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Background: Several lines of evidence have led us to postulate that afferent vagal hyperactivity could be an important factor in the pathophysiology of the eating disorder bulimia nervosa. Ondansetron is a peripherally active antagonist of the serotonin receptor 5-HT3, and is marketed for prevention of vagally-mediated emesis caused by cancer chemotherapeutic agents. We investigated the effects of ondansetron on bulimic behaviours in patients with severe and chronic bulimia nervosa in a randomised, double-blind, placebo-controlled study.Methods: We enrolled patients with severe bulimia nervosa (at least seven coupled binge/vomit episodes per week). The patients were otherwise healthy, their weight was normal, and they were not receiving medical or psychiatric treatment. During the first week of the study, patients recorded all eating-behaviour events to establish a baseline. In the second week, all patients received placebo, but were told that they were receiving either placebo or active drug. At the end of this single-blind phase, patients were randomly assigned placebo or ondansetron (24 mg daily) for a further 4 weeks. The primary outcome measure was the number of binge/vomit episodes per week. Data were analysed by intention to treat.Findings: 29 patients met the inclusion criteria, of whom 28 completed the baseline study, and 26 completed the single-blind placebo week. 12 patients were assigned placebo, and 14 ondansetron; one patient in the ondansetron group dropped out owing to accidental injury. During the 4th week of double-blind treatment, mean binge/vomit frequencies were 13.2 per week (SD 11.6) in the placebo group, versus 6.5 per week (3.9) in the ondansetron group (estimated difference 6.8 [95% CI 4.0-9.5]; p<0.0001). The ondansetron group also showed significant improvement, compared with the placebo group, in two secondary indicators of disease severity. The amount of time spent engaging in bulimic behaviours was decreased on average by 7.6 h per week in the ondansetron group, compared with 2.3 h in the placebo group (estimated difference 5.1 [0.6-9.7]). Similarly, the number of normal meals and snacks increased on average by 4.3 normal eating episodes without vomiting per week in the ondansetron group, compared with 0.2 in the placebo group (estimated difference 4.1 [1.0-7.2]).Interpretation: The decrease in binge-eating and vomiting under ondansetron treatment was not achieved by compensatory changes in eating behaviour such as by a smaller number of binges of longer duration, or by not eating, or by binge-eating without vomiting. Instead, our findings indicate a normalisation of the physiological mechanism(s) controlling meal termination and satiation. Since meal termination and satiety are mainly vagally mediated functions, since binge-eating and vomiting produce intense stimulation of vagal afferent fibres, and since ondansetron and other 5-HT3 antagonists decrease afferent vagal activity, the symptom improvement may result from a pharmacological correction of abnormal vagal neurotransmission. [ABSTRACT FROM AUTHOR]

Bulimia nervosa is characterized by consuming large amounts of food over a defined period with a loss of control over the eating. This is followed by a compensatory behavior directed at eliminating the consumed calories, usually vomiting. Current treatments include antidepressants and/or behavioral therapies. Consensus exists that these treatments are not very effective and are associated with high relapse rates. We review evidence from literature and present original data to evaluate the hypothesis that bulimia involves alterations in vago-vagal function. Evidence in support of this include (1) laboratory studies consistently illustrate deficits in meal size, meal termination, and satiety in bulimia; (2) basic science studies indicate that meal size and satiation are under vagal influences; (3) anatomical, behavioral and physiological data suggest that achieving satiety and the initiation of emesis involve common neural substrates; (4) abnormal vagal and vago-vagal reflexive functions extend to non-eating activational stimuli; and (5) studies from our laboratory modulating vagal activation have shown significant effects on binge/vomit frequencies and suggest a return of normal satiation. We propose a model for the pathophysiology of bulimia based upon de-stabilization of a bi-stable positive vago-vagal feedback loop. This model is not meant to be complete, but rather to stimulate anatomical, psychobiological, and translational neuroscience experiments aimed at elucidating the pathophysiology of bulimia and developing novel treatment strategies.

