The effect of neurotropic substances on the self-stimulation reaction at the thalamic level]

The effect of d-amphetamine, cocaine, caffeine, morphine, imipramine, phenobarbital, LSD-25, benactyzine, meprobamate, diazepam, chloridiazepoxide on the lateral hypothalamic self-stimulation of rats was investigated. D-amphetamine, cocaine, caffeine, morphine, imipramine decreased the threshold of selfstimulation. Meprobamate, diazepam, chlordiazepoxide failed to influence this index, but increase the intensity of self-stimulation during the threshold, the optimum and more than the optimum cirrent intensity. Benactyzine, LSD-25, phenobarbital decreased the threshold and increased the frequency of self-stimulation during all the current intensities. A comparative study of the above results showed the agents of the first group to exert a direct stimulating action on the positive reinforcement system. Tranquillizers activated this system due to their depressive action on the negative reinforcement system. Benactyzine, LSD-25, phenobarbital activated the system and depressed the system of negative reinforcement.     

Analysis of the effect of morphine and promedol on uptake and release of noradrenaline by myocardial tissue]

A study was made of the effect of morphine and promedol on the content, uptake, and release of norepinephrine (NE) on rat myocardium. Promedol proved to decrease the NE level in the myocardium. Morphine failed to influence the release of the NE-14C from the isolated perfused heart, whereas promedol increased it significantly, altering both the "slow" and the "rapid" release of the mediator. Promedol failed to influence the uptake of NE-14C by the perfused heart, whereas morphine decreased it significantly. The competition between morphine and NE was characterized by the effect of incomplete inhibition: morphine and NE produced reciprocal effects on the affinity of one another to the receptor, and their interaction depended on the ratio of the concentrations of these drugs.     

Possible role of positive reinforcement zones in the mechanisms of pain regulation and their relation to the endogenous opiate system

The consequences of self-stimulation reaction (RSS) to pain threshold in tail withdrawal test (55 degrees C) and naloxone effect have been investigated in tests, using male rats with chronically implanted electrodes into the hypothalamus (AP = 1.5, L = 1.5, H = 8.5) and suture dorsal nucleus (AP = 7.0, L = 0, H = 7.0) (coordinates according to Fifková atlas). It was established that right after RSS, pain threshold in both zones increased 2-2.5-fold and 30 min later reached the initial level. Naloxone injected before RSS increased pain thresholds and decreased RSS frequency from hypothalamus but failed to change these RSS parameters from suture dorsal nucleus. However, naloxone did not affect the increase in pain thresholds caused by RSS from both zones. Taking into account the fact that analgesia appearing after RSS from the anterior hypothalamus as well as from suture dorsal nucleus is not reversed by naloxone, it is suggested that positive reward zones activation partially realized by opioidergic mechanisms or having no connection with them may lead to the development of non-opiate type analgesia.     

Long-term changes in self-stimulation threshold by repeated morphine and naloxone treatment

To analyse the interaction between endogenous opioid systems and brain reward, the influence of repeated treatment for 3 weeks with morphine and the opioid antagonist naloxone was investigated in rats with self-stimulation electrodes in the ventral tegmental area. Changes in threshold of self-stimulation determined by a response rate insensitive two lever method were considered as changes in reward. Morphine induced a temporary decrease of the response rate which lasted 3 days, and decreased the threshold for self-stimulation. The effect on threshold remained present till morphine treatment was discontinued, indicating that tolerance does not develop to this effect of morphine. Repeated naloxone treatment gradually increased the threshold for self-stimulation. This effect persisted after discontinuation of naloxone treatment. It is concluded that blockade of opioid receptors induces long term changes in the setpoint of self-stimulation reward.     

