Area postrema and the anorectic actions of dexfenfluramine and amylin

The present study examined whether the area postrema and adjacent nucleus of the solitary tract (AP/NTS) is necessary for the expression of anorexia to two classes of anorectic agent. The first agent is the serotonergic agonist, dexfenfluramine (DFEN) and the second is the pancreatic peptide, amylin. Rats were prepared with either aspiration lesions of the AP/NTS or a sham operation. Rats with such lesions (APX) displayed normal anorexia following administration of DFEN, but the anorectic effect of amylin was completely eliminated. The magnitude of a conditioned flavor aversion to DEN was similar in APX and sham operated controls but, unlike controls, APX rats did not reduce total intake in the two-bottle preference test. Finally, the induction of Fos-like immunoreactivity (Fos-ir) following either DFEN or amylin was examined in both APX and sham operated groups. Both agents induced Fos-ir in the AP and/or NTS of sham operated rats, and this region was entirely absent in the APX rats. DFEN-induced Fos-ir was reduced greatly in the PVN of APX rats, but appeared normal in several other regions surveyed, including the central nucleus of the amygdala and the dorsal striatum. In contrast, amylin-induced Fos-ir was reduced in many rostral brain regions of APX rats. These data indicate that neither the anorexia nor the flavor aversion that are produced by DFEN are dependent upon the AP, and in particular that Fos-ir induced by DFEN in the LPBE is not due to afferents from the AP/NTS. In contrast, the anorectic effect of amylin seems to be due principally to its direct action at the AP/NTS.     

Effects of vagotomy on cholecystokinin- and dexfenfluramine-induced fos-like immunoreactivity in the rat brain

This study compared the effects of bilateral subdiaphragmatic vagotomy on the Fos-like immunoreactivity (FLI), a marker of neuronal activation, in rat brain induced by two anorectic agents, cholecystokinin (CCK) and the serotonin agonist, dexfenfluramine (DFEN). In the nonvagotomized rats, both CCK (5 μg/kg, IP) and DFEN (2 mg/kg, IP) Induced FU in the nucleus of the solitary tract (MST), the external subdivision of the lateral parabrachial nuclei (LPBE), the lateral subdivision of the central amygdeloid nucleus (CeL), and the bed nucleus of the stria terminallis (BST). However, subregional distribution of the FLI induced by the two agents was different in most of these regions. Additionally, the area postrema and the medial subdivision of the hypothalamic paraventricular nucleus were preferentially activated by CCK but not DFEN, while the caudate-putemen was activated by DFEM but not CCK. Bilateral subdiaphragmatic vagotomy completely abolished CCK-induced FLI in all the brain regions but did not attenuate DFEN-Induced FLI in any of these regions, including the NST. The results of the present study suggest that DFEN-activation of the NST-LPBE-CeL/BST neuraxis is not mediated by the vague nerve. On the other hand, and consistent with a variety of other data, activation of various parts of the brain by peripherally administered CCK depends on a vagal pathway. These data are discussed in relation to a previously proposed interaction between CCK and serotonin in mediating satiety.     

Medial versus lateral parabrachial nucleus lesions in the rat: effects on cholecystokinin- and D-fenfluramine-induced anorexia

The two major components of the pontine parabrachial nucleus (PBN), the medial (gustatory) and lateral (visceral) subdivisions, have been implicated in a variety of ingestive behaviors. The present study examined the influence of bilateral ibotenic acid lesions of the medial or lateral PBN on the anorectic effects of two systemically administered drug treatments. In Experiment 1, 24-h food-deprived rats where injected with sulfated cholecystokinin (26-33) (CCK; 0, 4.0, or 8.0 microg/kg) and then given 60 min access to food. In Experiment 2, the influence of D-fenfluramine (DFEN; 0, 0.5, 1.0, or 2.0 mg/kg) on deprivation-induced feeding was examined in the same rats using the same behavioral procedure as in Experiment 1. Lesions of the lateral PBN abolished CCK-, but not DFEN-induced anorexia whereas lesions of the medial PBN augmented DFEN-, but had no influence on CCK-induced anorexia. The results suggest that the satiating effects of CCK and DFEN are mediated through different mechanisms involving, respectively, visceral and orosensory processing.     

