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PubMed2001

Can satiety be measured?

An energy-controlled study on a Western diet composed of 45% fat, 40% carbohydrate and 15% protein by energy was carried out. The study consisted of four test phases having a length of 9 days in each case, where 8 healthy free-living subjects were adjusted to individual energy requirements at maintenance level. Between the tests, wash-out phases of 4-5 months were inserted to avoid adaptation effects. By using a standard breakfast of constant composition, satiety was evaluated by applying the concept of categorical comparison, which was based on the common fact, that the perception between two meals is changed and usually a set of sensations can be discriminated. These were termed very full and full (just after finishing a meal), appetite and hungry (just before the next meal). These sensations were used as categories on a categorical scale. The evaluation of satiety was performed such that on each day of the four test phases the subjects had to select over a period of 4 h every 30 min one category out of the four, what corresponded to the individual sensation at that time. This procedure was followed by a mathematical treatment of data such that the individual judgements were transformed into a numerical system. As a result, the time course of satiety was available characterizing the time-dependent change of the interoception after consuming the test meal. Using this concept highly reliable results were obtained as demonstrated by the comparison of the four test series.

Adult↗

PubMed1984

Behavioural effects of manipulation of basal ganglia neurotransmitters.

Topographically organized dopaminergic projections from the extrapyramidal structures of the ventral mesencephalon (substantia nigra and ventral tegmental area) to the dorsal (body of caudate-putamen) and ventral (anterior-ventral caudate, nucleus accumbens, tuberculum olfactorium) striatum subserve sensorimotor integration in the rat. Selective depletion of DA impairs the animal's ability to integrate sensory input with motor output; in the dorsal striatum the exteroceptive sensory input and in the ventral or limbic striatum the interoceptive input principally related to motivation and affect. Grafts of fetal DA neurons to the damaged dorsal striatum reverse sensorimotor asymmetry and sensory neglect. A large number of other excitatory and inhibitory neurotransmitters, including recently discovered neuropeptides, contribute to the functional balance afforded by the DA neurons. This chemical heterogeneity of the basal ganglia offers the possibility that novel therapeutic approaches with drugs could be used to control the chemical imbalances in basal ganglia that are associated with a number of neurological and psychiatric conditions.

Acetylcholine↗

PubMed2007

Human brain structural change related to acute single exposure to sarin.

OBJECTIVE: This study aimed to identify persistent morphological changes subsequent to an acute single-time exposure to sarin, a highly poisonous organophosphate, and the neurobiological basis of long-lasting somatic and cognitive symptoms in victims exposed to sarin. METHODS: Thirty-eight victims of the 1995 Tokyo subway sarin attack, all of whom had been treated in an emergency department for sarin intoxication, and 76 matched healthy control subjects underwent T1-weighted and diffusion tensor magnetic resonance imaging (DTI) in 2000 to 2001. Serum cholinesterase (ChE) levels measured immediately and longitudinally after the exposure and the current severity of chronic reports in the victims were also evaluated. RESULTS: The voxel-based morphometry exhibited smaller than normal regional brain volumes in the insular cortex and neighboring white matter, as well as in the hippocampus in the victims. The reduced regional white matter volume correlated with decreased serum cholinesterase levels and with the severity of chronic somatic complaints related to interoceptive awareness. Voxel-based analysis of diffusion tensor magnetic resonance imaging further demonstrated an extensively lower than normal fractional anisotropy in the victims. All these findings were statistically significant (corrected p < 0.05). INTERPRETATION: Sarin intoxication might be associated with structural changes in specific regions of the human brain, including those surrounding the insular cortex, which might be related to elevated subjective awareness of internal bodily status in exposed individuals.

Adult↗

PubMed2001

Postnatal development of catecholamine inputs to the paraventricular nucleus of the hypothalamus in rats.

