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Interactive report
Posterodorsal amygdala lesions reduce feeding stimulated by
18-OH-DPAT
a,b ,
*
c a a d dD.V. Coscina
, P.J. Currie , C. Bishop , G.C. Parker , B.L. Rollins , B.M. King
a
Department of Psychology, Wayne State University, 71 W. Warren Ave., Detroit, MI 48202, USA
b
Department of Psychiatry and Behavioral Neurosciences, Wayne State University, Detroit, MI 48201, USA
c
Department of Psychology, Barnard College, New York, NY 10027, USA
d
Department of Psychology, University of New Orleans, New Orleans, LA 70148, USA
Accepted 13 September 2000
Abstract
Injections of the serotonin (5-HT)1A agonist, 8-hydroxy-2(di-n-propylamino)tetralin, (8-OH-DPAT), either systemically or into the midbrain raphe nuclei, elicit food intake in otherwise satiated rats. Lesions of the paraventricular nucleus of the hypothalamus are well known for producing long-term overeating, but past research has excluded this site as a potential locus for short-term 8-OH-DPAT feeding effects. More recent work shows that small lesions of the posterodorsal amygdala (PDA) elicit overeating in their own right. Since this and related regions of the amygdala receive 5-HT innervations from the dorsal raphe nucleus (DRN), we determined if PDA lesions might alter feeding after injecting 8-OH-DPAT into this midbrain region. Adult female rats received either bilateral electrolytic lesions of the PDA or sham lesions. After recording weight gains for over 1 month, all rats were implanted with DRN cannulae, then randomly tested every 3–4 days for 1 h intake of standard lab chow after 0, 0.4, 0.8 or 1.6 nmol injections of 8-OH-DPAT. Additional 90 min measures of intake were also made after 0 vs. 250mg (760 nmol) 8-OH-DPAT s.c. At the two highest DRN doses tested, lesioned rats showed 50% less intake compared to shams. A similar profile emerged after the single s.c. dose. These results suggest that the PDA may be an important locus at which reduced release of endogenous 5-HT stimulates feeding. Alternatively, the PDA may represent part of a larger brain circuit whose integrity is necessary for eliciting intake in response to a variety of feeding stimuli. 2000 Elsevier Science B.V. All rights reserved.
Theme: Neural basis of behavior
Topic: Ingestive behavior
Keywords: Serotonin; Overeating; Dorsal raphe; Intracerebral injection; Subcutaneous; Brain mapping
5-HT agonist, 8-hydroxy-2(di-n-propylamino)tetralin
(8-1. Introduction 1A
OH-DPAT), or (2) blocking brain 5-HT receptors follow-ing systemic [11,13,41], intraventricular [5] or intra-cere-A variety of research has suggested that impairing
bral [8] injections of 5-HT antagonists. neurotransmission in the brain’s serotonin
(5-hydroxy-Attempts to determine where 8-OH-DPAT’s feeding tryptamine or 5-HT) system can lead to overeating [2].
effects are localized in the brain have implicated dopamine Two experimental techniques that have convincingly
dem-and opiate systems in portions of the caudate-putamen onstrated this in rats using acute perturbations are by: (1)
[14,17] and the nucleus accumbens [14,15]. Since the suppressing endogenous 5-HT release through systemic
hypothalamus is well known for its involvement in control-[4,10,12,18] or intra-raphe [6,7,9,14–17] injections of the
ling feeding behaviors, and enhancing 5-HT neurotrans-mission in several of its nuclei can suppress feeding [32], it
1
Published on the World Wide Web on 10 October 2000.
might be expected that the increased food intake stimulated
*Corresponding author. Tel.: 11-313-577-2810; fax: 1
1-313-577-by 8-OH-DPAT is due to a subnormal release of
hypo-7636.
