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 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.     

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.     

Effect of ethanol on central mechanisms of alimentary and defensive motivation in the rabbit

A single intravenous administration of ethanol (0.5 g/kg) to rabbits had different effects on the excitability of feeding and defensive motivational centers of the lateral and ventromedial hypothalamus. Ethanol abolished both inhibitory effects of the dorsal hippocampus and facilitatory action of the midbrain reticular formation on alimentary and defensive motivations. It elicited new power distributions of the main rhythms of general electrical cortical activity in the background and under stimulation of limbic-midbrain structures. Analysis of the activity of organello-specific enzymes in limbic-midbrain neurones revealed disturbances of cellular energetic processes caused by ethanol.     

Role of the hypothalamus in inhibiting the hypophysis-adrenal cortex system through the feedback mechanism

Chronic experiments were made on intact rabbits and rabbits with destroyed paraventricular and ventromedial nuclei of the hypothalamus to explore the hydrocortisone-induced inhibition of the stressor response of the pituitary-adrenocortical system. Intravenous injection of hydrocortisone in a dose of 100 micrograms/kg 5 minutes before immobilization stress led to inhibition of corticosteroid elevation induced by immobilization of the animals. Inhibition of the stressor reaction was maximal in intact animals, less in rabbits with destroyed ventromedial nuclei, and further less in animals with destroyed paraventricular nuclei. The paraventricular and ventromedial nuclei of the hypothalamus are necessary for inhibition of the pituitary-adrenocortical system by the feedback mechanisms.     

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.     

Influence of renin on the effects of electric stimulation on the ventromedial hypothalamus

The influence of intraventricular injection of different doses of renin on the effects of electrical stimulation of the ventromedial hypothalamus was studied. Injection of renin (10 micrograms/kg) into the lateral ventricles of the brain of experimental animals elicited a prolonged elevation of arterial pressure and a decrease of the heart rate, while given in doses of 20 and 30 micrograms/kg it also provoked arrhythmias and ventricular extrasystoles, and a lowering of the threshold of ventromedial hypothalamus stimulation. It was found that under the central action of renin, a short-term stimulation of the ventromedial hypothalamus provoked ventricular extrasystoles.     

Limbico-reticular relations during formation of various motivation responses in rabbits subjected to ethanol administration

Chronic experiments on rabbits with electrodes implanted into different limbic-midbrain structures were made to study the effects of a single intravenous injection of ethanol (0.5 g/kg) on the background EEG during formation of food motivation and avoidance behavior from the criterion of the power of the main EEG rhythms. Intravenous injection of ethanol resulted in an increase in the power of beta-, alpha- and theta-rhythms in the frontal cortex, and in that of alpha- and theta-rhythms in the occipital area of the neocortex. New patterns of the powers of the main EEG rhythms recorded in animals exposed to ethanol during electric stimulation of the lateral and ventromedial hypothalamus, evoking food motivation and avoidance behavior, as well as during electrical stimulation of the dorsal hippocamp and mesencephalic reticular formation that correlate with changes in the functions of the study limbic-mesencephalic structures attest to profound ethanol-induced abnormalities of the central mechanisms of food motivation and avoidance behavior.     

Vasoactive peptides in the structure of defensive motivational excitation

In experiments on rabbits, the action was studied of vasoactive peptides angiotensin-II, bradykinin and lysyl-vasopressin, injected into the brain ventricles, on a passive defensive reaction to electrical stimulation of the ventromedial hypothalamus. It was found that angiotensin-II and lysyl-vasopressin had a pronounced inhibitory influence, while bradykinin had a facilitatory effect on this reaction. Electrical stimulation of the ventromedial hypothalamus predominantly facilitated reactions of individual neurones of the sensorimotor cortex to angiotensin-II and bradykinin. Intraperitoneal injection of P-substance to rats in conditions of an acute conflict situation producing an emotional stress, brought about a significant diminution of sudden death incidence from cardiovascular insufficiency.     

Functional state of the frontal cortex and ventromedial hypothalamus during physical overexertion and experimental neurosis in the rabbit

A change of excitability, pO2 and local cortical blood flow under a long-term maximum physical load and in conditions of experimental neurosis, was investigated in rabbits with electrodes implanted in the frontal cortex and ventromedial hypothalamus. It was found that functional activity of these structures under physical orverstrain rises as the blood flow and pO2 increase, and the excitability also increases. In experimental neurosis, a discoordination in functioning of the cortex and hypothalamus is observed. Relative stabilization of the functional state of tested structures, observed during physical overstrain, is absent in conditions of experimental neurosis.     

