Neural bases of reward anticipation in healthy individuals with low, mid, and high levels of schizotypy.

A growing body of research has placed the ventral striatum at the center of a network of cerebral regions involved in anticipating rewards in healthy controls. However, little is known about the functional connectivity of the ventral striatum associated with reward anticipation in healthy controls. In addition, few studies have investigated reward anticipation in healthy humans with different levels of schizotypy. Here, we investigated reward anticipation in eighty-four healthy individuals (44 females) recruited based on their schizotypy scores. Participants performed a variant of the Monetary Incentive Delay Task while undergoing event-related fMRI.Participants showed the expected decrease in response times for highly rewarded trials compared to non-rewarded trials. Whole-brain activation analyses replicated previous results, including activity in the ventral and dorsal striatum. Whole-brain psycho-physiological interaction analyses of the left and right ventral striatum revealed increased connectivity during reward anticipation with widespread regions in frontal, parietal and occipital cortex as well as the cerebellum and midbrain. Finally, we found no association between schizotypal personality severity and neural activity and cortico-striatal functional connectivity. In line with the motivational, attentional, and motor functions of rewards, our data reveal multifaceted cortico-striatal networks taking part in reward anticipation in healthy individuals. The ventral striatum is connected to regions of the salience, attentional, motor and visual networks during reward anticipation and thereby in a position to orchestrate optimal goal-directed behavior.

Reduced Neural Satiety Responses in Women Affected by Obesity.

Overweight and obesity are major risk factors for a number of chronic diseases, including diabetes, cardiovascular diseases, and cancer. Obesity rates are on the rise worldwide with women more frequently affected than men. Hedonic responses to food seem to play a key role in obesity, but the exact mechanisms and relationships are still poorly understood. In this study, we investigate the perceived pleasantness of food rewards in relation to satiety and calories consumed during an ad libitum meal in women. Using functional magnetic resonance imaging (fMRI) and a milkshake consumption task, we studied how experienced food values are encoded in women with healthy weight, overweight or obesity. Participants rated the pleasantness and intensity of high and low caloric milkshakes in the fMRI scanner during both the fasted and fed states. We found differences in the neural responses and experienced pleasantness of high and low caloric milkshakes depending on satiety and Body Mass Index (BMI). Women with both high ad libitum consumption levels and high BMI reported greater experienced pleasantness for milkshakes. In contrast, among women with low ad libitum consumption levels, greater BMI was associated with less experienced pleasantness. At the neural level, satiety affected women with obesity to a lesser degree than women with healthy weight. Thus, having obesity was associated with altered relationships between food consumption and the hedonic responses to food rewards as well as reduced satiety effects in women.

Sensitivity to gains during risky decision-making differentiates chronic cocaine users from stimulant-naïve controls.

BACKGROUND: Chronic cocaine use has been consistently associated with decision-making impairments that contribute to the development and maintenance of drug-taking. However, the underlying cognitive processes of risk-seeking behaviours observed in chronic cocaine users (CU) have so far remained unclear. Here we therefore tested whether CU differ from stimulant-naïve controls in their sensitivity to gain, loss, and probability of loss information when making decisions under risk. METHOD: A sample of 96 participants (56 CU and 40 controls) performed the no-feedback version of the Columbia Card Task, designed to assess risk-taking in relation to gain, loss, and probability of loss information. Additionally, cognitive performance and impulsivity were determined. Current and recent substance use was objectively assessed by toxicological urine and hair analysis. RESULTS: Compared to controls, CU showed increased risk-seeking in unfavourable decision scenarios in which the loss probability was high and the returns were low, and a tendency for increased risk aversion in more favourable decision scenarios. In comparison to controls, CU were less sensitive to gain, but similarly sensitive to loss and probability of loss information. Further analysis revealed that individual differences in sensitivity to loss and probability of loss information were related to cognitive performance and impulsivity. CONCLUSION: Reduced sensitivity to gains in people with CU may contribute to their propensity for making risky decisions. While these alterations in gain sensitivity might directly relate to cocaine use per se, the individual psychopathological profile of CU might moderate sensitivity to loss information.

