Substance P in the central mechanisms of the escape reaction

The role of substance P in the central mechanisms of escape reaction elicited by electrical stimulation of the ventromedial hypothalamus was investigated in chronic experiments on rabbits. Intravenous injection of substance P (30 micrograms/kg) led to a short-term (less than 10 min) increase in the threshold of stimulation of the ventromedial hypothalamus and to more stable (up to 1.5 h) disorders of the hippocampal-hypothalamic relations. After substance P injection the inhibitory effects of the dorsal hippocampus but not the facilitating influences of the midbrain reticular formation on excitability of the hypothalamic motivation center were found to be lacking. Disorders of the central mechanisms of escape reaction after substance P injection correlated with new patterns of the main EEG rhythms in different areas of the brain cortex in response to the ascending excitations of the limbic-midbrain structures. Interpreting the mechanisms of substance P involvement in escape reaction the authors point to the ability of the given peptide to interact with different transmitter systems of the brain and opiate receptors and to alter the brain blood circulation.     

Substance P and the ethanol-evoked changes in the independent motivated behavioral reactions of rabbits

Ethanol (0.5 g/kg) administered intravenously led to alterations in central mechanisms of feeding and escape, elicited by threshold electrical stimulation either of lateral or of ventromedial hypothalamic centers of the rabbit. Subsequent intravenous injection of substance P (30 mcg/kg) restored the excitability of the ventromedial hypothalamus and facilitatory effects on this motivational center of the midbrain reticular formation. The restoration of both inhibitory influences of the dorsal hippocampus and facilitatory ones of the midbrain reticular formation on the excitability of the lateral hypothalamus was also observed after SP administration. Data obtained suggest that oligopeptides could be used to increase the tolerance to ethanol or to cure the negative acute effects of alcohol in motivated behaviours.     

Role of substance P in regulating the feeding behavior and the avoidance reaction in the rabbit

Similar changes in feeding and avoidance reaction in spite of the way of substance P administration (30 mgk/kg intravenously or 14,8 nmol intraventricular) were found in rabbits with electrodes implanted in various limbic-midbrain structures. Feeding was found to be more sensitive to substance P administration, as it was shown by the decrease of excitability of the hypothalamic "feeding center" and abolishing of the inhibitory and facilitatory effects on this center from the dorsal hippocampus and the midbrain reticular formation, correspondingly. New cortical-subcortical integration under substance P was presented in new characteristics of EEG activity in neocortical areas, both background and in response to stimulation of various limbic-midbrain structures. Biochemical data let to suggest that at the neural level substance P led to destabilization of membrane structures in endoplasmatic reticulum and to redistribution of membrane-connected N-acetylneuramine acid which was directly involved in neurotransmission.     

Enhancement of the resistance of the escape reaction to ethanol after substance P]

An ability of substance P (30 micrograms/kg intravenously) to prevent deleterious effects of ethanol (E) (0.5 g/kg intravenously) on central mechanisms of escape reaction elicited by threshold electrical stimulation of the ventromedial hypothalamus was investigated in chronic experiments upon rabbits. Substance P was found to prevent E effects on excitability of the ventromedial hypothalamus (VMH) and on facilitatory influences of the midbrain reticular formation on this emotional centre which were observed in intact animals. Inhibitory effects of the dorsal hippocampus on the VMH could not be evaluated due to its alterations in response to previous substance P administration. The authors suggest that substance P can be considered to be a possible endogenous factor to increase a tolerance of emotional behavioural reactions of an organism to alcohol.     