Background: The rapidly expanding gambling business has resulted in an increasing number of gamblers, and the problem is likely to get worse in the future. Traditionally, mood and gambling symptoms have been known to overlap. In the present review we attempt to examine the diagnostic associations and implications for treatment., Method: Selected published papers on the frequencies of mood disorders among patients who have gambling disorder or gambling disorder among patients who have mood disorder have been reviewed. Recently emerging new treatment methods for gambling disorder have been reviewed and a brief summary has been added., Results: SCID based study results show a close link between gambling and mood disorders. The prevalence of manic disorder reaches to approximately one fourth of the pathological gambling disorder population. The prevalence of depression is much higher, reaching to over half of the population in some studies., Limitations: The studies included in the present paper involve inpatients, outpatients, subjects recruited through advertisements and prison populations. Thus the data need to be interpreted as such. Standardized assessment instruments are not used in all studies. Methodological issues such as primary or secondary nature of depression have not been addressed adequately in these studies. The findings, however, offer new insights for the assessment and treatment of complicated gambling disorder cases., Conclusions: A high prevalence rate of manic and depressive disorders has been recorded among pathological gambling disorder patients. A rational treatment approach to each defined subset of complicated gambling disorder is discussed.

Background: The bilateral vagus nerves (Cranial X) provide both afferent and efferent connections between the viscera and the caudal medulla. The afferent branches increasingly are being recognized as providing significant input to the central nervous system for modulation of complex behaviors. In this paper, we review evidence from our laboratory that increases in vagal afferent activity are involved in perpetuating binge-eating and vomiting in bulimia nervosa. Preliminary findings are also presented which suggest that a subgroup of depressions may have a similar pathophysiology., Methods: Two main approaches were used to study the role of vagal afferents. Ondansetron (ONDAN), a 5-HT3 antagonist, was used as a pharmacological tool for inhibiting or reducing vagal afferent neurotransmission. Second, somatic pain detection thresholds were assessed for monitoring a physiological process known to be modulated by vagal afferents, including the gastric branches involved in meal termination and satiety. High levels of vagal activity result in an increase in pain detection thresholds. Depressive symptoms were assessed using the Beck Depression Inventory (BDI). Positron Emission Tomography (PET) was used to identify higher cortical brain areas activated by vagal stimulation produced by proximal gastric distention in normal eating subjects., Results: Double-blind treatment of severe bulimia nervosa subjects with ONDAN resulted in a rapid and significant decrease in binge-eating and vomiting compared to placebo controls. The decrease in abnormal eating episodes was accompanied by a return of normal satiety. Pain detection thresholds measured weekly over the course of the treatment protocol were found to dynamically fluctuate in association with bulimic episodes. Thresholds were the most elevated during periods of short-term abstinence from the behaviors, suggesting that not engaging in a binge/vomit episode is accompanied by an increase in vagal activity. ONDAN also resulted in abolition of the fluctuations in pain thresholds. Depressive symptoms in these subjects also were reduced by ONDAN. Like pain thresholds, depressive symptoms varied dynamically with the bulimic behaviors, with BDI scores increasing (more depressed) as more time elapsed since the last bulimic episode. PET studies indicated that mechanical distention of the stomach with a balloon (a non-nutritive stimulus) was associated with the activation of several brain loci, including those associated with vagal activation (parabrachial nucleus), emotive aspects of eating (lateral inferior frontal and orbitofrontal), and depressive symptoms (anterior cingulate)., Conclusions: The results of the ONDAN study in bulimia nervosa subjects suggest that cyclic increases in vagal activity drive the urge to binge-eat and vomit. The alterations in vagal firing patterns are possibly a physiological adaptation to the high levels of vagal stimulation initially provided by voluntarily binge-eating and vomiting for weight control. The depressive symptoms that occur in association with the urge to binge-eat are also likely due to the cyclic increase in vagal activity. This suggestion is supported by the reduction of depressive symptoms during ONDAN treatment in bulimia subjects and PET imaging studies in normal eating subjects showing that brain loci classically involved in depression are activated by vagal stimulation administered by mechanical gastric distention. In normal eating individuals, depressions accompanying visceral diseases may also be vagally mediated. Ondansetron and other drugs known to modulate vagal activity may be helpful in treating depressions of this origin.

This study aimed to measure brain activation during gastric distention as a way to investigate short-term satiety. We estimated regional cerebral blood flow with positron emission tomography (15O-water) during gastric balloon inflation and deflation in 18 healthy young women. The contrast between inflated minus deflated conditions showed activation in the following four key regions that were identified a priori: dorsal brain stem; left inferior frontal gyrus; bilateral insula; and right subgenual, anterior cingulate cortex. Extant neuroimaging literature provides context for these areas as follows: the brain stem represents vagal projection zones for visceral afferent processing; the inferior frontal gyrus serves as a convergence zone for processing food-related stimuli; and both the insula and subgenual anterior cingulate cortex respond to emotional stimulation. The identification of neural correlates of gastric distention is a key step in the discovery of new treatments for obesity. New therapies could intervene by modifying the perception of gastric distention, an important contributor to meal termination and short-term satiety. This first study of brain activation during nonpainful, proximal gastric distention provides the groundwork for future research to discover novel treatments for obesity.