Adaptive Value Normalization in the Prefrontal Cortex Is Reduced by Memory Load.

Adaptation facilitates neural representation of a wide range of diverse inputs, including reward values. Adaptive value coding typically relies on contextual information either obtained from the environment or retrieved from and maintained in memory. However, it is unknown whether having to retrieve and maintain context information modulates the brain's capacity for value adaptation. To address this issue, we measured hemodynamic responses of the prefrontal cortex (PFC) in two studies on risky decision-making. In each trial, healthy human subjects chose between a risky and a safe alternative; half of the participants had to remember the risky alternatives, whereas for the other half they were presented visually. The value of safe alternatives varied across trials. PFC responses adapted to contextual risk information, with steeper coding of safe alternative value in lower-risk contexts. Importantly, this adaptation depended on working memory load, such that response functions relating PFC activity to safe values were steeper with presented versus remembered risk. An independent second study replicated the findings of the first study and showed that similar slope reductions also arose when memory maintenance demands were increased with a secondary working memory task. Formal model comparison showed that a divisive normalization model fitted effects of both risk context and working memory demands on PFC activity better than alternative models of value adaptation, and revealed that reduced suppression of background activity was the critical parameter impairing normalization with increased memory maintenance demand. Our findings suggest that mnemonic processes can constrain normalization of neural value representations.

Dopamine D2/3- and µ-opioid receptor antagonists reduce cue-induced responding and reward impulsivity in humans.

Increased responding to drug-associated stimuli (cue reactivity) and an inability to tolerate delayed gratification (reward impulsivity) have been implicated in the development and maintenance of drug addiction. Whereas data from animal studies suggest that both the dopamine and opioid system are involved in these two reward-related processes, their role in humans is less clear. Moreover, dopaminergic and opioidergic drugs have not been directly compared with regard to these functions, even though a deeper understanding of the underlying mechanisms might inform the development of specific treatments for elevated cue reactivity and reward impulsivity. In a randomized, double-blind, between-subject design we administered the selective dopamine D2/D3 receptor antagonist amisulpride (400 mg, n=41), the unspecific opioid receptor antagonist naltrexone (50 mg, n=40) or placebo (n=40) to healthy humans and measured cue-induced responding with a Pavlovian-instrumental transfer task and reward impulsivity with a delay discounting task. Mood was assessed using a visual analogue scale. Compared with placebo, amisulpride significantly suppressed cue-induced responding and reward impulsivity. The effects of naltrexone were similar, although less pronounced. Both amisulpride and naltrexone decreased average mood ratings compared with placebo. Our results demonstrate that a selective blockade of dopamine D2/D3 receptors reduces cue-induced responding and reward impulsivity in healthy humans. Antagonizing µ-opioid receptors has similar effects for cue-induced responding and to a lesser extent for reward impulsivity.

Fatal attraction: ventral striatum predicts costly choice errors in humans.

Animals approach rewards and cues associated with reward, even when this behavior is irrelevant or detrimental to the attainment of these rewards. Motivated by these findings we study the biology of financially-costly approach behavior in humans. Our subjects passively learned to predict the occurrence of erotic rewards. We show that neuronal responses in ventral striatum during this Pavlovian learning task stably predict an individual's general tendency towards financially-costly approach behavior in an active choice task several months later. Our data suggest that approach behavior may prevent some individuals from acting in their own interests.

Functional organisation of the saccadic reference system processing extraretinal signals in humans.

In order to investigate the neuronal network involved in processing extraretinal signals, functional magnetic resonance imaging (fMRI) was applied to subjects performing the double step saccade paradigm. There, the calculation of the amplitude of the second saccade must rely on extraretinal signals of the first. When compared to a task where both saccades could be performed by means of retinal signals alone, a parieto-frontal cortical network was activated, including lateral intraparietal area, precuneus, insula, inferior frontal gyrus and anterior cingulum.

Total versus unspecific binding: standardization and optimization of receptor-ligand binding assays.