Substance P in the central mechanism of the rabbit feeding response evoked by stimulation of the lateral hypothalamus

The effects of substance P on the central mechanisms of food motivation elicited by electrical stimulation of the lateral hypothalamus were studied in chronic experiments on rabbits. Intravenous injection of substance P (30 micrograms/kg) brought about a dramatic reduction in the excitability of the "food center" in the hypothalamus, which returned to normal 45-60 minutes after injection. Higher concentrations of substance P provoked food behavior inversion up to the replacement of food motivation by avoidance behavior. Intravenous injections of substance P disturbed the relationships between the hippocamp, midbrain reticular formation and hypothalamus seen in health. This manifested in complete cessation of the inhibitory effects of the dorsal hippocamp and facilitating influences of the midbrain reticular formation on the excitability of the hypothalamic "food center". It is assumed that disorders of the central mechanisms of food motivation may arise from the effects produced by substance P directly on the central nervous system or on the brain via changes in the hormonal balance and responses of the autonomous nervous system.     

The hypothalamic-pituitary-interrenal axis and the control of food intake in teleost fish

Although environmental, social and physical stressors have been shown to inhibit food intake and feeding behavior in fish, little is known about the mechanisms that mediate the appetite-suppressing effects of stress. Since the hypothalamic-pituitary-interrenal (HPI) axis is activated in response to most forms of stress in fish, components of this axis may be involved in mediating the food intake reductions elicited by stress. Recent investigations into the brain regulation of food intake in fish have identified several signals with orexigenic and anorexigenic properties. Among these appetite-regulating signals are related neuropeptides that can activate the HPI axis, namely corticotropin-releasing factor (CRF) and urotensin I (UI). Central injections of CRF or UI, or treatments that result in an increase in hypothalamic CRF and UI gene expression, can elicit dose-dependent decreases in food intake that can be reversed by pre-treatment with a CRF-receptor antagonist. Evidence also suggests that cortisol, the end product of HPI activation in most fishes (i.e. Osteichthyes), may be involved in the regulation of food intake. Overall, while elements of the HPI axis may mediate some of the appetite-suppressing effects of stress, it is undetermined how either CRF-related peptides, cortisol, or other elements of the stress response interact with the complex circuitry of the hypothalamic feeding center.     

Implications of the feeding current structure of Euchaeta rimana, a carnivorous pelagic copepod, on the spatial orientation of their prey

Many marine planktonic organisms create water currents to entrainand capture food items. Rheotactic prey entrained within thesefeeding currents often exibit escape reactions. If the directionof escape is away from the feeding current, the prey may successfullydeter predation. If the escape is towards the center of thefeeding current, the prey will be re-entrained towards its predatorand remain at risk of predation. The direction of escape isdependent on (i) the ability of the prey to escape in a directiondifferent than its pre-escape orientation and (ii) the orientationcaused by the interaction of the prey's body with the movingfluid. In this study, the change in orientation of Acartia hudsonicanauplii as a result of entrainment within the feeding currentof Euchaeta rimana, a planktonic predatory copepod, was examined,When escaping in still water, A.hudsonica nauplii were ableto vary their pre-escape direction by only 10. This allowsonly a limited ability to escape in a direction different thantheir pre-escape orientation. Analyses of the feeding currentof E.rimana show the flow speed to be most rapid in the centralregion with an exponential decrease in speed distally. In contrast,flow vorticity is minimal in the center of the feeding currentand maximal at 1.75 mm along the antennae. As a result, thedegree of rotation of the prey towards the center of the feedingcurrent shows a strong dependency on the prey's location withinthe feeding current. The feeding current of E.rimana rotatedthe prey 14 when near the center of the flow field and up to160 when located more distal in the feeding current Since theprey's escape abilities cannot compensate for the rotation dueto the flow, this mechanism will maintain the escaping preywithin the feeding current of their predator. Therefore, thefeeding current facilitates predatory copepods in capturingprey by (i) increasing the amount of water which passes overtheir sensors and through their feeding appendages and (ii)controlling the spatial orientation of their prey prior to escape.     