Serotonin 5-HT(3) antagonists have been suggested for treatment of several disorders involving altered gastrointestinal (GI) function. CCK also has well documented GI actions on both food intake and vago-vagal reflexes. To evaluate potential interactions, the effect of a 5-HT(3) antagonist, ondansetron, on exogenous CCK induced satiety and c-fos activation was determined. Ondansetron reduced both actions of CCK by approximately 50%. The reduction in c-fos was localized to a specific subregion of the dorsal medulla, suggesting that a distinct subpopulation of CCK receptive fibers are modulated by 5-HT(3) ligands. Treatments using 5-HT(3) antagonists also may affect endogenous CCK functions.

Background: Conflicting data have been published regarding pain threshold in subjects with anorexia nervosa (AN), with some studies indicating elevated pain threshold and others indicating normal thresholds. Previous research has indicated the presence of elevated pain threshold in eating disorder subjects with binge-eating behavior., Methods: In this study pressure pain detection thresholds (PDT) (assessed by a pressure analgesiometer) in binge-eating/purging and restricting subtypes of AN subjects were compared to control subjects., Results: PDT was elevated in AN compared to control subjects at baseline. There was no difference in PDT between the subgroups of AN subjects., Conclusions: The etiology of elevated PDT in AN subjects is most likely different from the etiology of elevated PDT in bulimia nervosa subjects.

Subjects with bulimia nervosa (BN) have been shown to exhibit abnormal satiety responses. Short-term satiety is largely mediated by afferent vagal activity. Activation of afferent vagal fibers has also been found to stimulate a descending pain inhibitory pathway that leads to elevation in somatosensory pain thresholds. Therefore, the study of pain thresholds in BN subjects may lead to a better understanding of afferent vagal function in this disorder. In this preliminary study, pressure pain thresholds were assessed in nine subjects with BN on 3 consecutive days during a binge-eating and vomiting (B/V) episode, during a normal meal, and after an overnight fast. A significant time versus condition effect was found with a significant change in the pain threshold in BN subjects under the B/V condition only. These data are consistent with the hypothesis that vagal afferent activation by a B/V episode also activates the descending pain inhibitory pathway.

We sought to determine whether pontomesencephalic cholinergic neurons which we have been shown previously to project to the substantia nigra and ventral tegmental area also contribute to the thalamic activation projection from the pedunculopontine and laterodorsal tegmental nuclei. Retrograde tracing, immunohistochemical localization of choline acetyltransferase and statistical methods were used to determine the full extent of the cholinergic projection from the pedunculopontine and laterodorsal tegmental nuclei to the thalamus. Progressively larger Fluoro-Gold injections in to the thalamus proportionally labeled increasing numbers of pontomesencephalic cholinergic cells both ipsi- and contralaterally in the pedunculopontine and laterodorsal tegmental nuclei. Multiple large thalamic injections left only a small fraction of the ipsilateral pontomesencephalic cholinergic group unlabeled. This small remainder did not correspond to the populations which project to the substantia nigra and ventral tegmental area, thereby indicating that substantia nigra- and ventral tegmental area-projecting cholinergic neurons must also project to the thalamus. We examined whether there existed any set of cholinergic neurons in the pedunculopontine and laterodorsal tegmental nuclei which did not innervate a thalamic target. The distribution of descending projections of the pedunculopontine and laterodorsal tegmental nuclei demonstrated that the unlabeled remainder cannot correspond to a purely descending group. We also show that substance P-positive cholinergic cells in the laterodorsal tegmental nucleus project to the thalamus. Further studies demonstrated that the small population of cholinergic cells left unlabeled from the thalamus were the smallest sized cholinergic cells, and included two groups of small, light-staining cholinergic cells located in the parabrachial area and central gray, adjacent to the main pedunculopontine and laterodorsal tegmental nuclei cholinergic groups. These small cells, in contrast to thalamic-projecting cholinergic cells, did not stain positively for reduced nicotinamide adenine dinucleotide phosphate-diaphorase. Taken together, these results indicated that all of the reduced nicotinamide adenine dinucleotide phosphate diaphorase-positive/choline acetyltransferase-positive neurons of the pedunculopontine/laterodorsal tegmental nuclei ascend to innervate some portion of the thalamus, in addition to the other targets they innervate. These findings indicate that the diverse physiological and behavioral effects attributed to the activity of pontomesencephalic cholinergic neurons should not be dissociated from their activating effects in the thalamus.