Intra- and interassay imprecision was evaluated in 3 in vitro ligand binding assays using different types of filtering devices, glass fiber filters and variations in methodology. In the [3H]-spiroperidol test, the already low unspecific binding seemed to be dependent on the type of filters employed, whereas in the [3H]-ketanserin- and [3H]-GR 65630-binding tests, differences were within the range of the normal variabilities. However, in the latter test, which is problematic owing to the high unspecific binding of [3H]-GR 65630, it was found that although the percentage of specific binding was fairly constant on different sheets, large differences in the absolute amounts of total and unspecific binding were observed on consecutive sheets in the same experiment. Thus, it is critically important to filter samples for total and unspecific binding together on the same filter sheet for the calculation of specific binding. Under these precautions, highly reproducible results for IC50-values in the screening of potential 5HT3-receptor ligands were obtained in spite of using rat entorhinal cortex, a relatively large area with suboptimal 5HT3-receptor density. In contrast, when using rat area postrema, which is optimal with respect to receptor density, more than 10 times the number of rats is necessary for a competition experiment due to the small size of this brain part. Since IC50-values for both areas compare favorably, entorhinal cortex should be used for ethical reasons and to minimize costs.

High-performance liquid chromatographic system for the separation of dynorphin A (1-17) fragments and its application in enzymolysis studies with rat nerve terminal membranes.

A high-performance liquid chromatographic method capable of separating a large number of C- and N-terminal degradation fragments of dynorphin A (1-17) (dyn 1-17) in 1 h has been developed. The system has been applied to study the metabolism profiles of various dyn 1-17-derived peptides following in vitro incubation with rat striatum and spinal cord nerve terminal membranes. In addition to the removal of the N-terminal amino acid Tyr, major sites of cleavage between the following amino acids could be established: Leu5-Arg6 in dyn 1-7 (formation of dyn 1-5); Arg6-Arg7 and Leu5-Arg6 in dyn 1-8 (formation of dyn 1-6 and dyn 1-5, respectively); Arg7-Ile8 in dyn 1-9 (formation of dyn 1-7) and Arg9-Pro10 in dyn 1-10 (formation of dyn 1-9). Studies with inhibitors of the enzymes involved show that dyn 1-5 is formed directly from dyn 1-8 via an endopeptidase insensitive to the angiotensin-converting enzyme inhibitor MK 422 acting on the scissile Leu5-Arg6 bond in dyn 1-8. The method circumvents the use of [3H]Tyr-labelled dynorphins, which have the inherent drawback that fragments lacking the N-terminal Tyr cannot be detected. Owing to the high resolution, also for the larger dynorphins dyn 1-14, dyn 1-15 and dyn 1-16, the chromatographic system should prove especially useful in the elucidation of the enzymolysis pattern of dyn 1-17. Furthermore, the method offers a way to evaluate simultaneously the selectivity of new enzyme inhibitors for several cleavage sites in the same assay.

Calcitonin gene-related peptide and its binding sites in the human central nervous system and pituitary.

Binding sites for synthetic human 125I-labeled calcitonin gene-related peptide (125I-CGRP) have been demonstrated in membranes of the human nervous system. Binding was high in the cerebellar cortex (1.35 +/- 0.27 fmol/mg of tissue; mean +/- SEM), spinal cord (1.06 +/- 0.27 to 1.27 +/- 0.23 fmol/mg), and nucleus dentatus (1.02 +/- 0.15 fmol/mg), intermediate in the inferior colliculus (0.80 +/- 0.14 fmol/mg) and substantia nigra (0.75 +/- 0.14 fmol/mg), low in the neocortex, globus pallidus, nucleus caudatus, hippocampus, amygdala, superior colliculus, thalamus, and hypothalamus (0.15-0.32 fmol/mg), and negligible in spinal and sympathetic ganglia and pituitary (less than 0.04 fmol/mg). Autoradiography showed distinct 125I-CGRP binding over the molecular and Purkinje cell layers of the cerebellar cortex and over the substantia gelatinosa posterior of the spinal cord. The highest levels of CGRP-like components were recognized in the dorsal part of the spinal cord and the pituitary gland. In the ventral part of the spinal cord as well as in the pituitary and thyroid glands, CGRP values were higher when measured by radioreceptorassay as compared to RIA, indicating that at least two CGRP-like components are present. The predominant CGRP-like peak on HPLC had the retention time of synthetic human CGRP. Immunohistochemistry revealed the presence of a dense plexus of CGRP immunoreactive nerve fibers in the dorsal horn of the spinal cord.