Adrenergic and noradrenergic neural projections to the paraventricular nucleus of the hypothalamus (PVN) contribute importantly to viscerosensory modulation of pituitary hormone secretion. Immaturity of ascending catecholamine pathways may partially underlie the documented hyporesponsiveness of PVN neurosecretory cells to certain interoceptive stimuli in rats during the first few weeks of postnatal development. To explore this possibility, the present study compared the distribution and number of dopamine-beta-hydroxylase (DBH)- and phenylethanolamine-N-methyltransferase (PNMT)-positive neurons projecting to the PVN in newborn and adult rats. In addition, a quantitative analysis of DBH- and PNMT-immunoreactive fibers in the medial parvocellular subnucleus, dorsal division (PVNmpd) and posterior magnocellular subnucleus, lateral division (PVNpml) was performed in adult rats and in developing rats on postnatal day (P)1, P7, P14, and P21. The numbers of PVN-projecting neurons in the A1, C1, A2/C2, C3, or A6 catecholamine cell groups were similar in newborn and adult rats, as were the proportions of PVN-projecting neurons in each region that were PNMT-positive. However, fewer PVN-projecting neurons in the C1 and C3 regions expressed DBH immunolabeling in newborn rats compared to adults. DBH immunolabeling increased progressively in the PVNmpd and PVNpml between postnatal days P1 and P21, when adult-like levels were achieved. Conversely, PNMT immunolabeling in the same PVN subdivisions was most dense at P1, gradually decreasing to adult-like levels by P21. These dynamic developmental changes in catecholamine synthetic enzyme immunolabeling densities in the PVN may reflect functional changes in noradrenergic and adrenergic signaling capacity in rats during the first few weeks of postnatal development.

Aging↗

PubMed2004

Distribution of trigeminothalamic and spinothalamic lamina I terminations in the macaque monkey.

Thalamic terminations from trigeminal, cervical, and lumbosacral lamina I neurons were investigated with Phaseolus vulgaris leucoagglutinin (PHA-L) and labeled dextrans. Iontophoretic injections guided by physiological recordings were restricted to lamina I or laminae I-II. PHA-L-labeled trigemino- and spinothalamic (TSTT) terminations were identified immunohistochemically. TRITC- and FITC-labeled dextrans were injected at different levels to confirm topography. Terminations consistently occurred in two main locations: a distinguishable portion of posterolateral thalamus identified cytoarchitectonically as the posterior part of the ventral medial nucleus (VMpo) and a portion of posteromedial thalamus designated as the ventral caudal part of the medial dorsal nucleus (MDvc). In addition, isolated fibers bearing boutons of passage were observed in the ventral posterior medial and lateral (VPM and VPL) nuclei, and spinal terminations occurred in the ventral posterior inferior nucleus (VPI). Isolated terminations occasionally occurred in other sites (e.g., suprageniculate, zona incerta, hypothalamic paraventricular n.). Terminations in MDvc occurred in concise foci that were weakly organized topographically (posteroanterior = rostrocaudal). Terminations in VMpo consisted of dense clusters of ramified terminal arbors bearing multiple large boutons that were well organized topographically (anteroposterior = rostrocaudal). Terminations in VMpo colocalized with a field of calbindin-immunoreactive terminal fibers; double-labeled terminals were documented at high magnification. This propitious marker was especially useful at anterior levels, where VMpo can easily be misidentified as VPM. These findings demonstrate phylogenetically novel primate lamina I TSTT projections important for sensory and motivational aspects of pain, temperature, itch, muscle ache, sensual touch, and other interoceptive feelings from the body.

Animals↗

PubMed2006

Afferents to the orexin neurons of the rat brain.

Emotions, stress, hunger, and circadian rhythms all promote wakefulness and behavioral arousal. Little is known about the pathways mediating these influences, but the orexin-producing neurons of the hypothalamus may play an essential role. These cells heavily innervate many wake-promoting brain regions, and mice lacking the orexin neurons have narcolepsy and fail to rouse in response to hunger (Yamanaka et al. [2003] Neuron 38:701-713). To identify the afferents to the orexin neurons, we first injected a retrograde tracer into the orexin neuron field of rats. Retrogradely labeled neurons were abundant in the allocortex, claustrum, lateral septum, bed nucleus of the stria terminalis, and in many hypothalamic regions including the preoptic area, dorsomedial nucleus, lateral hypothalamus, and posterior hypothalamus. Retrograde labeling in the brainstem was generally more modest, but labeling was strong in the periaqueductal gray matter, dorsal raphe nucleus, and lateral parabrachial nucleus. Injection of an anterograde tracer confirmed that most of these regions directly innervate the orexin neurons, with some of the heaviest input coming from the lateral septum, preoptic area, and posterior hypothalamus. In addition, hypothalamic regions preferentially innervate orexin neurons in the medial and perifornical parts of the field, but most projections from the brainstem target the lateral part of the field. Inputs from the suprachiasmatic nucleus are mainly relayed via the subparaventricular zone and dorsomedial nucleus. These observations suggest that the orexin neurons may integrate a variety of interoceptive and homeostatic signals to increase behavioral arousal in response to hunger, stress, circadian signals, and autonomic challenges.