Thresholds for detection of both pressure and thermal pain are elevated in patients with bulimia nervosa. The present study was aimed at determining (1) if pressure pain detection thresholds (PDT) varied dynamically with the primary disease symptoms of binge eating and vomiting and (2) if the elevation in PDT was effected by treatment with ondansetron (ONDAN), a 5-HT3 receptor antagonist. PDT was defined as the mean of the minimal amount of pressure (measured in g) perceived as painful when exerted by a 1 mm2 blunted point onto the center of the ventral surface of the ungual phalanx of digits 2-5 of the non-dominant hand. Fourteen female patients with severe bulimia nervosa (currently >seven binge/vomit episodes per week; > 2 years illness duration) served as participants. PDT were evaluated at weekly intervals during the course of ongoing treatment studies (double-blind and 'open' label) investigating the therapeutic effects of ONDAN. Data were analyzed by random regression analyses, allowing for the repeated-measures and non-orthogonal design. Data collected from 14 patients under the no-drug condition indicated that PDT increased over the interval between binge/vomit episodes, with significant elevations occurring at times when patients had naturally exceeded their average inter-binge interval. Eleven of these 14 patients underwent 4 weeks of ONDAN treatment. Under this drug condition, the time since the last binge/vomit episode was no longer a significant predictor of PDT. These patients also experienced a significant reduction in the frequency of bulimic behaviors, a finding reported in detail elsewhere. The above finding from untreated patients support the involvement of a common underlying mechanism driving both the increase in pain detection thresholds and the occurrence of the next bulimic episode. This possibility is further supported by the findings that ONDAN treatment is associated with a significant moderation of both variables. The effect of ONDAN may be mediated by blockade of afferent vagal neurotransmission, although other mechanisms must be considered.

Background: Inclusion of obsessive-compulsive disorder (OCD) as an anxiety disorder in DSM-i.v. assumes that anxiety is the primary symptom of OCD; however, persuasive empirical evidence in support of this view has not been presented yet. In the present study we hypothesized that provoked anxiety symptoms respond better to intravenous diazepam than would provoked obsessions. We, therefore, reasoned that anxiety symptoms are secondary symptoms of OCD., Methods: To test the hypothesis we designed a double-blind, randomized, placebo-controlled crossover study. Patients underwent four experimental conditions in which the sequence of symptom provocation and i.v. injection of (placebo or diazepam) were alternated. Baseline and i.v. injection-induced symptom changes were assessed using visual analogs., Results: Obsessions and anxiety correlated strongly for all four experimental conditions in which the sequence of the symptom provocation and diazepam i.v. injections was alternated. i.v. diazepam injection before and after symptom provocation failed to preferentially modulate anxiety symptoms over obsessions. Unexpectedly, in the group in which i.v. diazepam injection preceded the symptom provocation, reduction of mean obsessions was even more pronounced., Conclusions: Strong correlations between anxiety and obsessions at baseline, during symptom provocation, and after i.v. diazepam infusion suggest that anxiety and obsessions are tightly coupled phenomena in OCD.

Ischemic brain injury in neonates can result in the degeneration of cortical and subcortical areas of brain and is associated with neurologic deficits. One approach to restoring function in conditions of ischemic brain injury is the use of neural transplants to repair damaged connections. This approach has been shown to reestablish neural circuitry and to ameliorate associated motor deficits in models of neonatal sensorimotor cortex damage. In this study, we utilized the Rice et al. rodent model of neonatal ischemic-hypoxic (IH) brain injury to assess whether transplantation of fetal neocortical tissue can promote functional recovery in tests of sensorimotor and locomotor ability throughout development and as adults. We show that animals that received neocortical grafts 3 days following the IH injury performed significantly better as adults on two measures of motor ability, the Rota-Rod treadmill and apomorphine-induced rotations, than did control animals that received sham transplants after the IH injury. Transplants were identifiable in 72% of the animals 10-12 weeks after implantation. Histochemical studies revealed that while the transplanted tissue did not establish normal cortical cytoarchitecture, cells and fibers within the grafts stained for nicotinamide adenine dinucleotide phosphate-diaphorase (NADPH-d), choline acetyl transferase (ChAT), cholecystokinin (CCK), and glial fibrillary acidic protein (GFAP). These results suggest that transplantation of fetal neocortical tissue following IH injury in the neonatal period is associated with amelioration of motor deficits and that the grafted tissue demonstrated a neurochemical phenotype that resembled normal neocortex. This approach warrants continued investigation in light of potential therapeutic uses.