Naloxone blockade of growth hormone-releasing factor-induced feeding

The opiate antagonist naloxone was used to examine the possibility that endogenous opioid function is involved in the expression of the increased feeding observed following intracerebroventricular (i.c.v.) administration of rat hypothalamic growth hormone-releasing factor (GRF). It was found that systemically administered naloxone (0.125, 0.25 and 0.50 mg/kg) significantly suppressed the increased food intake observed following i.c.v. GRF (4.0 pmol) treatment. Though potent enough to eliminate ingestive effects of GRF, baseline food intake was unaffected by 0.125 mg/kg naloxone. Examination of 0.4, 4.0 and 40.0 pmol i.c.v. administered GRF-(3-40), a structurally related but physiologically inactive peptide, revealed no effect on food intake. The present results suggest involvement of endogenous opioid function in GRF-stimulated feeding.     

Hypothalamic substance P as a candidate for transmitter of primary afferent neurons.

A peptide that exerts a depolarizing action on frog spinal motoneurons was found in the dorsal root of bovine spinal nerve. Pharmacological, chemical, and immunological properties of this motoneuron-depolarizing peptide were investigated and the results indicated that the peptide is identical with an undecapeptide, substance P, recently isolated from bovine hypothalamus by M.M.Chang and S.E.Leeman. The amount of hypothalamic substance P in bovine dorsal root determined by bioassay or radioimmunoassay was 24-130 pmole/g wet wt, whereas that in the ventral root was 9-27 times less. The effects of synthetic hypothalamic substance P on the isolated spinal cord of the frog and the newborn rat were studied. The peptide exerted a powerful depolarizing action on the motoneurons, its potency being about 200 times higher than that of L-glutamate. Distribution of substance P in the cat spinal cord was studied. The concentration of the peptide was highest in the dorsal part of dy lowered. When the dorsal root of the cat was ligated, substance P accumulated in a high concentration on the ganglion side of the ligature. These results, taken together, support the hypothesis that hypothalamic substance P is an excitatory transmitter of primary afferent neurons.     

The influence of systemically administered selective dopamine antagonists of D1 and D2/D3 types on alimentary and escape conditioned placing reactions in cats

Systemic administration of the specific antagonists of D1 (SCH23390, 0.005-0.1 mg/kg) and D2/D3 (raclopride, 0.1-0.25 mg/kg) dopamine receptors leeds to dose-dependent increase of the reaction time and decrease of conditined reflex probability up to full blocking (in the case of SCH23390) of alimentary and escape conditioned placing reaction in cats. The action of both antagonists was far more suppressive regarding conditioned escape reflex. The action of SCH23390 was far more effective than that of raclopride concerning both types of conditioned reflexes.     

Up-regulation of galanin and corticotropin-releasing hormone mRNAs in the key hypothalamic and amygdaloid nuclei in a mouse model of visceral pain

Cyclophosphamide (CP)-induced cystitis is often used as an animal model of visceral pain. Various neuropeptides in the hypothalamic and amygdaloid nuclei are implicated in pain-induced responses. However, little information is available regarding the regulation of the neuropeptides in response to visceral pain. In the present study, we examined the effects of CP-induced cystitis on the levels of mRNAs encoding galanin, corticotropin-releasing hormone (CRH), substance P, and enkephalins in the hypothalamic and limbic nuclei using in situ hybridization histochemistry in mouse. Galanin mRNA levels in CP-treated group increased significantly in the arcuate nucleus and the paraventricular nucleus (PVN) but not in the medial preoptic area after the intraperitoneal administration of CP (200 mg/kg body weight) in comparison to those in saline-treated group. CRH mRNA levels in CP-treated group also increased significantly in the central amygdala as well as the PVN after the CP administration. In contrast, CP-induced cystitis failed to upregulate the preprotachykinin-A and preproenkephalin genes which encode substance P and enkephalins, respectively in the hypothalamic and limbic nuclei at any of the time points examined. These results suggest that visceral nociception may upregulate both galanin and CRH gene expression in the hypothalamic and limbic nuclei.     