Afferent Pathways↗

PubMed2006

Retrograde analyses of spinothalamic projections in the macaque monkey: input to posterolateral thalamus.

The distribution of retrogradely labeled spinothalamic tract (STT) neurons was analyzed in macaque monkeys following variously sized, physiologically guided pressure or iontophoretic injections of cholera toxin subunit B (CTb) in order to determine whether different STT termination sites receive input selectively from different sets of STT cells. This report focuses on posterolateral thalamus, where prior anterograde tracing observations identified the posterior part of the ventromedial nucleus (VMpo) as the major projection target of lamina I STT neurons. Large injections in posterolateral thalamus labeled predominantly STT cells in lamina I throughout the spinal cord. In cases with medium-sized or small injections centered in VMpo, almost all labeled STT cells ( approximately 90%) were lamina I neurons. Small injections revealed a posteroanterior (foot to hand) somatotopographic organization consistent with that observed in prior anterograde tracing work; injections in posterior VMpo labeled primarily lumbosacral lamina I cells, whereas injections placed more anteriorly in VMpo labeled primarily cervical lamina I cells. These findings support the concept that VMpo is a primate lamina I spinothalamocortical relay nucleus important for pain, temperature, itch, muscle ache, sensual touch, and other interoceptive feelings from the body, and they provide strong evidence for the general hypothesis that the STT consists of several functionally and anatomically differentiable components.

Animals↗

PubMed1985

The central neural connections of the area postrema of the rat.

We applied the neuroanatomical tracers cholera toxin-horseradish peroxidase and wheat germ agglutinin-horseradish peroxidase to investigate the neural connections of the area postrema (AP) in the rat. We find that the AP projects to the nucleus of the solitary tract (NTS) and dorsal motor nucleus of the vagus bilaterally both rostral and caudal to obex; the nucleus ambiguus; the dorsal aspect of the spinal trigeminal tract and nucelus and the paratrigeminal nucleus; the region of the ventrolateral medullary catecholaminergic column; the cerebellar vermis; and a cluster of structures in the dorsolateral pons which prominently include a discrete set of subnuclei in the lateral parabrachial nucleus. The major central afferent input to the area postrema is provided by a group of neurons in the paraventricular and dorsomedial hypothalamic nuclei whose collective dendrites describe a horizontally oriented plexus which encircles the parvocellular nucleus of the hypothalamus bilaterally. In addition, the caudal NTS may project lightly to the AP. The lateral parabrachial nucleus provides a very light input as well. These connections, when considered in the context of the known vagal afferent input and reduced blood-brain barrier of AP, place this structure in a unique position to receive and modulate ascending interoceptive information and to influence autonomic outflow as well.

Afferent Pathways↗

PubMed1995

A1 catecholamine cell group: fine structure and synaptic input from the nucleus of the solitary tract.