The retrosplenial cortex (RSC) is a target of the forebrain cholinergic projecting system. It receives extensive cholinergic innervation from the medial septal nucleus and the diagonal band of Broca. These cholinergic afferents travel along the paths of cingulate bundle and fornix. In the present study we investigated the ability of cholinergic fetal septal grafts to reinnervate the deafferented RSC. Four groups of rats were used: (1) normal control rats (NC); (2) rats with bilateral transections of the cingulate bundle (CgX); (3) rats with simultaneous lesions of both the cingulate bundle and the fornix (FX), and (4) rats with intra-retrosplenial fetal septal grafts and lesions in both cingulate bundle and the fornix (RSCsep-TPL). We found that lesions in the cingulate bundle alone produced a modest reduction of cholinergic innervation whereas lesions in both the fornix and cingulate bundle resulted in a complete loss of cholinergic inputs in this area, indicating that both the cingulate bundle and the fornix are involved in mediating cholinergic projections from the septal-diagonal area to the RSC. Transplantation of cholinergic fetal septal neurons into the RSC of animals with simultaneous lesions in both the fornix and cingulate bundle restored the cholinergic innervation pattern to that which is typical of the normal septo-retrosplenial inputs. These results provide the neuroanatomical basis for behavioral studies which have documented graft-mediated recovery of spatial memory function in rats with lesions of the cholinergic septo-retrosplenial pathways.

Chicken gonadotropin-releasing hormones I and II (cGnRH I and II) were measured by radioimmunoassay (RIA) in extracts of microdissected regions of turkey hen brain (preoptic area [POA], region of periventricular nuclei [PHN], septum [SEP], hippocampus [HP], dorsomedial thalamus/habenula [DMT], midbrain central gray [MCG], and caudal lateral hypothalamus [LH]) at five stages of the reproductive cycle: before photostimulation, during egg laying, during incubation, during photorefractoriness, and after return to short daylengths. The highest concentration of cGnRH I occurred in PHN, followed by POA, SEP, DMT, HP, LH, and MCG, in decreasing order, whereas the highest concentration of cGnRH II occurred in SEP, followed by POA, DMT, HP, MCG, PHN, LH. These results agree, with some exceptions, with the distribution of fibers and cells as determined by immunohistochemistry. cGnRH II was from 1.3 to 24 times as abundant as cGnRH I in different brain areas. During incubation, cGnRH I concentrations were significantly elevated in the POA and cGnRH II levels were significantly elevated in HP; few other significant differences were detected. Correlation analysis detected occasional significant positive and negative correlations between cGnRH I and II concentrations in forebrain areas and MCG of laying birds and in PHN and LH of incubating birds. These results demonstrate an approximate correspondence between hormone concentrations measured in tissue extracts by RIA and immunohistochemistry and indicate an abundance of cGnRH II as compared with cGnRH I. cGnRH I and II concentrations did not, however, change in parallel in all brain areas, suggesting that these peptides do not function in an exactly parallel fashion. Thus, an extent to which cGnRH II is involved in gonadotropin release remains unresolved.

The distribution of cells and fibers immunoreactive (ir) for either chicken gonadotropin-releasing hormone I (cGnRH I; [Gln8]GnRH) or II ([His5,Trp7,Tyr8]GnRH) was determined in brains of turkey hens to reveal whether these peptides occur in separate neuronal systems. ir-cGnRH I cells were located: along the medial aspect of the ventriculus lateralis, nucleus accumbens, and bed nucleus of the stria terminalis; ventral to the tractus septomesencephalicus and extending medially to the third ventricle, and caudally into the lateral hypothalamic area; and in a diffuse band extending from the nucleus preopticus medialis to the nucleus dorsomedialis anterior thalami. cGnRH I fibers were evident in these areas in addition to the hippocampus, nucleus subhabenularis medialis, nucleus ventromedialis hypothalami, and median eminence. Two groups of ir-cGnRH II cells were observed: a magnocellular group lying between the substantia grisea centralis and the nucleus ruber; and a parvicellular group lying medial to the nucleus of the basal optic root and extending into the lateral hypothalamic area. ir-cGnRH II fibers were prominent in limbic structures (cortex piriformis, lateral to nucleus taeniae, hippocampus); olfactory areas (tuberculum olfactorium, nucleus subhabenularis lateralis, nucleus septalis lateralis); areas that in other avian species have steroid-concentrating cells or receptors (medial edge of lobus parolfactorius, nucleus septalis medialis, nucleus periventricularis magnocellularis, nucleus dorsomedialis posterior thalami); and areas containing ir-GnRH I cells or fibers but not in median eminence. These results suggest that cGnRH I and II occur in separate neuronal systems and that cGnRH II does not directly promote pituitary gonadotropin secretion.