E-mail address: [email protected] (D.V. Coscina). thalamic 5-HT [12,24]. In particular, it might be expected
that impeding 5-HT release in the paraventricular nucleus 3 weeks. They were then shipped to Wayne State Univer-(PVN) — a primary site at which lesions induce overeat- sity for the next phase of investigation.
ing [19–21,29] and where 5-HT infusions impair feeding
induced by food deprivation or infusions of norepinephrine 2.3. DRN implants [43] — would also enhance food intake. Contrary to this
prediction, feeding produced by intra-raphe injections of Upon arrival, rats were housed in a colony with a 12:12 8-OH-DPAT are not reversed by infusing 5-HT directly h light / dark cycle (lights on 0500 h) and controlled into the PVN [16] and PVN infusions of the 5-HT temperature (22128C) plus ad lib access to lab chow antagonist, metergoline, do not induce overeating [5]. (Rodent Diet 5001; LabDiet, Brentwood, MO) and water. Recent work has shown that small lesions localized to After 2 weeks of adaptation and body weight measure-the posterodorsal region of measure-the amygdala (PDA) produce ments, all rats were anesthetized with sodium pentobarbital reliable overeating and weight gain [28,39]. However, this (50 mg / kg i.p.), placed in a Kopf small animal stereotaxic newer literature has not yet characterized which neuro- instrument, and implanted in the DRN with 26 gauge transmitter system(s) may underlie these effects. Since the stainless steel guide cannulae (Plastics One, Roanoke, VA) PDA and related regions of the amygdala receive 5-HT using methods previously described [6]. With the incisor innervations from the midbrain’s dorsal raphe nucleus bar set 3.5 mm below interaural line (to achieve a level (DRN) [1], it is possible that aspects of this PDA lesion skull between lamda and bregma), a single cannula for effect are mediated by damaging local 5-HT neurocir- each animal was positioned at a 208 angle relative to the cuitry. If that is the case, we predicted that infusing following vertical coordinates: 1.2 mm anterior to interaur-8-OH-DPAT into the DRN would elicit less feeding in al zero, 1.6 mm lateral to midsaggital suture, 7.5 mm PDA-lesioned rats compared to controls. The results below the skull. Each implant was secured with acrylic reported here confirm that possibility. dental cement that attached to the skull and three stainless steel screws which penetrated it. Guide cannulae were fitted with 33 gauge stainless steel inner stylets (Plastics One) to maintain patency.
2. Materials and methods
2.4. Feeding tests 2.1. Animals
During 7 days of recovery, all rats were handled, Sixteen adult female Long-Evans hooded rats (Harlan weighed and acclimated to mock DRN injections. Then, all Sprague–Dawley, Indianapolis, IN) were used. During all were tested for 60 min intake of fresh lab chow at mid-phases of study, animals were housed individually in light cycle following 0 (0.15 M saline vehicle; VEH), 0.4, stainless steel cages with mesh bottoms and had free 0.8 and 1.6 nmol 8-OH-DPAT hydrobromide (Research access to standard lab chow pellets and water. Biochemicals, Natick, MA). Each rat received all four doses once on a semi-randomized schedule across animals, with 3–4 days between sequential injections. All doses
2.2. PDA lesions were delivered in a volume of 0.4 ml through a 33 gauge
microinjector attached to a 5ml Hamilton syringe. The tip Rats were acclimated to food (Harlan Teklad rat diet of the microinjector extended 4 mm beyond the tip of the LM-485) and housing conditions at the University of New indwelling guide cannula. Injections were infused over 1 Orleans before receiving bilateral electrolytic lesions of the min, then injectors left in place for 1 additional min. All PDA (Lesion: n58) or sham lesions (Control: n58) as feeding tests were conducted in animals’ home cages. previously described [39]. Briefly, all rats were anes- Following the DRN injection series, all remaining rats thetized with sodium pentobarbital (50 mg / kg i.p.), placed were tested for 90 min lab chow intake at mid-light cycle in a Kopf small animal stereotaxic instrument, and the 0.2 after VEH and 250 mg (760 nmol) 8-OH-DPAT injected mm uninsulated tips of otherwise insulated no. 0 insect s.c. with 3–4 days intervening between injections. pins positioned at the following coordinates (upper incisor
bar level with interaural line): 1.7 mm posterior to bregma, 2.5. Histology and data analyses 4.5 mm lateral to midsaggital suture, 8.4 mm below skull
3. Results injections, cannulae became blocked for 2 Control and 2 Lesion rats. Therefore, intake data described below reflect 3.1. Post-lesioning weight changes ns ranging from 5 to 7 for Control and 6–8 for Lesion groups. The absolute body weights of rats remaining in At the time of PDA lesion surgery, Control rats weighed these two groups did not differ significantly for the 298.667.0 g (mean6S.E.M.) while Lesion rats weighed remainder of these investigations.
