anorexia is the recruitment of stress-like states after stimulation of CRF2 receptors within the LS.

Figure 1.

Microstructural analysis of eating (top row) and drinking (bottom row) after UCN infusion into LS. Shown are effects on total food/water intake over 45 min (A, B), latency to eat/drink (C, D), total number of eating/drinking bouts in the entire test session (E, F), total time spent eating/drinking during the entire session (G, H), and average duration of an eating/drinking bout during the middle portion (minutes 16–30 after infusion) of the test session (I, J). Values represent mean ± SEM for each treatment. *p < 0.05, compared with vehicle. VEH, Vehicle. UCN doses are in nanograms per 0.5 μl/side.

Figure 2.

Effects of UCN infusion into LS on noningestive behaviors over a 45 min test session: A, locomotion; B, rearing; C, total number of grooming bouts; D, total time spent grooming; E, average duration of a grooming bout; F, total number of stereotypy bouts. Values represent mean ± SEM for each treatment. ⁺p < 0.08, *p < 0.05, **p < 0.01, compared with vehicle. VEH, Vehicle. UCN doses are in nanograms per 0.5 μl/side.

Figure 3.

Effects of intra-LS UCN infusion in the elevated plus-maze during a 5 min test session: A, percentage of time spent in open arms; B, percentage of entries into open arms; C, risk assessment indexed by the total number of stretch-attends; D, total entries into open and closed arms. Values represent mean ± SEM for each treatment. *p < 0.05, compared with vehicle. VEH, Vehicle. UCN doses are 125 ng/0.5 μl/side.

Figure 4.

Behavioral sequelae of UCN infusion into sites adjacent to the LS during a 45 min test session. Shown are effects on total time spent eating (A), total time spent drinking (B), total time spent grooming (C), and total number of stereotypy bouts (D). Values represent mean ± SEM for each treatment. *p < 0.05, **p < 0.01, compared with vehicle. VEH, Vehicle. UCN doses are in nanograms per 0.5 μl/side.

Figure 5.

Effects over a 45 min test session of intra-LS CRF receptor antagonists on UCN-induced suppression of food intake (A) and increases in total time spent grooming (B). Values represent mean ± SEM for each treatment. **p < 0.01, compared with VEH/VEH; ⁺p < 0.05, compared with VEH/UCN. VEH, Vehicle; ANTAG, antagonist. UCN doses are 250 ng/0.5 μl/side.

Figure 6.

Effects of intra-BLA CRF₁ receptor antagonist infusion on CRF-induced suppression of food intake (A) and increases in total time spent grooming (B) over a 45 min test session. Values represent mean ± SEM for each treatment. *p < 0.05, **p < 0.01, compared with VEH/VEH; ⁺p < 0.05, ⁺⁺p < 0.01, compared with VEH/CRF. VEH, Vehicle. Doses are as follows: CRF, 200 ng/0.5 μl/side; NBI, 1000 ng/0.5 μl/side.

Figure 7.

Location of injector tip placements within the LS (A, B), the MC (C), and the BLA (D).