We studied whether neurons containing nitric oxide synthase (NOS) are localized to the rostral ventrolateral medulla (RVM) and, if so, whether they are distinct from the adrenergic neurons of the C1 group. NOS-containing neurons and/or C1 neurons were visualized using NADPH diaphorase histochemistry and phenylethanolamine N-methyltransferase (PNMT) immunohistochemistry, respectively. A column of NADPH diaphorase-positive neurons, extending 2 mm in the rostrocaudal plane, was observed lateral to the inferior olive and medial to the C1 neurons. Double labelling studies showed that NADPH diaphorase-positive neurons were not immunoreactive for PNMT, indicating that the two enzymes were localized in the different cells. Furthermore, only a small fraction of NADPH diaphorase neurons were retrogradely labelled after injections of fluorogold into the thoracic cord. We conclude that the RVM contains a well-defined group of neurons endowed with NOS that are distinct from the adrenergic neurons of the C1 group and have only limited monosynaptic projections to the spinal cord. Since the RVM is involved in the control of arterial pressure and in oxygen-conserving reflexes, the findings raise the possibility that nitric oxide participates in central autonomic regulation and oxygen chemoreception.

The demonstrated existence of opioid and nonopioid forms of pain control has raised questions as to how they interact. Previous indirect evidence suggests that activation of one system inhibited the activation of the other. The present study assessed this directly using morphine as an opiate form of analgesia and continuous cold-water swims (CCWS, 4 degrees C, 2 min) as the nonopioid form. A significant reduction in morphine (8 mg/kg, SC) analgesia on the tail-flick test was observed if rats were acutely exposed to CCWS immediately prior to morphine administration. The inability of naloxone (10 mg/kg, SC) to reduce CCWS analgesia verified its nonopioid nature. The antagonism of morphine (3 mg/kg, SC) analgesia was greater following preexposure to 2 min of CCWS than 1 min of CCWS. CCWS was also more effective in antagonizing analgesia induced by the 3 mg/kg than the 8 mg/kg dose of morphine. The antagonism of morphine analgesia by CCWS was dependent upon the temporal patterning of stimulus presentation: exposure to CCWS 20 or 60 min prior to morphine failed to alter subsequent morphine analgesia. A significant reduction in analgesia induced by intraperitoneal administration of morphine (10 mg/kg) was also observed when CCWS was presented immediately prior to injection, suggesting that pharmacokinetic factors such as altered drug absorbance by CCWS-induced vasoconstriction do not appear to explain these effects. These data provide direct support for the existence of collateral inhibitory mechanisms activated by CCWS and morphine, and suggests that these opioid and nonopioid forms of analgesia do not function synergistically, but instead involve some form of hierarchical order.

Monosodium glutamate and bipiperidyl mustard both produce mediobasal hypothalamic lesions and have been reported to alter the subsequent feeding behavior and/or insulin levels of treated animals. In our previous studies bipiperidyl mustard alone had no effects on insulin levels or feeding, but in combination with glutamate produced hyperphagic obesity. Administration of exogenous cholecystokinin octapeptide also has been shown to affect feeding behavior and plasma insulin. In order to determine if endogenous cholecystokinin played a role in the effects of glutamate or bipiperidyl mustard, concentrations of cholecystokinin in the pituitary glands of lesioned rats were measured. Bipiperidyl mustard alone increased cholecystokinin content while combined lesioning with glutamate prevented the increase. The potential role of cholecystokinin-containing elements of the hypothalamus and pituitary in modulation of feeding is discussed.