Medial versus lateral parabrachial nucleus lesions in the rat: effects on cholecystokinin- and -fenfluramine-induced anorexia

The two major components of the pontine parabrachial nucleus (PBN), the medial (gustatory) and lateral (visceral) subdivisions, have been implicated in a variety of ingestive behaviors. The present study examined the influence of bilateral ibotenic acid lesions of the medial or lateral PBN on the anorectic effects of two systemically administered drug treatments. In Experiment 1, 24-h food-deprived rats where injected with sulfated cholecystokinin_26-33 (CCK; 0, 4.0, or 8.0 μg/kg) and then given 60 min access to food. In Experiment 2, the influence of -fenfluramine (DFEN; 0, 0.5, 1.0, or 2.0 mg/kg) on deprivation-induced feeding was examined in the same rats using the same behavioral procedure as in Experiment 1. Lesions of the lateral PBN abolished CCK-, but not DFEN-induced anorexia whereas lesions of the medial PBN augmented DFEN-, but had no influence on CCK-induced anorexia. The results suggest that the satiating effects of CCK and DFEN are mediated through different mechanisms involving, respectively, visceral and orosensory processing.     

Medial parabrachial nucleus neurons modulate d-fenfluramine-induced anorexia through 5HT2C receptors

We previously reported that lesions of the medial parabrachial nucleus (PBN) enhanced d-fenfluramine (DFEN)-induced anorexia; a finding that suggests these lesions may potentiate the release of serotonin (5HT) or increase the postsynaptic action of 5HT. In the present study, we used SB 206553 (a 5HT2B/2C receptor antagonist) or m-CPP (a 5HT2C/1B receptor agonist) in a standard behavioral procedure (deprivation-induced feeding) to further explore the role of the medial PBN in drug-induced anorexia. In Experiment 1, DFEN (0 or 1.0 mg/kg) was given alone or in combination with SB 206553 (2.0 or 5.0 mg/kg). In Experiment 2, we investigated the food-suppressive effects of m-CPP (0.5, 1.0 or 2.0 mg/kg). The results of Experiment 1 show that SB 206553, while having no influence on the performance of control subjects, attenuated (2.0 mg/kg) or abolished (5 mg/kg) the potentiating effect of the lesions on DFEN-induced anorexia. In Experiment 2, m-CPP induced a suppression of food intake in nonlesioned animals that was significantly potentiated in rats with medial PBN lesions. These results are consistent with the hypothesis that medial PBN neurons mediate anorexia through 5HT2C receptors.     

c-fos expression in the rat brain following central administration of neuropeptide Y and effects of food consumption

Administration of neuropeptide Y (NPY) intracerebroventricularly (i.c.v.) results in the release of a number of hypothalamic and pituitary hormones and stimulation of feeding and suppression of sexual behavior. In this study, we sought to identify cellular sites of NPY action by evaluating perikaryal Fos-like immunoreactivity (FLI), a marker of cellular activation, in those hypothalamic and extrahypothalamic sites previously implicated in the control of neuroendocrine function and feeding behavior. Additionally, we compared the topography of FLI in these brain sites when food was either available ad libitum or withheld after NPY injection (1 nmol/3 μl, i.c.v.). The results showed that one hour after NPY injection a large number of cells in the parvocellular region of the paraventricular nucleus (PVN) were FLI-positive in the absence of food consumption. However, in association with food intake, a significant number of cells were intensely stained in the magnocellular region of the PVN. An analogous increase in FLI in association with feeding was apparent in the supraotic nucleus (SON), the dorsomedial nucleus and the bed nucleus of the stria terminalis in the hypothalamus. Anong the extrahypothalamic sites, feeding facilitated FLI in a large number of cells located in the lateral subdivision of the central amygdaloid nucleus and the lateral subdivision of the solitary tract. FLI was observed in a moderate number of cells in the hypothalamic arcuate nucleus (ARC) and ventromedial nucleus, and this response was not changed by feeding. Cumulatively, these results show that neurons in a number of discrete hypothalamic and extrahypothalamic sites, previously implicated in the control of neuroendocrine function and feeding behavior, are activated by NPY and further, a divergent pattern of c-fos expression emerged in some of these sites if feeding occurs after NPY injection. Stimulation of FLI in cells of the PVN, SON and ARC by NPY imply the presence of NPY target cells that play a role in the neuroendocrine control of pituitary function. The finding that NPY induced FLI in cells located in the parvocellular subdivision of the PVN even in the absence of feeding, imply that cells involved in initiation of food intake by NPY may reside in this subdivision of the PVN. On the other hand, the appearance of Fos-cells in the magnocellular subdivision of the PVN in response to feeding, suggests neural mechanisms that operate during the post-ingestion period, including those associated with termination of NPY-induced feeding, may impinge upon this subdivision of the PVN.     