somewhat less (275.0613.4 g) but not significantly so
(t1451.675, NS). By 10 days after surgery, Control rats 2.2. Feeding tests weighed approximately the same (300.366.0 g) while
Lesion rats weighed 327.6615.8 g. A t-test on weight Fig. 1 summarizes the results of 60 min feeding tests for changes over this time revealed that the average gain of both groups after DRN injections of 8-OH-DPAT. Inspec-Lesion rats was 52.564.5 g, which was highly significant tion of this figure shows that neither saline nor the lowest (t14510.378, P,0.0001) compared to the 1.662.6 g (0.4 nmol) dose elicited substantial feeding. The two gained by Controls. By 20 days after surgery (just before higher doses reliably enhanced intake but did so differen-rats were shipped to Wayne State), group body weights tially between groups. A 2-way ANOVA (2 Groups34 were essentially the same as they were at day 10 (i.e., Doses) showed significant effects of Group (F1,855.405, Control5307.366.4 g, Lesion5327.3614.7 g). P,0.05), Dose (F3,24551.522, P,0.0001) and a Group3 As anticipated, rats lost weight during shipping. By the Dose Interaction (F3,2458.501, P50.0005). These main time of surgery for DRN implants, Control rats had effects demonstrated that Lesion rats overall ate less than regained weight to levels that were comparable to those Controls, and that 8-OH-DPAT overall reliably enhanced seen before shipping (30765.6 g). Lesion rats’ weights feeding. However, the Group3Dose Interaction further (311613.8 g) now equaled that of Controls on an absolute qualified these main effects. T-tests revealed that Lesion basis, but still exceeded them based on pre-surgical rats ate approximately 50% less than Controls only at the weights (135.664.4 g gain for Lesion;18.463.3 g gain two highest doses (0.8 nmol: t1253.504, P,0.005; 1.6 for Control; t1455.3119, P,0.005). Immediately after nmol: t1153.227, P,0.01) — those that significantly surgery, 1 Control rat died. During the course of DRN enhanced intake in Controls (see Fig. 1).
Fig. 1. Sixty minute food intake of PDA Lesion vs. Control rats after 0, Fig. 2. Ninety minute food intake of PDA Lesion vs. Control rats after 0 0.4, 0.8 and 1.6 nmol 8-OH-DPAT infused into the dorsal raphe. Reliable and 250mg (760 nmol) 8-OH-DPAT s.c. Reliable feeding was induced by feeding in Controls only occurred at the two highest doses. Lesion rats the drug in Controls. Lesion rats showed approximately a 50% blunted showed reliable blunting of those responses (i.e., about 50% of Control response, but this did not reach statistical significance due to the small
Fig. 2 summarizes the results of the s.c. saline vs. 250 Control levels, which is in agreement with the results of mg (760 nmol) 8-OH-DPAT test in the remaining 4 the DRN injection study run previously.
Control and 5 Lesion rats deemed healthy enough to
participate. Due to the small numbers tested, a 2-way 2.3. Histology relative to DRN 8-OH-DPAT feeding ANOVA (2 Groups32 Doses) showed only a main effect effects
of Dose (F1,757.118, P,0.05) with no significant effect of
Group or Group3Dose Interaction. However, inspection of Fig. 3 depicts the maximal extent of lesion damage for Fig. 2 shows that Lesion rats again ate about 50% of the 7 individual rats tested on the highest (1.6 nmol) dose
of 8-OH-DPAT in the DRN. Shown to the right of each OH-DPAT / feeding linkage derived from the dose–re-coronal plate is the 60 min intake response for each sponse data obtained from DRN injections. The lowest animal. The two rats that showed essentially no feeding (0 8-OH-DPAT dose was ineffective in enhancing feeding or 0.3 g) had very small, discrete, bilateral injury to the compared to control infusions. However, at the two higher PDA. The three rats that ate 1.0 g as well as one that ate doses, the enhanced feeding seen in Controls was sup-1.1 g also had fairly small bilateral damage in the PDA but pressed on average by 50% in Lesion rats. The suppression which also compromised adjacent areas. The remaining rat of feeding following systemic 8-OH-DPAT was of similar that ate the most (1.3 g) sustained the greatest asymmetri- magnitude but failed to reach statistical significance. This cal damage, with injury to only the most posterior extent of was almost certainly due to the small numbers of animals the PDA in one hemisphere. Most of the damaged tissue in that remained testable at this stage of the experiment for this animal was asymmetrically localized to the CA3 and two reasons. First, the body weights of rats remaining in CA2 regions of Ammon’s horn. the Lesion vs. Control groups did not differ at the time of systemic injections. Therefore, there is no possibility that the results obtained reflect differential dosing of rats in these two groups. Second, since this work was completed,