Preembedding immunoperoxidase staining methods were used to characterize tyrosine hydroxylase-immunoreactive (TH-ir) elements in the caudal ventrolateral medulla, and to determine the extent to which neurons of the A1 cell group are directly innervated by projections of the nucleus of the solitary tract (NTS). TH-ir neurons in the A1 region were medium-sized and multipolar. They possessed rounded nuclei with infrequent invaginations, well-developed Golgi apparati, high cytoplasmic densities of mitochondria, and a low to moderate tendency for rough endoplasmic reticulum (RER) to align in parallel stacks. A1 cell bodies were commonly juxtaposed to TH-positive and TH-negative neurons, myelinated profiles, glia and/or vascular elements, but close membrane appositions were only seen with glial elements. Synaptic input to A1 neurons was predominantly asymmetric, provided virtually exclusively by non-TH-ir terminals, and directed principally to dendritic shafts; A1 somata are relatively sparsely innervated. In a second experiment, silver-intensified immunogold localization of TH-ir was combined with immunoperoxidase labeling for anterogradely transported Phaseolus vulgaris-leucoagglutinin (PHA-L), following tracer injections in the caudal aspect of the medial division of the NTS. These experiments revealed a small proportion of PHA-L-labeled axon terminals that made asymmetric contacts with dendritic shafts of TH-ir neurons. These results suggest that the fine structure and synaptic input of A1 neurons are somewhat distinct from that of rostrally situated C1 catecholamine cells. In addition, while they document a direct NTS-A1 projection that may participate in the interoceptive control of vasopressin secretion, the bulk of ventrolaterally directed projections from the caudomedial NTS contact noncatecholaminergic elements in the A1 region, some of which may correspond to so-called depressor neurons implicated in the baroreflex control of sympathetic outflow and vasopressin secretion.

Animals↗

PubMed2003

Six-month open trial of haloperidol as an adjunctive treatment for anorexia nervosa: a preliminary report.

OBJECTIVE: To evaluate the effectiveness of haloperidoll as an adjunctive treatment for resistant anorexia nervosa restricting subtype (AN-R). METHOD: Thirteen outpatients with treatment-resistant AN-R were treated for 6 months with haloperidol in addition to standard treatment. Treatment resistance was defined as persistent and resistant anorectic symptoms despite multiple standard therapies. Assessments were carried out at baseline and after 1, 3, and 6 months with the Eating Disorder Inventory (EAT), the Eating Attitude Test (EAT), and the Clinical Global Impression and Improvement Scale (CGI-I). RESULTS: Significant change from baseline to end point was observed on EDI total score (p =.02) and on the subscales Drive for Thinness (p =.009), Bulimia (p =.01), and Interoceptive Awareness (p =.02), as well as on the EAT (p =.009) and CGI scores (p =.001). Body mass index changed significantly from baseline (15.7 +/- 1.9) to end point (18.1 +/- 2.5; p =.03). DISCUSSION: These preliminary data suggest that low doses of haloperidol might be effective as an adjunctive treatment for patients with severe AN-R. Larger controlled studies are warranted to confirm these data.

Adrenergic Uptake Inhibitors↗

PubMed2003

A test of the continuity perspective across bulimic and binge eating pathology.

OBJECTIVE: This article examines the continuity/discontinuity perspective of eating pathology among 375 women seeking treatment. METHODS: Participants were categorized into five separate groups: obese nonbingers, subthreshold binge eating disorder (BED), BED, subthreshold bulimics, and bulimics. We tested whether differences in core eating pathology (drive for thinness, body dissatisfaction, current body image, body image ideal) and psychiatric symptoms (depression, interoceptive awareness) differentiated the groups quantitatively (supporting the continuity perspective) or qualitatively (supporting the discontinuity perspective). RESULTS: Our results, overall, supported the continuity perspective of eating pathology. A discriminant function analysis using the eating pathology and psychiatric symptom variables as predictor variables found that one primary factor differentiated the five groups on both core eating pathology and psychiatric variables. DISCUSSION: The implications of testing this model within a treatment-seeking sample are discussed.

Adolescent↗

PubMed2006

The influence of sex on extracellular dopamine and locomotor activity in C57BL/6J mice before and after acute cocaine challenge.

C57BL6/J (C57) mice serve as a useful animal model of cocaine abuse because they self-administer cocaine, exhibit place conditioning to cocaine, discriminate the interoceptive cues of cocaine, and are used for backcrossing strains of genetically modified mice. The present study was to examine the influence of sex on extracellular DA and locomotor activity in C57 mice in response to acute cocaine challenge. In the first experiment, male and female mice were implanted with guide cannulae aimed at the dorsal striatum. Microdialysates were collected in three consecutive phases: baseline, post-saline injection, and post-cocaine injection. Sex did not influence DA measurements during baseline or after intraperitoneal (i.p.) saline injection. Cocaine (20 mg/kg) injections increased peak extracellular DA of both sexes, and the increase was greater for males (278%+/-14.0%) than females (182.5%+/-10.8%) (P<0.05). In the second experiment, under conditions similar to the microdialysis experiment, locomotor activity of male and female mice was assessed during baseline, after saline injection, and after cocaine injection (5, 10, 20, or 40 mg/kg). Cocaine dose-dependently increased activity; however, sex did not influence locomotor activity during baseline, after saline, or after any cocaine dose. Results of the experiments established that cocaine (20 mg/kg) increased extracellular DA in the dorsal striatum to a greater extent in male than in female mice; however, when cocaine was administered under similar experimental conditions, sex did not influence cocaine stimulation of locomotor activity over a wide range of doses.