Differential effects of mu and kappa opioid antagonists on Fos-like immunoreactivity in extended amygdala

It was previously reported that systemic administration of the nonselective opioid antagonist, naltrexone, induces Fos-like immunoreactivity (FLI) within the central nucleus of the amygdala (CeA), bed nucleus of the stria terminalis (lateral-dorsal division; BSTLD), nucleus accumbens shell (NACshell) and ventral tegmental area (VTA) of free-feeding rats. These findings suggest that cellular activity in these brain regions is subject to opioid-mediated inhibitory control under basal conditions. Considering the involvement of mesoaccumbens dopamine neurons and components of the 'extended amygdala' in motivated behavior and reward, it was hypothesized that the induction of c-Fos by naltrexone accounts for the motivational-affective consequences of opioid antagonism. In Experiment 1, naltrexone was administered intracerebroventricularly (i.c.v.; 100 microg) to determine whether results obtained in the prior immunohistochemical studies could be attributed to blockade of opioid receptors in brain as opposed to peripheral tissues that convey visceral sensory inputs to the CeA and BSTLD. Naltrexone produced a marked increase in FLI within the CeA and BSTLD, and a moderate increase in NACshell. In Experiment 2, the kappa opioid antagonist, nor-binaltorphimine (Nor-BNI; 20.0 microg, i.c.v.) reproduced the effect of naltrexone in BSTLD and CeA, suggesting that the induction of c-Fos in these two structures is a consequence of kappa receptor blockade. The selective mu antagonist, CTAP (2.0 microg, i.c.v.), reproduced the effect of naltrexone in NACshell, suggesting that the induction of c-Fos in this structure is a consequence of mu receptor blockade. The functional implications of these results are discussed in terms of the known functions of these brain regions and opioid receptor types, and the prior observation that chronic food restriction eliminates the FLI induced by naltrexone in CeA and BSTLD. It is suggested that tonic mu opioid-mediated inhibition in NACshell has a predisposing effect on goal-approach behavior in general while kappa opioid-mediated inhibition in CeA and BSTLD has a predisposing effect on palatability-driven feeding in particular. Finally, a possible relationship between food restriction-induced suppression of the kappa opioid mechanism in CeA/BSTLD, local CRH function, and sensitization of the neural substrate for incentive-motivating effects of abused drugs is discussed.     

Differential effects of μ and κ opioid antagonists on Fos-like immunoreactivity in extended amygdala

It was previously reported that systemic administration of the nonselective opioid antagonist, naltrexone, induces Fos-like immunoreactivity (FLI) within the central nucleus of the amygdala (CeA), bed nucleus of the stria terminalis (lateral–dorsal division; BSTLD), nucleus accumbens shell (NACshell) and ventral tegmental area (VTA) of free-feeding rats. These findings suggest that cellular activity in these brain regions is subject to opioid-mediated inhibitory control under basal conditions. Considering the involvement of mesoaccumbens dopamine neurons and components of the ‘extended amygdala' in motivated behavior and reward, it was hypothesized that the induction of c-Fos by naltrexone accounts for the motivational-affective consequences of opioid antagonism. In Experiment 1, naltrexone was administered intracerebroventricularly (i.c.v.; 100 μg) to determine whether results obtained in the prior immunohistochemical studies could be attributed to blockade of opioid receptors in brain as opposed to peripheral tissues that convey visceral sensory inputs to the CeA and BSTLD. Naltrexone produced a marked increase in FLI within the CeA and BSTLD, and a moderate increase in NACshell. In Experiment 2, the κ opioid antagonist, nor-binaltorphimine (Nor-BNI; 20.0 μg, i.c.v.) reproduced the effect of naltrexone in BSTLD and CeA, suggesting that the induction of c-Fos in these two structures is a consequence of κ receptor blockade. The selective μ antagonist, CTAP (2.0 μg, i.c.v.), reproduced the effect of naltrexone in NACshell, suggesting that the induction of c-Fos in this structure is a consequence of μ receptor blockade. The functional implications of these results are discussed in terms of the known functions of these brain regions and opioid receptor types, and the prior observation that chronic food restriction eliminates the FLI induced by naltrexone in CeA and BSTLD. It is suggested that tonic μ opioid-mediated inhibition in NACshell has a predisposing effect on goal–approach behavior in general while κ opioid-mediated inhibition in CeA and BSTLD has a predisposing effect on palatability-driven feeding in particular. Finally, a possible relationship between food restriction-induced suppression of the κ opioid mechanism in CeA/BSTLD, local CRH function, and sensitization of the neural substrate for incentive-motivating effects of abused drugs is discussed.     