Distribution of intraventricular salmon calcitonin and suppression of gastric secretion.

Intracerebroventricularly (ICV) administered [125I] salmon calcitonin (sCT) was rapidly transported to the blood, but the permeability of the blood-brain barrier to sCT was low. ICV injected intact [125I]sCT was predominantly deposited in the periventricular mesencephalon and in the kidneys, and intravenously (IV) injected [125I]sCT in the kidneys, respectively. After both ICV and IV administration [125I]sCT was not retained by the stomach in large amounts. ICV and subcutaneously (SC) injected sCT caused suppression of gastric secretion volume, and of acid and pepsin outputs; the potency ratios between half maximal inhibitory amounts of sCT administered SC and ICV were 161, 252 and 13, respectively. On the other hand, perfusion of isolated whole mouse stomachs with sCT did not affect basal or stimulated acid and pepsin secretion. These findings indicate that sCT inhibits gastric acid secretion via receptors localized in the hypothalamus and in adjacent areas of the brain.

Calcitonin gene-related peptide in the human thyroid, pituitary and brain.

Alternative splicing of rat calcitonin (CT) gene transcripts resulting in the production of calcitonin gene-related peptide (CGRP) in neural tissue and of CT in the thyroid has been proposed by Rosenfeld et al. (1983b). We have recognized CGRP- and CT-like peptides in extracts of the human brain, pituitary and thyroid using a combination of gel filtration analysis and HPLC, and specific RIAs. Immunoreactive CGRP was estimated in a heterologous RIA using 125I-labelled rat CGRP as ligand and antibodies raised to the rat hormone, and human CT in a homologous RIA. The levels of CGRP and CT are measured against synthetic rat CGRP and monomeric human CT, respectively, and expressed in ng and micrograms equivalents (eq). The content of immunoreactive CGRP of the neocortex (n = 3), the cerebellar cortex (n = 6), the periventricular mesencephalic region (n = 3) and the thyroid (n = 5) was similar (mean +/- SE, 0.79 +/- 0.16 ng eq/g wet tissue, 1.51 +/- 0.14 ng eq/g, 1.84 +/- 0.12 ng eq/g and 5.0 +/- 0.9 ng eq/g, respectively), whereas pituitary glands (n = 21) and medullary thyroid carcinomas (n = 6) contained higher levels (31.3 +/- 5.1 ng eq/g and 7.66 +/- 5.42 micrograms eq/g, respectively). Immunoreactive CT was lowest in the neocortex, cerebellar cortex and the periventricular mesencephalon (0.31 +/- 0.07 ng eq/g, 0.30 +/- 0.09 ng eq/g and 0.26 +/- 0.09 ng eq/g, respectively), followed by the pituitary and thyroid (2.77 +/- 0.62 ng eq/g and 146 +/- 26 ng eq/g, respectively), and was highest in medullary thyroid carcinoma tissue (680 +/- 372 micrograms eq/g).(ABSTRACT TRUNCATED AT 250 WORDS)

Salmon and human calcitonin-like peptides in man.

Calcitonin-like peptides have been identified in the serum of normal subjects and of medullary thyroid carcinoma (MTC) patients. Using specific homologous radioimmunoassays (RIA) in combination with reversed-phase high performance liquid chromatography and gel permeation chromatography under denaturing conditions, we have recognized major components which coeluted with human calcitonin-(1-32), PDN-21, a carboxyl-terminal flanking peptide derived from the calcitonin mRNA sequence, and salmon calcitonin-(1-32). An additional 12000 molecular weight peak possibly represents a human calcitonin-PDN-21 polyprotein. In both the human calcitonin-(1-32) (normal value less than 0.043 ngEq/ml; MTC 140 +/- 80 ngEq/ml, mean value +/- SEM) and the PDN-21 (normal value less than 0.050 ngEq/ml; MTC 33.6 +/- 16.5 ngEq/ml) RIAs, serum levels were increased in MTC patients. Circulating levels of the salmon calcitonin-like peptide were indistinguishable between normal subjects (0.038 +/- 0.006 ngEq/ml) and MTC patients (0.037 +/- 0.011 ngEq/ml).