The effect of acute alcoholization on the neuronal activity of the normal ventromedial hypothalamus and in pharmacological actions on the brain monoaminergic and opiate systems]

In experiments on white outbred male rats the specificity was studied of the influence and mechanisms of action of acute alcoholization (30%-solution of ethanol, intraperitoneally, 0.7 g/kg) on the activity of functionally different neurones of the ventromedial hypothalamus. Experimental results showed that the neurones, the activity of which lowered after saturation (I-st type), increased the discharges frequency at administration of ethanol. Nerve cells, the activity of which increased (II-nd type) and did not change (III-nd type) after saturation, had inhibitory character of reaction in response to alcoholization. The increase of serotonin content in the brain elicited by intraperitoneal administration of 5-OTPh (50 mg/kg) blockaded the action of ethanol on the nerve cells of the I-st type and did not change the effect of the alcohol on the neurones of the II-nd and III-nd types. Preliminary lowering of the noradrenaline level in the brain (disulphiram, intraperitoneally, 100 mg/kg) and blockade of opiate receptors (nalorphine, 5 mg/kg) fully eliminated ethanol influence on the activity of all types of neurones.     

The influence of substance P central administration on ethanol intake in rats chronically exposed to alcohol

The influence of central substance P (SP) administration on alcohol intake and brain dopamine metabolism within mesocortico-limbic and nigrostiatal systems of rats exposed to ethanol, was studied. During 6 months, the rats consumed 15% ethanol solution instead of water. Central administration of SP (3 mcg/kg) decreased alcohol consumption by 41% in alcohol-preference animals. After long-term ethanol exposure ratios DOPAC/DA and HVA/DA were reduced in striatum and accumbens. SP in dose 3 mcg/kg increased content of DOPAC by 17% and HVA by 23% as well as DOPAC/DA by 9%, HVA/DA by 19% in accumbens. Whereas in striatum only increased DOPAC (28%) and HVA (29%) were observed as compared with saline-treated rats.     

Role of angiotensin II in elaborating the escape reaction during electric stimulation of the ventromedial hypothalamus in rabbits

The action of angiotensin-II, saralazin, captopril and antiserum to angiotensin-II, injected into the brain ventricles, on avoidance reaction to electrical stimulation of ventromedial hypothalamus was studied in experiments on rabbits. It has been found that angiotensin-II had a pronounced inhibitory effect, while saralazin, captopril and antiserum to angiotensin-II had a facilitating effect on the reaction.     

Gastrin in the mechanisms of genetic determination of feeding behavior in rabbits

Spreading of a dominant motivation to the molecular intracellular mechanisms of genetic memory was studied. Blockage of protein synthesis in the nervous system selectively abolishes food motivation in rabbits during stimulation of the lateral hypothalamus but exerts no noticeable effect on avoidance responses during stimulation of the ventromedial hypothalamus. During protein synthesis blockage, food motivation returns to normal upon pentagastrin intracerebroventricular (i.c.v.) injection. Intracerebroventricular administration of antigastrin immunoglobulin inhibits feeding reaction to lateral hypothalamic stimulation but not avoidance response to ventromedial hypothalamic stimulation. It was concluded that feeding motivation translates into feeding behavior in the following stages: motivational excitation, gene activation, mRNA synthesis, formation of a gastrin-like peptide, and expression of feeding behavior.     

Influence of substance P on carotid sinus nerve baro- and chemoreceptor activity in rabbits.

Substance P (SP) is abundant in the carotid sinus nerve (CSN) and has been implicated in baro- and chemoreceptor reflexes. We examined the effect of SP on blood pressure, heart rate, phrenic nerve activity, hindlimb perfusion pressure, and cardiac contractile strength in urethane-anesthetized rabbits with bilaterally cut cervical sympathetic, vagus, and aortic depressor nerves. Retrograde simultaneous injection of SP (0.5-2.7 micrograms/kg in 0.2-0.3 ml saline) into both carotid sinus areas via the internal carotid arteries decreased blood pressure (by 56%), heart rate (by 13%), cardiac contractility (by 25%) and phrenic nerve activity (by 77%). The effect on hindlimb perfusion pressure was variable. There was both a reflex effect and direct hindlimb vasodilation. In another group of rabbits, the carotid sinus areas were vascularly isolated and perfused with SP (0.19 micrograms/min dissolved in Locke's solution) or Locke's solution alone for 5 min. While carotid sinus perfusion pressure was maintained in the range of 80-120 mmHg, mean arterial blood pressure, heart rate, and unit activity from the CSN were recorded. SP increased the activity of 11 of 18 baroreceptor fibers and inhibited all of 20 chemoreceptor fibers. SP decreased mean arterial blood pressure and heart rate, but the changes were less than those obtained with injection of SP into nonisolated carotid sinus arteries because systemic effects of SP, which in some cases counteracted the reflex effects, were eliminated.     

Effect of centrally administered cholecystokinin on feeding behavior induced by electric stimulation of the lateral hypothalamus in the rabbit

In experiments on 15 freely moving rabbits cholecystokinin octapeptide sulfate (CCK-8-S) in a dose of 10 ng considerably suppressed alimentary behaviour of the animals elicited by electrical stimulation of the lateral hypothalamus. Increasing of the peptide doses to 100 and 200 ng elicited an analogous effect. CCK-8-NS in 10 ng dose produced a lesser effect on feeding of the animal, but increasing of the dose of nonsulphated CCK to 100 ng led to a considerable prolongation of feeding. CCK-8-S and CCK-8-NS in doses used did not affect the reaction of avoidance in rabbits caused by electrical stimulation of the ventromedial nucleus of the hypothalamus.     