Microinjection of galanin-like peptide into the medial preoptic area stimulates food intake in adult male rats

Galanin-like peptide (GALP) is a neuropeptide implicated in the regulation of feeding behaviour, metabolism and reproduction. GALP is an endogenous ligand of the galanin receptors, which are widely expressed in the hypothalamus. GALP is predominantly expressed in arcuate nucleus (ARC) neurones, which project to the paraventricular nucleus (PVN) and medial preoptic area (mPOA). Intracerebroventricular or intraparaventricular (iPVN) injection of GALP acutely increases food intake in rats. The effect of GALP injection into the mPOA on feeding behaviour has not previously been studied. In the present study, intra-mPOA (imPOA) injection of GALP potently increased 0-1-h food intake in rats. The dose-response effect of imPOA GALP administration on food intake was similar to that previously observed following iPVN administration. The effects of GALP (1 nmol) or galanin (1 nmol) on food intake were then compared following injection into the PVN, mPOA, ARC, dorsal medial nucleus (DMN), lateral hypothalamus and rostral preoptic area (rPOA). GALP (1 nmol) increased food intake to a similar degree when injected into the imPOA or iPVN, but produced no significant effect when injected into the ARC, DMN, lateral hypothalamus or rPOA. Similarly, galanin (1 nmol) significantly increased food intake following injection imPOA and iPVN. However, the effect was significantly smaller than that following administration of GALP (1 nmol). Galanin also had no significant effect on food intake when administered into the ARC, DMN, lateral hypothalamus and rPOA. These data suggest that the mPOA and the PVN may have specific roles in mediating the orexigenic effect of GALP and galanin.     

Expression of c-fos protein in rat brain elicited by electrical stimulation of the pontine parabrachial nucleus.

The expression of Fos, the protein product of the primary response gene c-fos, was used metabolically to map the short-term (1 hr) effects of urethane and sodium pentobarbital anesthesia in rat. Subsequently, urethane-anesthetized rats were used to study the integrated response to electrical stimulation (1-1.5 hr) of the pontine parabrachial nucleus (PBN), an important center for relay of autonomic information in the brain. Immunohistochemistry was used to localize Fos-like immunoreactivity (FLI) in the brain. To approximate amounts of FLI in the conscious animal, rats were killed immediately after attaining surgical anesthesia with sodium pentobarbital (50 mg/kg) or urethane (1.2-1.7 gm/kg). No FLI was found in the brains of these rats. In rats killed 1 hr after anesthesia with sodium pentobarbital, FLI was found only in the habenulae. After 1 h of urethane anesthesia, low levels of FLI were found in the following areas: nucleus of the tractus solitarius (NTS); caudal and rostral ventrolateral medulla (VLM); lateral PBN; ventromedial, paraventricular, and supraoptic nuclei (SON) of the hypothalamus; medial preoptic area; central nucleus of the amygdala (ACE); endopiriform cortex; insular cortex; piriform cortex; and islands of Calleja. Electrical stimulation of the PBN (10 sec on, 10 sec off; 15-50 microA at 20 Hz for 60-90 min) in rats anesthetized with urethane led to increases in mean arterial pressure (10-30 mm Hg) and to ipsilateral increases of FLI in the lateral PBN, dorsal division of SON, ACE, endopiriform nucleus, insular cortex, piriform cortex, and islands of Calleja. In two animals, ipsilateral increases were found in the ventromedial hypothalamus and medial amygdaloid nucleus.(ABSTRACT TRUNCATED AT 250 WORDS)     

Expression of Fos immunoreactivity in rat brain during dehydration: effect of duration and timing of water deprivation