Substance P affects the GABAergic system in the hypothalamo-pituitary axis

In the present work we examined the effect of the neutralization of endogenous substance P by the administration of an anti-substance P serum (ASPS) on GABA concentration in the anterior pituitary in hyperprolactinemic conditions induced by 5-hydroxytryptophan or by grafting anterior pituitaries. ASPS reduced the increase in the anterior pituitary GABA concentration induced by hyperprolactinemia. In vitro experiments showed that substance P inhibited K⁺-evoked GABA efflux from hypothalamic fragments and decreased GABA concentration in the anterior pituitary but ASPS increased it. Our results demonstrate that substance P modifies hypothalamic GABA release and anterior pituitary GABA concentration and suggest that an interaction exists between substance P and GABA.     

Bilateral neural transections at the level of mesencephalon increase food intake and reduce latency to onset of feeding in response to neuropeptide Y

Administration of neuropeptide Y (NPY) into the IIIrd ventricle of the rat brain induces robust ingestive behavior with a latency to onset of feeding (LOF) ranging from 12 to 20 min. Since substantial amounts of NPY found in hypothalamic sites that mediate the control of feeding behavior originate from the brain stem, we studied the effects of NPY on LOF and food intake in male and female rats after bilateral severing of brain stem NPY input to the hypothalamus at the level of the mesencephalon. NPY in doses of 117 pmol significantly increased food intake and decreased LOF in both male and female transected rats. Higher doses of 470 pmol NPY decreased only the LOF in transected rats as compared to sham control rats. Additionally, 117 pmol NPY in transected rats elicited food consumption equivalent to that produced by 470 pmol NPY in control rats. These studies show that decreases in NPY levels found in the paraventricular nucleus and neighboring hypothalamic sites as a result of these neural transections may render rats hyperresponsive to NPY, presumably due to denervation-induced hypersensitivity in these sites.     

Topographic studies of the effects of microinjections of muscimol on the hypothalamic control of feed intake in sheep

Ten sheep were used to define the anatomical basis for the feeding systems sensitive to gamma-aminobutyric acid, by using intrahypothalamic microinjections of the gamma-aminobutyric acid agonist, muscimol. In satiated sheep, 1 microL of muscimol (0.5 nmol/microL) elicited feeding when injected into paraventricular, ventromedial, and anterior hypothalamic areas. Similar injections into 39 sites tested in 6-h fasted sheep failed to decrease feed intake. The data suggest that neurons sensitive to gamma-aminobutyric acid in medial hypothalamus may be involved in the initiation of feeding.     

Morphological equivalent of the bifunctional role of somatostatin

Summary Using the immunoenzyme bridge-technique at the light and electron microscopic levels, somatostatin can be demonstrated in the perikarya of the anterior periventricular nucleus, in the median eminence and in the parvocellular hypothalamic nuclei of the rat. In the latter regions the perikarya are negative, whereas a positive reaction for somatostatin is found in a delicate network of fibers and middle-sized granules of very small axons. In light of these results, the double function of somatostatin — as release inhibiting hormone and as transmitter — is discussed. The positive staining reaction in the organum vasculosum laminae terminalis of male and female rats as well as in the subfornical organ, the nucleus dorsalis thalami and the nucleus medialis habenulae in female controls and pregnant rats is not due to somatostatin-containing structures, but partly to substance P and partly to a substance which could not be defined.Supported by the Deutsche Forschungsgemeinschaft (Grant Nr. Kr. 569/1) and Stiftung Volkswagenwerk     

Substance P and effects of ethanol on the central mechanisms of the escape reaction in rabbits

Substance P (SP) effects on the central mechanisms of escape reaction, elicited by threshold electrical stimulation of the ventromedial hypothalamus were investigated in rabbits pretreated with ethanol (0.5 g/kg). SP (30 micrograms/kg) was demonstrated to normalize in 71.4% of cases the excitability of the ventromedial hypothalamus which was decreased by ethanol and restored in 83.3% of cases the facilitatory effects of the midbrain reticular formation in escape reactions. However, SP was ineffective in the restoration of the inhibitory effects of the dorsal hippocamp on the excitability of the ventromedial hypothalamus that was obvious in intact animals. Partial normalizing effect of SP on escape reaction in rabbits after previous ethanol administration can be accounted for by the fact that both undecapeptide and ethanol are similar in their realization of central effects such as an interaction with the same brain neurotransmitters, interference with neuronal enzyme processes and reactions with opiate receptors.     