Angiotensin II in the mechanisms of hypothalamic pressor reactions

The influence of intracerebroventricular injections of the angiotensin II antagonist--saralasin on the cardiovascular reactions elicited by electrical stimulation of different structures of the hypothalamus in rabbit was studied. The saralasin in doses from 1 to 1.5 mg reduced arterial pressure by 9 +/- 0.2 mm Hg and decreased the amplitude of the hypertensive reactions elicited by electrical stimulation of the paraventricular, supraoptic, ventromedial, supramammillary nucleus of the hypothalamus, area hypothalamic anterior and lateral. It has been shown that most suppressing influence of the saralasin on amplitude of the hypertensive reactions elicited by electrical stimulation of the paraventricular (68%) and supraoptic (76%) nucleus of the hypothalamus which contain magnocellular neurosecretory neurons.     

Effect of S 17092, a novel prolyl endopeptidase inhibitor,on substance P and alpha-melanocyte-stimulating hormone breakdown in the rat brain

In the present study, we have investigated the effects of a novel prolyl endopeptidase (EC 3.4.21.26, PEP) inhibitor, compound S 17092, on substance P (SP) and alpha-melanocyte-stimulating hormone (alpha-MSH) metabolism in the rat brain. In vitro experiments revealed that S 17092 inhibits in a dose-dependent manner PEP activity in rat cortical extracts (IC50 = 8.3 nm). In addition, S 17092 totally abolished the degradation of SP and alpha-MSH induced by bacterial PEP. In vivo, a significant decrease in PEP activity was observed in the medulla oblongata after a single oral administration of S 17092 at doses of 10 and 30 mg/kg (-78% and -82%, respectively) and after chronic oral treatment with S 17092 at doses of 10 and 30 mg/kg per day (-75% and -88%, respectively). Concurrently, a single administration of S 17092 (30 mg/kg) caused a significant increase in SP- and alpha-MSH-like immunoreactivity (LI) in the frontal cortex (+41% and +122%, respectively) and hypothalamus (+84% and +49%, respectively). In contrast, chronic treatment with S 17092 did not significantly modify SP- and alpha-MSH-LI in the frontal cortex and hypothalamus. Collectively, the present results show that S 17092 elevates SP and alpha-MSH concentrations in the rat brain by inhibiting PEP activity. These data suggest that the effect of S 17092 on memory impairment can be accounted for, at least in part, by inhibition of catabolism of promnesic neuropeptides such as SP and alpha-MSH.     

Effect of ethanol on excitatory and inhibitory processes in the visual cortex of rabbits undergoing learning

Subcutaneous ethanol injection to waking rabbits in a dose of 2-6 g/kg causes discoordination of movements, a decline in motor reactions to inhibitory and reinforced light flashes, and appearance of equalizing and paradoxical relations in the number of reactions to these stimuli. Under the influence of ethanol, activating and disinhibitory action of the pain reinforcement on neurones of the visual area temporarily weakens, while the disinhibitory influence of light flashes (CS) is preserved. Judging from the dynamics of phasic reactions to the inhibitory light flashes, the ethanol in a dose of 2-6 g/kg does not influence the inhibitory hyperpolarization processes in the cerebral cortex of rabbits. Tonic inhibition of the cortical unit activity temporarily intensifies after the ethanol injection.     

The central efferent mechanism of brown adipose tissue thermogenesis induced by preoptic cooling

This study was performed to investigate central efferent mechanisms for brown adipose tissue thermogenesis. In unanesthetized rats, the effects of local anesthesia of the ventromedial hypothalamus, anterior hypothalamus, and lateral hypothalamus were observed on the brown adipose tissue thermogenesis induced by preoptic cooling. Rats had a thermode, thermocouple, and bilateral injection cannulae chronically implanted in the hypothalamus and a thermocouple beneath the interscapular brown adipose tissue. The experiments were done at an ambient temperature of 24-25 degrees C. Preoptic cooling increased brown adipose tissue and colonic temperatures without shivering. Injecting lidocaine bilaterally into the ventromedial hypothalamus during preoptic cooling reduced brown adipose tissue temperature (Tbat). The mean maximum decrease of Tbat was 0.51 +/- 0.26 degrees C and occurred 5-8 min after lidocaine injection. When lidocaine was injected into the anterior hypothalamus, Tbat increased. The mean maximum increase of Tbat was 0.85 +/- 0.29 degrees C and occurred 4-9 min after lidocaine injection. In the lateral hypothalamus, lidocaine had no effect on Tbat. Tbat was not influenced by injection of saline into the ventromedial, anterior, or lateral hypothalamus. The efferent pathway from preoptic to brown adipose tissue may thus traverse the medial part of hypothalamus. The ventromedial hypothalamus facilitates and anterior hypothalamus inhibits brown adipose tissue thermogenesis induced by preoptic cooling.