Water deprivation induces expression of the immediate early gene c-fos in specific brain regions, most likely as a result of the activation of cells that are responsive to changes in osmolality and/or blood volume. We hypothesized that the magnitude of c-fos expression would be a function of both the duration of water deprivation and the time of day at which the deprivation started. This study was designed to examine the pattern of Fos-like immunoreactivity (FLI) following water deprivation in rats under normal light/dark conditions (nLD) and reverse light/dark conditions (rLD). Rats were deprived of water but not food either for 0, 5, 16, 24 or 48 h. As expected, hematocrit ratio (HCT), osmolality (OSM), plasma renin activity (PRA) and weight loss increased as a function of duration of water deprivation. In non-deprived rats (0 h), very little FLI was observed in most brain regions. The number of cells showing FLI increased with duration of water deprivation in the supraoptic nucleus (SON), paraventricular nucleus (PVN), organum vasculosum laminae terminalis (OVLT), median preoptic nucleus (MnPO) and subfornical organ (SFO) in both nLD and rLD conditions. However, the pattern of FLI differed between nLD and rLD conditions. Compared to corresponding nLD groups after 5 or 24-h water deprivation, rLD groups had significantly more FLI in SON and PVN, and higher PRA and HCT. Also, weight loss and FLI in the MnPO were greater after 5 h, and FLI in the SFO was greater after 24 h under rLD compared to nLD conditions. Our findings indicate that the magnitude of c-fos expression, and change in weight and plasma parameters were a function of both the duration of water deprivation and the time of day at which the deprivation started. This may result from ingestion of food early in the deprivation periods during the rLD tests, thus producing greater change in osmolality and blood volume.     

Urocortin in the ventromedial hypothalamic nucleus acts as an inhibitor of feeding behavior in rats

Urocortin (UCN), a member of the corticotropin-releasing factor (CRF) family, inhibits food intake when it is injected intracerebroventricularly in rats. To explore the site of action of UCN in feeding behavior, we examined the effects of injection of UCN into various hypothalamic nuclei on food and water intake in 24-h fasted rats. Injection of UCN into the ventromedial hypothalamic nucleus (VMH) significantly inhibited food and water intake over 3 h without sedative effect, but no significant effect was observed following injection either into the lateral hypothalamic area, or the paraventricular nucleus of the hypothalamus. To further explore the physiological significance of endogenous UCN of the VMH in feeding behavior, the effect of immunoneutralization of hypothalamic UCN on food intake was examined. Injection of anti-rat UCN rabbit gamma-globulin into the bilateral VMH in freely fed rats significantly potentiated food and water intake compared with rats that received normal rabbit gamma-globulin. These results suggest that endogenous UCN in the VMH exert inhibitory control on ingestive behavior.     

Acoustic brainstem nuclei express Fos after flurothyl-induced generalized seizures in rats

The inferior colliculus (IC) plays a key role in modulating audiogenic seizures (AS) in rats. We investigated whether acoustic brainstem nuclei express Fos-like immunoreactivity (FLI) after flurothyl-induced generalized seizures in rats. Compared to controls, experimental animals showed significantly (P<0.05) more FLI in the dorsal and external cortex of the IC, as well as in the medial part of the medial geniculate body (MGB), perigeniculate area, and dorsal cochlear nucleus. No significant increase of FLI was observed in the central nucleus of the IC, ventral and dorsal parts of the MGB, dorsal nucleus of the lateral lemniscus, or ventral cochlear nucleus. Because this pattern of FLI closely resembles that observed after AS in previous studies, these results suggest that Fos expression in acoustic brainstem nuclei is not specific for AS.     

Distribution of Fos-like immunoreactivity within the rat brain following intraventricular injection of the selective NK(3) receptor agonist senktide

Neurokinin B (NKB) is one member of an evolutionarily conserved family of neuropeptides, the tachykinins. Preferential binding of NKB to endogenous NK(3) receptors affects a variety of biological and physiological processes, including endocrine secretions, sensory transmission, and fluid and electrolyte homeostasis. In light of its widespread biological actions, immunohistochemical detection of the c-Fos protein product was used to study the distribution of neuronal activation in the rat brain caused by intraventricular (icv) injections of the selective NK(3) receptor agonist (succinyl-[Asp(6), N-Me-Phe(8)] substance P [6-11]), senktide. Quantitative analysis revealed that treatment with isotonic saline or 200 ng senktide resulted in the differential expression of Fos-like immunoreactivity (FLI) throughout the brain. Senktide induced the highest number of FLI neurons in the lateral septum, bed nucleus of the stria terminalis, amygdala, paraventricular nucleus of the hypothalamus, median preoptic nucleus, organum vasculosum of the lamina terminalis, supraoptic nucleus, periaqueductal gray, and medial nucleus of the solitary tract compared to isotonic saline controls. Additional regions that contained elevated FLI following icv injection of senktide, relative to saline injection, included the cerebral cortex, lateral hypothalamic nucleus, suprachiasmatic nucleus, ventral tegmental area, substantia nigra, inferior colliculus, locus coeruleus, zona incerta, and arcuate nucleus. Our data indicate that activation of NK(3) receptors induces the expression of FLI within circumscribed regions of the rat brain. This pattern of neuronal activation overlaps with nuclei known to regulate homeostatic processes, such as endocrine secretion, cardiovascular function, salt intake, and nociception.     