Individual differences in the levels of pain sensitivity and analgesic effect of morphine in noninbred mice

The initial threshold of pain sensitivity and the degree of morphine analgesia (12, 12, 70 mg/kg, i. p.) were assessed during mechanical, thermal and electrical stimulation, respectively, in noninbred white male mice. Two tests were performed, the second a week after the first one. A slight positive correlation (r = +0.39) between the initial threshold of pain reaction and the analgetic effect of morphine was found only during electrical stimulation in the first test, and positive correlation between the first and the second test during electrical and mechanical stimulation (0.34 and 0.27, respectively) was determined. The degree of morphine analgesia in different animals during second testing could either increase or decrease. It is suggested that previous testing of morphine analgetic effect cannot predict the efficacy of analgesia during the second testing and that the initial threshold of pain sensitivity cannot serve as a reliable predictor of morphine analgesia level.     

Effect of stimulation of emotiogenic zones of the rat hypothalamus on the course of pregnancy and the growth of the progeny

The course of pregnancy and progeny development was studied in white rats with different emotional background during pregnancy. Self-stimulation of emotionally positive zones of the lateral hypothalamus and forced stimulation of emotionally negative zones of the ventral hypothalamus were taken as models of emotional states. Stimulation or self-stimulation of these structures, while causing unidirected negative effect on pregnancy and progeny, affected in different ways the speed of conditioning in viable progeny. Stimulation of emotionally negative zones of the ventromedial hypothalamus in the last third of pregnancy caused an acceleration of conditioning in the progeny. The self-stimulation of emotionally positive zones of the lateral hypothalamus failed to produce such effect.     

The influence of damage to the septum pellucidum on the effects of electrical stimulation of the hypothalamus in rabbits]

In chronic experiments the influences of septal lesions on the behavioural emotional effects of electrical stimulation of various hypothalamic nuclei were investigated. The total ablation of the septum caused irreversible increase of the lateral hypothalamus self-stimulation and reversal of the negative emotional responses (escape--avoidance) to the medial hypothalamus stimulation into the positive self-stimulation behaviour. When the septal ablation was only partial, involving mainly the medial nucleus, effects were weaker and lasted only 2-3 days after the surgery. The role of the septum in the septohippocampal behavioural inhibition system (J. Gray) is discussed.     

Cyclic nucleotides in the rat brain in the dynamics of hypothalamic self-stimulation

The content of cyclic nucleotides was measured in the brain structures of rats performing hypothalamic self-stimulation. Changes of the cAMP content were shown to possess a specific pattern corresponding to the features of self-stimulation. An increasing self-stimulation frequency (SSF) was followed by the maximum increase in the above index in the sensorimotor cortex; a stable SSF was accompanied by activation of the cAMP-dependent mechanisms of the septum, hypothalamus, and posterior hypophysis, while a decreasing SSF correlated with suppression of these processes in the septum, hypothalamus, and anterior hypophysis. Changes in the cAMP phosphodiesterase activity were less intensive and did not depend on the cGMP level. Changes in the cGMP content were nonspecific and unidirectional: this index increased, with the maximum at the stable self-stimulation mode. The ratio of cyclic nucleotides shifted toward cAMP when the SSF increased, and towards cGMP when the SSF decreased, while at a stable frequency their content was equal to the control level. The changes in the cyclic nucleotide contents were non-reciprocal (except an inverse correlation between their contents in the hypothalamus observed when the SSF dropped).     

Psychopharmacological analysis of hypothalamically-induced emotions

The effect of minor tranquilizers and neuroleptics was compared on self-stimulation and escape behaviourelicited by electrical stimulation of the hypothalamic nuclei in rabbits. It was shown that while tranquilizers (diazepam, oxazepam and meprobamate) increased the rate of self-stimulation elicited from the lateral hypothalamus, neuroleptics considerably suppressed such behaviour. Tranquilizers caused a remarkable reversal of the escape behaviour into a high-rate self-stimulation, both responses being induced from the same electrodes within the medial hypothalamus. Neuroleptics (chlorpromazine, reserpine and haloperidol) had not such an influence, though they somewhat increased the general activity of the animals. The reversing effect of the tranquilizers was compared with similar findings obtained after electrolytic ablation of the ventral hippocampus. It is suggested that the hippocampus has an inhibitory influence on the hypothalamic motivational system thus providing substantially for the animals' survival in a hostile environment.     