Animals↗

PubMed2002

The neuroanatomical axis for control of energy balance.

The hypothalamic feeding-center model, articulated in the 1950s, held that the hypothalamus contains the interoceptors sensitive to blood-borne correlates of available or stored fuels as well as the integrative substrates that process metabolic and visceral afferent signals and issue commands to brainstem mechanisms for the production of ingestive behavior. A number of findings reviewed here, however, indicate that sensory and integrative functions are distributed across a central control axis that includes critical substrates in the basal forebrain as well as in the caudal brainstem. First, the interoceptors relevant to energy balance are distributed more widely than had been previously thought, with a prominent brainstem complement of leptin and insulin receptors, glucose-sensing mechanisms, and neuropeptide mediators. The physiological relevance of this multiple representation is suggested by the demonstration that similar behavioral effects can be obtained independently by stimulation of respective forebrain and brainstem subpopulations of the same receptor types (e.g., leptin, CRH, and melanocortin). The classical hypothalamic model is also challenged by the integrative achievements of the chronically maintained, supracollicular decerebrate rat. Decerebrate and neurologically intact rats show similar discriminative responses to taste stimuli and are similarly sensitive to intake-inhibitory feedback from the gut. Thus, the caudal brainstem, in neural isolation from forebrain influence, is sufficient to mediate ingestive responses to a range of visceral afferent signals. The decerebrate rat, however, does not show a hyperphagic response to food deprivation, suggesting that interactions between forebrain and brainstem are necessary for the behavioral response to systemic/ metabolic correlates of deprivation in the neurologically intact rat. At the same time, however, there is evidence suggesting that hypothalamic-neuroendocrine responses to fasting depend on pathways ascending from brainstem. Results reviewed are consistent with a distributionist (as opposed to hierarchical) model for the control of energy balance that emphasizes: (i) control mechanisms endemic to hypothalamus and brainstem that drive their unique effector systems on the basis of local interoceptive, and in the brainstem case, visceral, afferent inputs and (ii) a set of uni- and bidirectional interactions that coordinate adaptive neuroendocrine, autonomic, and behavioral responses to changes in metabolic status.

Animals↗

PubMed1995

The differences in learning abilities between spontaneously hypertensive (SHR) and Wistar normotensive rats are cue dependent.

We examined the performance of spontaneously hypertensive (SHR) and Wistar normotensive (NT) rats in acquisition, retention after a 2-month interval, and reversal learning in two tasks: simultaneous brightness discrimination (Experiment I) and conditional discrimination of directional locomotor responses (Experiment II). In both tasks food reinforcement was used. In Experiment I both SHR and NT groups comprised younger (3-month-old) and older (10-month-old) rats. In each experimental stage SHRs of both age groups mastered the task earlier and made fewer errors than the respective NT groups. Reversal learning took longer than acquisition of discrimination in both age groups of NT rats. Conversely, reversal learning was an easier task for SHR. In Experiment II only younger rats were used. The forced turn at the start in the modified T-maze was utilized as the cue to guide performance at the choice point of the maze. In acquisition and retention, rats were trained to select at the choice point the arm in the same direction as in the forced turn; in the reversal, opposite contingencies were applied. At all stages the choice accuracy of SHR was the same as that in NT rats. The contrasting findings of Experiment I and Experiment II indicate that SHR learned better than NT when exteroceptive visual stimuli were used, but performed at the same level as NT rats in the task where interoceptive kinesthetic cues were relevant. We suggest that SHR pay more attention to visual stimuli than NT rats.