Decreased NPY innervation of the hypothalamic nuclei in rats with cancer anorexia

Whether the decrease in food intake that occurs at the onset of anorexia in tumor bearing (TB) rats is related to a change in the hypothalamic neuropeptide Y (NPY) system was tested by comparing NPY expression in sham operated Fischer Control and anorectic TB rats. Coronal cryocut sections of their fixed brain were processed by the peroxidase-antiperoxidase method with NPY polyclonal antibodies. NPY-immunoreactive fibers were widely distributed throughout the forebrain, but were most prominent in the hypothalamic paraventricular, suprachiasmatic, arcuate and periventricular nuclei. NPY-immunoreactive neurons were visualized in Control and anorectic TB rats in the preoptic region, the arcuate nucleus, and occasionally in the lateral hypothalamus. Semiquantitative image analysis showed a significant decrease in the NPY immunostaining in some hypothalamic nuclei of the anorectic TB rats, most prominently in the supraoptic nucleus, the parvocellular portion of the paraventricular nucleus, and, to a lesser extent, the suprachiasmatic and arcuate nuclei. No changes in NPY innervation were seen in the ventromedial nucleus and the lateral hypothalamus. The data support the hypothesis of an altered hypothalamic NPY system at the onset of anorexia in TB rats and also reveal the hypothalamic nuclei through which NPY influences food intake.     

Commissural nucleus of the solitary tract lesions reduce food intake and body weight gain in rats

This study investigated the effects of an electrolytic lesion of the commissural subnucleus of the nucleus of the solitary tract (commNTS) on body weight, daily food and water intake, and plasma glucose and insulin in rats. In the first 6 days following brain surgery, commNTS lesioned rats reduced daily food intake by 80% compared to rats with sham lesions. After this period rats with lesions of commNTS started recovering food intake, but intake remained significantly reduced until the 12th day after surgery. A reduction in body weight was observed 4 days after surgery and reached a maximum on the 12th day. After this, a partial recovery of body weight was observed, but weight remained significantly reduced compared to weights of rats with sham lesions through the conclusion of the study. Food intake and body weight gain in other rats with partial lesions of the commNTS or with lesions outside the commNTS did not differ from rats with sham lesions with regard to those variables. Daily water intake and plasma glucose and insulin were not changed by the commNTS lesions. These results suggest that commNTS is involved with mechanisms that control food intake and body weight in rats.     

Extensive brain mapping of calcitonin-induced anorexia

The purpose of this study was to compare the localization in the brain of calcitonin-induced anorexia to the distribution of calcitonin binding sites (as described by others). We, thus, performed an extensive mapping of brain structures to determine those involved in calcitonin-induced anorexia. A significant anorexia is found after injection of calcitonin (15 ng in 0.3 μl) into several brain areas. Forebrain: lateral septum, lateral part of the anterior commissure, and bed nucleus of the stria terminalis; hypothalamus: floor of the anterior part of the hypothalamus, paraventricular nucleus and adjacent perifornical area; thalamus: nucleus reuniens, an area internal to the mamillo-thalamic tract, and medial geniculate body; other areas: amygdala, lateral hippocampus, and central gray. No significant effect is found in the following areas: forebrain: nucleus accumbens, striatum, and medial septum; hypothalamus: lateral, ventro-medial, dorso-medial, and posterior nuclei; thalamus: centro-medial nucleus, lateral part of the zona incerta, and lateral geniculate body; hippocampus: dorsal and ventral parts; midbrain: central tegmentum, ventral tegmental area, and substantia nigra. When these results are compared to the distribution of calcitonin binding sites in the brain, two types of discrepancies are found. The first is the absence of effect in areas containing receptors: these areas may be involved in calcitonin-induced behaviors other than food intake. The second is the occurence of anorexia in areas where no receptors are found: this finding is not easy to explain and raises some speculative hypotheses. In conclusion, calcitonin is active to decrease food intake in several brain areas, the strongest effect occurring in the paraventricular/perifornical area. This is consistent with other evidence from the literature supporting a role of this area in the control of food intake. The reason why calcitonin also acts in areas not known to be involved in food intake and devoid of calcitonin receptors, as well as the mechanism by which calcitonin inhibits feeding, remains to be investigated.     