Recent evidence supports an antagonistic interaction between cholecystokinin (CCK) and opiate peptides. The present study determined the effects of various levels of morphine treatment on hypothalamic levels of CCK as determined by radioimmunoassay. Acute treatment with morphine sulfate (10 mg/kg) or implantation of one morphine pellet (75 mg free base) increased levels of CCK in whole hypothalamus. Increased exposure to morphine by either chronic injections or implantation of two pellets did not result in a further change in whole hypothalamic CCK levels. In samples dissected into hypothalamic subregions, the effect of morphine on CCK levels was localized to medial but not lateral or posterior regions. These experiments extend earlier in vitro findings and suggest that some of the physiological and behavioral effects of opiate peptides may result from modulation of endogenous CCK.

The endogenous neuropeptide cholecystokinin, when administered systemically or perispinally, potently antagonizes opiate analgesia produced by foot shock and morphine. Nonopiate foot-shock analgesia is not reduced by this neuropeptide. The spinal cord appears to be a critical site of cholecystokinin action. These experiments suggest a physiological role for cholecystokinin as a specific opiate antagonist in analgesia-mediating systems. A similar mode of action may explain other behavioral effects of cholecystokinin, such as suppression of food intake.

In rats, stimulation of the vaginal cervix with a glass rod reliably produces analgesia, as measured by the tail-flick test. The present studies sought to identify the neural substrates underlying this potent pain inhibition by examining the effects of decerebration, spinalization and bilateral dorsolateral funiculus (DLF) lesions on vaginal stimulation-produced analgesia (VSPA). These studies indicate that the neural circuitry mediating VSPA is contained within the caudal brainstem and spinal cord, since decerebration did not reduce VSPA when compared with sham-operated controls. A significant though markedly reduced level of analgesia was induced in spinalized rats, indicating that VSPA involves both intraspinal and descending pathways. This descending pathway, originating within supraspinal nuclei of the caudal brainstem, projects to the spinal cord via the DLF, since DLF lesions and spinalization produced equivalent reductions in VSPA compared to sham-operated controls. These results, considered in the light of previous electrophysiological and anatomical findings, indicate that the ventral medullary region may be the source of the descending DLF projection mediating VSPA.

Administration of cholecystokinin was recently found to attenuate opiate analgesia. In the present study, the role of endogenous cholecystokinin in opiate analgesia was examined. Endogenously released cholecystokinin was sequestered by antibodies to cholecystokinin developed in response to an active immunization procedure. Morphine analgesia was potentiated and prolonged in rats immunized against cholecystokinin. The rate of development of morphine tolerance, however, was not affected by the antibodies. Endogenous cholecystokinin appears to function as a short-term modulator of opiate action.

Because several effects of cholecystokinin (CCK) are opposite to those reported for opioids, it seemed likely that CCK may function as an endogenous antagonist of opiate action. This hypothesis was tested initially by assessing the effect of CCK on opiate analgesias. Systemic administration of CCK attenuated opiate analgesias produced by morphine and footshock, but did not reduce nonopiate footshock analgesia. When delivered directly to the lumbosacral spinal cord, a critical site of opiate action, 3.6 ng of CCK-8 significantly inhibited opiate-mediated footshock analgesia; however, 3.6 ng of desulfated CCK-8 did not have an effect. Sequestering of endogenously circulating CCK by antibodies raised against CCK through an active immunization procedure resulted in a potentiation of morphine analgesia. If CCK functions to inhibit opiate involvement in behaviors other than pain responsitivity, CCK-induced satiety may result from an inhibition of opiate-stimulated feeding. In immunohistochemical studies, we have found a dense CCK fiber plexus in the dorsal PVN, a critical site for opiate-induced feeding. Direct microinjections of CCK to this region reduced short-term food intake by 28%. The findings presented here support the hypothesis that an opiate antagonistic function of CCK may account for several previously reported effects of this peptide.

Since endogenous opiate mechanisms are activated during parturition, the present study examined in rats the effects of opiate antagonism on maternal care during and shortly after parturition. Endogenous opiate mechanisms were blocked in late pregnant rats by (1) naltrexone pellet implants (Experiment 1); (2) acute naloxone injections of 10 mg/kg (Experiment 2) or 0.1 mg/kg (Experiment 7); or (3) induction of opiate tolerance (Experiment 3). All methods resulted in a significant decrease in placentophagia and/or in cleaning pups of umbilical cords and birth fluids (Experiment 6). Other aspects of maternal care appeared relatively unaffected and 24 hr pup survival rats were lowered only by induction of morphine tolerance (probably via its effects on the young). In nonpregnant females, naloxone produced a small but significant decrease in placentophagia (Experiment 4) whereas morphine-tolerant nonpregnant females consumed placentas as readily as controls (Experiment 5). Thus the inhibition of placentophagia produced by opiate antagonism may be specific to conditions associated with parturition. These findings suggest that endogenous opiates support placenta eating and pup cleaning during and immediately after birth. Mediation may be via opiate effects on ingestive behavior, and/or via a reduction in the stress of parturition which otherwise can interfere with the female's ability to perform these tasks.