Salmon and human calcitonin-like peptides coexist in the human thyroid and brain.

A salmon calcitonin-like material indistinguishable from synthetic salmon calcitonin-(1-32) on high performance liquid chromatography (HPLC) has been recognized in thyroid extracts of normal subjects and of patients with medullary carcinoma. The same peptide was detected in extracts of the periventricular mesencephalic region which included the periventricular dorsal thalamus, the subthalamus and the hypothalamus. Human calcitonin-(1-32)- and carboxyl-terminal adjacent peptide (CCAP)-like components were also found. The content of immunoreactive salmon calcitonin of the periventricular mesencephalic region (n = 6) and of normal thyroid glands (n = 6) was comparable (mean +/- SE, 0.34 +/- 0.17 ngeq/g wet tissue and 0.39 +/- 0.22 ngeq/g, respectively); and the levels were slightly, but not significantly higher in medullary thyroid carcinoma extracts (1.95 +/- 0.69 ngeq/g) (P less than 0.1). Immunoreactive human calcitonin and CCAP occurred in roughly equimolar concentrations. They were lowest in the periventricular mesencephalic region (0.26 +/- 0.09 ngeq/g and 0.46 +/- 0.10 ngeq/g, respectively), followed by normal thyroid glands (146 +/- 26 ngeq/g and 94 +/- 19 ngeq/g, respectively), and they were highest in medullary thyroid carcinoma tissue (680 +/- 372 mu geq/g and 144 +/- 125 mu geq/g, respectively).

Identification and characterization of calcitonin forms in plasma and urine of normal subjects and medullary carcinoma patients.

Different immunoreactive calcitonin (CT) forms were identified by a reversed phase high performance liquid chromatography gradient system in plasma and urine of normal subjects. The separated CT components were characterized by chemical and enzymatic methods and found to be identical in normal subjects and medullary thyroid carcinoma patients. Of seven major CT forms we identified monomeric human CT-(1-32), its sulfoxide form, and dimeric CT in plasma. The monomeric, but not the dimeric form, was also detected in urine. A predominant CT component in plasma with a molecular weight of about 12,000 may correspond to a biosynthetic precursor of the hormone.

Potassium stimulates parathyroid hormone release in the absence of extracellular calcium.

Potassium-stimulated release of many hormones requires the presence of extracellular calcium. At variance with this mechanism, potassium-evoked parathyroid hormone (PTH) release from perifused dispersed bovine parathyroid cells also occurred in calcium-free medium containing 1 mM EGTA. Tetraethylammonium, which presumably suppresses the efflux of potassium from parathyroid cells, also stimulated PTH secretion. Removal of sodium did not suppress potassium-stimulated PTH secretion, but inhibited the release of the hormone evoked by calcium removal and by isoproterenol. Ouabain, on the other hand, suppressed the release of PTH evoked by calcium removal and by potassium, but not by isoproterenol. Unlike high potassium and removal of calcium, isoproterenol caused a parallel increase in cAMP release. In conclusion, PTH secretion is reversibly stimulated by potassium in the absence of extracellular calcium. Our findings suggest that potassium stimulates PTH secretion by a unique mechanism the nature of which remains to be elucidated.

Localization of salmon calcitonin binding sites in rat brain by autoradiography.

The regional distribution of [125I]salmon calcitonin (sCT) binding sites was examined in rat brain by receptor autoradiography. Dense specific labeling was recognized over the hypothalamus, preoptic and accumbent nuclei, amygdala, zona incerta, interpeduncular nucleus, periventricular gray and the reticular formation. Intermediate binding was seen over the arcuate and supramamillary nuclei and substantia nigra, and no binding in the neocortex, cerebellum, thalamus, basal ganglia and mamillary bodies. The well defined topographical distribution strongly indicates physiological roles for sCT in the mammalian brain.