Daily voluntary exercise alters the cardiovascular response to hemorrhage in conscious male rats

The present study tested the hypothesis that voluntary wheel-exercised rats would better tolerate severe hemorrhage (HEM) compared to age matched sedentary (SED) controls. Conscious rats housed with (EX, n = 8) or without (SED, n = 8) a running wheel for 6 weeks underwent a 30% total blood volume HEM over 15 min and were euthanized 90 min later and brain tissue was processed for Fos-like immunoreactivity (FLI). Both EX and SED groups displayed typical responses to HEM (initial tachycardia followed by decreased HR and MAP) but at the end of HEM, mean arterial pressure (93 ± 6 vs 58 ± 3 mm Hg) and heart rate (316 ± 17 vs. 247 ± 22 bpm,) were higher in the EX vs. SED animals and 60 min following the end of HEM, HR remained significantly elevated in the EX vs SED animals. The altered HR response to HEM in the EX animals was linked to a significant difference in sympatho-vagal drive identified by heart rate variability analysis and an augmented baroreflex response to hypotension tested in a separate group of animals (n = 4-5/group). In many of the brain regions analyzed, EX rats displayed lower levels of FLI compared to SED rats. Significantly lower levels of FLI in the EX vs SED rats were identified in the middle and caudal external lateral subnucleus of the lateral parabrachial nucleus and the dorsal cap of the hypothalamic paraventricular nucleus. These results suggest that enhanced tolerance to HEM following daily exercise may result from an EX-induced reduction in excitation or exaggerated inhibition in central circuits involved in autonomic control.     

Electrically induced Fos-like immunoreactivity in the auditory pathway of the rat: Effects of survival time, duration, and intensity of stimulation

The goal of the present study was to establish how Fos-like immunoreactivity (FLI) elicited in the rat auditory pathway by unilateral electric stimulation of the cochlea is affected by the following experimental parameters: duration and intensity of stimulation, duration of survival time after offset of stimulation. The dense FLI found in the ipsilateral dorsal cochlear nucleus, as well as the moderate FLI found in the contralateral dorsal cochlear nucleus and in the posteroventral cochlear nucleus on both sides, were consistent after survival times ranging from 0 to 2–3 h, but they significantly decreased after longer survival times (5 and 6 h). In the same nuclei, FLI was increased even by short durations of stimulation (5 and 10 min) as compared to control rats, although FLI progressively increased for longer stimulation (20 and 45 min). In the auditory thalamus, FLI was found mainly in the peripeduncular nucleus, the dorsal and medial divisions of the medial geniculate body, whereas its ventral division was virtually devoid of immunoreactive neurons. This pattern of FLI distribution in the auditory thalamus persisted even after relatively long survival times (5 and 6 h). In both the cochlear nucleus and auditory thalamus, the density of FLI slightly increased in parallel with the intensity of stimulation. In other auditory nuclei, such as the inferior colliculus and the nucleus of the lateral lemniscus, there was no simple relation between the density of FLI and the three tested experimental parameters. Thus, the distribution and density of FLI did not vary in parallel in the various nuclei of the auditory pathway as a function of the tested experimental parameters; different patterns of FLI changes were instead observed in different auditory nuclei.     

Decrease in stress-induced c-Fos-like immunoreactivity in the lateral septal nucleus of learned helpless rats

Inescapable stress can induce learned helplessness in many species of animals. Learned helplessness is a phenomenon which has some behavioral and neurotransmitter analogies with human clinical depression. Stress can also induce the expression of immediate early genes, including c-fos in many areas of the central nervous system. We examined stress-induced c-Fos-like immunoreactivity (FLI) using the learned helplessness paradigm. Naive rats showed significantly higher FLI than the tested groups in all the amygdaloid regions and in the hypothalamic paraventricular nucleus. However, in the lateral septal nucleus, helpless animals showed significantly reduced FLI in response to stress, compared to the other groups. These, and other previous data, highlight the importance of the septal area in mediating behavioral responses to inescapable stress.