4. Discussion we have confirmed that rats bearing lesions similar to the
PDA ones described here do, indeed, show blunted feeding The results of this experiment provide potentially novel in response to a range of systemic 8-OH-DPAT doses [37]. insights into the brain circuitry responsible for 8-OH- The importance of selective PDA damage to the blunted DPAT-induced feeding. It has been known for some time 8-OH-DPAT feeding response was reinforced further by that intracerebral infusions of this prototypic 5-HT1A qualitatively comparing the magnitudes of amounts eaten agonist are capable of stimulating food intake in otherwise by individual rats at the highest DRN dose relative to the satiated rats [6,7,9,14–17]. Since 8-OH-DPAT suppresses loci of their lesions. In two animals where damage was the release of endogenous 5-HT [24], this feeding effect bilateral and restricted to the PDA, 8-OH-DPAT - induced has been interpreted to result from acute suppression of feeding was essentially non-existent. In several others 5-HT neurotransmission [11,12]. What has remained uncer- where damage was less localized and less bilaterally tain is exactly which brain region(s) mediate the capacity symmetrical, sub-normal feeding was observed. Finally, in of such 5-HT1A agonism to stimulate food intake. one rat with asymmetrical lesions beyond the posterior A long-standing literature on brain feeding controls has extent of the PDA, 8-OH-DPAT feeding was maximal pointed to the medial hypothalamus as a critical site within within the Lesion group. While it has been reported that which 5-HT and other neurochemical agents exert their asymmetric amygdala damage may be as effective as feeding effects (e.g. [2,31,44]). While it is abundantly clear bilateral injury in producing short-term weight gain, le-that enhancing hypothalamic 5-HT neurotransmission can sions to adjacent regions of that structure correlate nega-suppress feeding [8,16,30,32,43], studies specifically de- tively with weight gain [28]. More recent work has signed to impede this function have proven ineffective in confirmed the importance of selectively damaging the PDA enhancing feeding [5,16]. This is of some concern for two in order to obtain maximal overeating and weight gain important reasons: (1) impaired 5-HT functioning has been effects [39]. Based on the data presented here, the ana-thought of as one causal biological mechanism underlying tomical specificity of such lesion-induced feeding appears hunger in human eating disorders [27,30,42], and (2) equally relevant to its capacity to block 8-OH-DPAT-pharmacological treatments for these disorders have been induced feeding.
largely targeted to enhancing insufficient 5-HT neuro-transmission [22,26].
Previous work from the first author’s laboratory has
shown that the capacity of 8-OH-DPAT to induce short- 5. Implications
term feeding is not due to its actions in the PVN, either
alone [16] or when interacting with local noradrenergic This study represents the first evidence that highly feeding systems [7,9]. Other work has indicated that opioid circumscribed portions of the amygdala may participate in and dopaminergic mechanisms mediate such feeding in the feeding stimulated in otherwise satiated animals fol-portions of the caudate / putamen and nucleus accumbens lowing 8-OH-DPAT treatment. Additional studies are [14,15]. Since portions of the amygdala interact with these underway to clarify this implication. At this early stage of structures [3,23,25,33–36,40,45] and 5-HT subsystems investigation, we can only conclude that (a) the PDA axis also innervate this limbic region [1], we performed the represents a potentially important nodal point in brain present experiments to determine if hyperphagia-inducing neurocircuitry that specifically mediates 5-HT1A feeding, lesions in the PDA area might alter 8-OH-DPAT–induced and / or (b) this brain region is part of a more complex
feeding. Clearly, they do. feeding circuit traversed by other as yet unknown
[18] P.J. Fletcher, M.H. Zack, D.V. Coscina, The influence of taste and
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