Age Factors↗

PubMed1998

Facilitatory and inhibitory actions of morphine on the discriminative stimulus properties of D-amphetamine.

Facilitatory and inhibitory actions of morphine on the discriminative stimulus properties of D-amphetamine were examined in rats trained to discriminate D-amphetamine (1 mg kg-1) from saline in a two-lever food reinforced operant task. Morphine (0.625-2.5 mg kg-1) did not itself generalize to amphetamine. When the percentages of rats selecting the drug-appropriate lever were plotted as a function of the individual lowest generalized dose (LGD), a log-linear model fitted to cell frequency indicated a rising single quote, left (low)morphinexamphetaminexlever selection' interaction. Subsequent comparisons indicated that morphine significantly increased or decreased drug lever selection in rats receiving one-half LGD or LGD, respectively. In both cases no difference was found among morphine doses. The present study confirms that the discriminative stimulus properties of amphetamine can be both potentiated and attenuated by morphine. The direction to which morphine modulates the interoceptive effects of 1 mg kg-1 amphetamine seems to be dependent on the individual sensitivity of animals to amphetamine rather than on the overall effect of the test dose of amphetamine alone. (c) 1998 The Italian Pharmacological Society.

Animals↗

PubMed1988

Similarities and differences between behavioral control by drug-produced stimuli and by sensory stimuli.

Drug-induced state-dependent learning and drug discriminations may be based on sensory stimuli induced by drug actions, or at least on events in the brain that have properties analogous to those of sensory stimuli. A variety of comparisons between behavioral control by drug-induced stimuli and by classically defined interoceptive and exteroceptive stimuli are possible. These allow inferences to be made about the nature of drug stimuli, the properties of behavioral paradigms that we use to investigate them, and the mechanisms by which drugs achieve behavioral control in drug discrimination and state-dependent learning paradigms. Each of these topics is selectively reviewed in this paper.

Animals↗

PubMed1986

The effect of training dose on discrimination of compound drug-exteroceptive stimuli.

Rats were trained to discriminate between two compound stimulus arrays that included exteroceptive (ES) and interoceptive (IS) stimulus components. The ES components were illumination and tactile cues, and the IS components were produced by d-amphetamine (A) or Na pentobarbital (P) treatment (drug versus drug discrimination). The relative ES-IS strength was then determined by testing with "mismatched" stimulus arrays consisting of combinations of ES and IS components that had not been presented simultaneously during training. Additional tests were done with ES only (no drug treatments). At training doses of 0.8 mg/kg A versus 10 mg/kg P, the ES were less salient than, but did share stimulus control with, the stronger IS components. In a second group, trained with lower doses (0.5 mg/kg A versus 4 mg/kg P), the ES were much more salient than the IS, although again, both types of stimuli did acquire some control. This dose-related sharing of stimulus control between ES and IS components is similar to relationships among components of compound arrays consisting entirely of ES, and thus further illustrates similarity between drug-produced and exteroceptive stimuli.

Animals↗

PubMed1986

Rolipram forms a potent discriminative stimulus in drug discrimination experiments in rats.

Long Evans rats were trained to discriminate 0.2 mg/kg IP (+/-)-rolipram from vehicle injection in a food-motivated two-lever operant task. Eight out of nine rats acquired the discrimination after an average of 91 sessions (min 65, max 137). The ED50 of (+/-)-rolipram was 0.06 mg/kg IP. Generalization tests with (-)- and (+)-rolipram showed that the (-)-isomer was 8 times more active than (+)-rolipram with an ED50 of 0.06 and 0.4 mg/kg IP respectively. The phosphodiesterase inhibitor RO 20-1724 partially (83%) generalized to (+/-)-rolipram in doses of 0.6 and 1.0 mg/kg IP. IBMX 5 mg/kg IP showed 63% generalization. Tests with imipramine and the (+)- and (-)-isomer of the noradrenaline uptake inhibitor oxaprotiline suggest that NA-uptake inhibiting drugs do not form an interoceptive cue which is (+/-)-rolipram-like. dbcAMP 12.5 mg/kg SC and 100 mg/kg SC dbcGMP did not generalize to the training drug. The nature of the discriminative stimulus produced by this dose of (+/-)-rolipram in rats remains to be elucidated.

Animals↗