Rapidity of plasma 1,25-dihydroxyvitamin D responses to hypo- and hypercalcemia in steers.

Experiments were designed to study the rapidity of changes in plasma 1,25-dihydroxyvitamin D [1,25-(OH)2D] levels in response to hypercalcemia and hypocalcemia induced by 10-h infusions of CaCl2 or EGTA in steers. In response to CaCl2 infusions, 1,25-(OH)2D was decreased within 4 h (P less than 0.05) and remained lower (P less than 0.05) than preinfusion concentrations for up to 14 h after termination of the infusions. PTH and inorganic phosphate (Pin) transiently decreased in response to the CaCl2 infusions, whereas total magnesium (Mg) continuously fell for up to 24 h after the start of the infusions. In response to infusions with EGTA, on the other hand, 1,25-(OH)2D continuously increased and was raised significantly (P less than 0.05) between 12 and 24 h after the start of the infusions. PTH increased within 2 h (P less than 0.05) and remained elevated (P less than 0.05) for up to 2 h after the end of the EGTA infusions, whereas Pin and Mg were not significantly changed. During and after 10-h control infusions of sodium chloride, the levels of 1,25-(OH)2D, PTH, Ca, Ca++, Pin, and Mg remained unaltered. In conclusion, plasma levels of 1,25-(OH)2D were lowered in response to hypercalcemia within 4 h and increased in response to hypocalcemia within 12 h. After termination of the infusions with CaCl2 or EGTA, levels of 1,25-(OH)2D remained decreased or elevated for at least 14 h, even though Ca, Ca++, and PTH levels were normalized. The slow changes in 1,25-(OH)2D contrast with the rapid responses of PTH to hyper- and hypocalcemia.

A new bioactive form of human calcitonin.

Distinct immunoreactive forms of calcitonin (CT), extracted with 2 M acetic acid from two pancreatic tumors, were characterized and identified by gel permeation chromatography and by reverse-phase high-performance liquid chromatography. The extracted CT forms were compared to CT obtained from medullary thyroid carcinoma and from normal thyroid glands, and were, furthermore, analyzed in a rat hypocalcemic bioassay. On gel filtration analysis, two broad peaks coeluting with synthetic human CT-(1-32) and extracted dimeric CT, respectively, were found in variable amounts. An acetonitrile gradient high-performance liquid chromatography system revealed two to three predominant CT peaks. Biologically active monomeric and dimeric CT and the biologically inactive sulfoxide form of human CT-(1-32) have been identified. Moreover, we have detected for the first time a new biologically active CT-like component which was most prominently recognized in a benign pancreatic tumor.

Identity of calcitonin extracted from normal human thyroid glands with synthetic human calcitonin-(1-32).

Calcitonin in human thyroid glands obtained at autopsy from normal subjects were extracted with 2 M acetic acid. The extracts were additionally purified by adsorption to Sep-Pak C18 cartridges, and calcitonin was identified after gel filtration analysis, reverse-phase high-performance liquid chromatography (HPLC), thin-layer chromatography and isoelectric focusing. The purification steps were monitored by radioimmunoassay, and partially purified calcitonin was used for biological and physicochemical comparison with synthetic human calcitonin-(1-32) and its Met8-sulfoxide form. On gel filtration analysis a predominant peak coeluted with the synthetic hormone, and on HPLC two discrete peaks with the retention times of monomeric and dimeric human calcitonin were found. Thin-layer chromatography allowed the detection of two peaks with the Rf of human calcitonin-(1-32) and of its sulfoxide, respectively. The pI (7.9) of the predominant peaks of synthetic calcitonin were identical. Our findings provide strong evidence that the predominant forms of human calcitonin extracted from normal thyroid glands correspond to synthetic calcitonin-(1-32) and to dimeric calcitonin.