Intraperitoneal administration of cholecystokinin (CCK) potently attenuated opiate analgesia produced by footshock. CCK also inhibited opiate footshock analgesia when delivered intrathecally to the lumbosacral spinal cord, a critical site of opiate action in mediating this form of analgesia. However, opiate-independent footshock analgesia was not attenuated by CCK. Morphine analgesia was attenuated by CCK and potentiated by sequestration of peripheral CCK through an active immunization procedure. CCK also was found to suppress food intake in rats when microinjected into the hypothalamic paraventricular nucleus, a site known to mediate opiate-induced feeding. Collectively, the findings reviewed here suggest that an opiate antagonistic action may underlie several of the effects of CCK.

Corticotropin-releasing factor (CRF) was localized in the brains of two passerine species, the European starling (Sturnus vulgaris) and the song sparrow (Melospiza melodia), by means of immunohistochemistry. The hypothalamic distribution of this peptide in these species includes a complex of immunoreactive perikarya observed in the paraventricular nucleus (PVN), in both its medial and lateral divisions. Nerve fibers were also seen running from these areas to the anterior median eminence (AME) where a terminal field is apparent. A wide variety of extrahypothalamic nuclei containing CRF-immunoreactive cells and fibers were identified. An apparent CRF terminal field can be visualized in the lateral septum. A dense fiber plexus is present in the nucleus accumbens (Ac) and more caudally in the nucleus of the stria terminalis (nST). In colchicine-pretreated animals, it was revealed that these areas also contain CRF-stained perikarya. The pattern of CRF immunoreactivity in the Ac-nST complex is continuous, with no distinction apparent between the nuclei. The medial preoptic area (mPOA) and the adjacent diagonal band of Broca contain CRF-fibers, while cells are apparent in the mPOA. In the mesencephalon, cells were visualized in the midbrain central gray; a terminal field and scattered positively stained perikarya were found in areas more ventral to the central grey that are adjacent to the third cranial nerve. Scattered cells were also seen at the border of the nucleus intercollicularis-nucleus mesencephalicus lateralis, pars dorsalis complex. In contrast to mammalian studies, no immunoreactive nerve fibers or perikarya were observed in telencephalic areas homologous to the mammalian neocortex.(ABSTRACT TRUNCATED AT 250 WORDS)

Immunohistochemistry was used to map the distribution of four neuropeptides in song control regions of two songbird species, the European starling (Sturnus vulgaris) and the song sparrow (Melospiza melodia). We searched for positively stained cell bodies or apparent terminals containing vasoactive intestinal peptide (VIP), methionine-enkephalin (MET), cholecystokinin (CCK), and substance P (SUB P). Intraventricular colchicine pretreatment was administered to enhance the visualization of peptide-containing cell bodies. Four areas implicated in the central control of song were examined. Three of these areas are sexually dimorphic telencephalic nuclei characteristic of songbirds: the caudal nucleus of the ventral hyperstriatum (HVc), the robust nucleus of the archistriatum (RA), and the magnocellular nucleus of the anterior neostriatum (MAN). The fourth region is the mesencephalic nucleus intercollicullaris (ICo), common to all birds, which contains the dorsomedial nucleus (DM) that appears to be specifically involved in the motor control of song. The pattern of neuropeptide localization was similar between the two species. However, the neuropeptides were heterogeneously dispersed among the four areas. VIP and MET were the most widely distributed, whereas CCK and SUB P were seen only in DM. MAN and HVc revealed remarkably similar patterns of staining for both MET and VIP. Fine varicosities immunolabeled for both these peptides appear to encircle nonreactive somata. In both these nuclei positively stained somata were observed for MET but not for VIP. In RA there was a dense accumulation of MET-positive multipolar cell bodies. VIP-containing neurons were seen in the surrounding archistriatum and caudal neostriatum but not in RA itself. Cell bodies and fibers for all four peptides were observed in DM; in no case were they limited to this subregion, but rather seemed to encompass the surrounding intercollicular area as well. The widespread distribution of VIP and MET strongly suggests a role for these peptides in the acquisition or production of passerine song.