Thyrotropin Releasing Hormone (TRH) suppresses stress induced eating

Thyrotropin releasing hormone (TRH) administered both intraventricularly and parenterally suppressed stress induced eating (using the mild tail pinch model) in a dose related manner. This suppression was partially reversed by intraventricular administration of the long acting synthetic enkephalin analog, D-Ala-Met-Enkephalin (p < 0.01). Preliminary data suggests that the naturally occurring metabolic breakdown product of TRH, histidyl-proline-diketopiperazine, may be the active substance with TRH acting as a pro-hormone. The TRH effect was present in hypophysectomized animals showing that the TRH-induced decrease in food ingestion was not secondary to an increase in thyrotropin or thyroid hormones. TRH did not alter blood glucose levels. Our data is compatible with a possible physiological role for TRH, as a peptidergic mediator of satiety acting as a direct antagonist of the lateral hypothalamic of satiety acting as a direct antagonist of the lateral hypothalamic enkephalin-mediated feeding center.     

Effect of substance P on catecholamine levels in the hypothalamus and midbrain in the rat during immobilization stress

Single intraperitoneal injection of substance P in a dose of 125 mcg/kg induced a significant increase of noradrenaline and dopamine level in the hypothalamus and the midbrain of intact rats. Under conditions of immobilization emotional stress, the substance P eliminated the stress induced decrease of hypothalamic noradrenaline and increase of its level in the midbrain; in other words the substance P normalized the noradrenaline level. Modulatory effect of a single injection of the substance P had a long-term character and was synchronized with an earlier found increase of resistability of rats to chronic emotional stress.     

31P NMR and computational studies on stereochemistry of conversion of phosphoramidate diesters into the corresponding phosphotriesters

31P NMR spectroscopy was used to investigate a stereochemical course of a nitrite-promoted conversion of phosphoramidate diesters into the corresponding phosphotriesters. It was found that this reaction occurred with almost complete epimerization at the phosphorus center and at the C1 atom in the amine moiety. On the basis of the 31P NMR data, a plausible mechanism for the reaction was proposed. The density functional theory calculation of the key step of the reaction, i.e., breaking of the P-N bond and formation of the P-O bond, suggested a one-step S(N)2(P) process with retention of configuration at the phosphorus center.     

Ghrelin induces feeding in the mesolimbic reward pathway between the ventral tegmental area and the nucleus accumbens

Ghrelin, a powerful orexigenic peptide released from the gut, stimulates feeding when injected centrally and has thus far been implicated in regulation of metabolic, rather than hedonic, feeding behavior. Although ghrelin's effects are partially mediated at the hypothalamic arcuate nucleus, via activation of neurons that co-express neuropeptide Y and agouti-related protein (NPY/Agrp neurons), the ghrelin receptor is expressed also in other brain sites. One of these is the ventral tegmental area (VTA), a primary node of the mesolimbic reward pathway, which sends dopaminergic projections to the nucleus accumbens (Acb), among other sites. We injected saline or three doses of ghrelin (0, 0.003, 0.03, or 0.3 nmol) into the VTA or Acb of rats. We found a robust feeding response with VTA injection of ghrelin, and a more moderate response with Acb injection. Because opioids modulate feeding in the VTA and Acb, we hypothesized that ghrelin's effects in one site were dependent on opioid signaling in the opposite site. The general opioid antagonist, naltrexone (NTX), injected into the Acb did not affect feeding elicited by ghrelin injection into the VTA, and NTX in the VTA did not affect feeding elicited by ghrelin injected into the Acb. These results suggest interaction of a metabolic factor with the reward system in feeding behavior, indicating that hedonic responses can be modulated by homeostatic factors.