Effect of diazepam, meprobamate and amizyl on the emotional reactions of the rabbit to hypothalamic stimulation

The influence of minor tranquilizers (diazepam, meprobamate and beuactizine) on the hypothalamically elicited emotional responses was studied in chronic experiments on rabbits. The positive self-stimulation elicited from the lateral hypothalamus was facilitated by all used tranquilizers. On the first day of administration of the drugs the rate of self-stimulation increased markedly. The rate of self-stimulation was still mildly enhanced on the second day and returned to its initial value on the third day. The avoidance behaviour elicited from the medial hypothalamus changed to obvious self-stimulation after the administration of diazepam and meprobamate. The reversed behaviour preserved on the second day, while on the third day the animals resumed their avoidance behaviour. It was depressed by benactizine injection and some activation of exploratory behaviour was observed.     

The self-stimulation reaction of rabbits in a helium-oxygen environment under increased pressure]

Change of intensity of hypothalamic self-stimulation was determined in rabbits during their stay in normoxic helium-oxygen medium under the pressures of 10, 15 and 40 kgf/cm2 at various speeds of compression. The experiments conducted testify to depressive influence on the hypothalamus self-stimulation of helium-oxygen medium under increased pressure; the influence was more expressed at higher pressures and great speed of compression. It is supposed that the decrease in frequency of pedal pressures was connected with the appearance of nervous syndrome of high pressures.     

Effect of myelopeptides on physiological and pathological pain

The action of bone marrow low-molecular peptides (myelopeptides) was studied in the models of physiologic and pathologic pain. Myelopeptides were demonstrated to have a pronounced analgetic effect: they increased the latent period of the rats' response in the hot plate test (physiologic pain) and suppressed severe spinal pain syndrome induced by the generator of pathologically enhanced excitation in the dorsal horn of the spinal cord (pathologic pain). In the experiments with naloxone (an opiate receptor blocker) the data on the opiate properties of myelopeptides were further substantiated. The analgetic effect of myelopeptides can be compared to that of morphine and promedol. Myelopeptides even in considerable doses did not have the side effects characteristic of the majority of opiate analgesics. Therefore, they may be recommended for clinical trials.     

The effect of self-stimulation of the lateral hypothalamus on the sleep-waking cycle in rats during alcoholization]

Directed activation of a system of positive emotional reinforcement induces regulatory effect on limbic-neocortical mechanisms of the sleep-waking cycle organization in rats after chronic alcoholization carried out in periods of decreased and increased circadian rhythms of emotional activity. In animals with high level of positive emotional drive after the alcoholization self-stimulation of the lateral hypothalamus suppresses hypersynchronous paroxysmal activity in waking EEG, decreases the content of waking in the sleep-waking cycle, restores the paradoxical phase of sleep. In animals with inhibition of positive emotional drive in consequence of alcoholization self-stimulation of the lateral hypothalamus has no essential effect on the mechanisms of regulation of the sleep-waking cycle.     

Action of naloxone on emotionally positive and antinociceptive effects of hypothalamic stimulation in rats

Naloxone (5 mg/kg subcutaneously) failed to effect significantly the reaction of electric self-stimulation in rats with electrodes implanted into lateral hypothalamic area. In 3 rats the analgesic effect manifested in an increase of the threshold of painful vocalization under electrostimulation of the tail was revealed. The antinociceptive effect was abolished with naloxone. Morphine (3 mg/kg) potentiated self-stimulation while naloxone antagonized this action. The role of opiate receptors in effects of self-stimulation and centrally produced analgesia is discussed.     

Participation of GABA- and dopaminergic mechanisms of the bed nucleus of stria terminalis in reinforcing effects of psychotropic drugs mediated via the lateral hypothalamus

The purpose of the investigation was to elucidate significance of GABA and dopamine systems of the bed nucleus of stria terminalis for the reinforcing effects of a number of psychotropic drugs (opiates, opioids, psychostimulants) on self-stimulation of the lateral hypothalamus in rats. To the Wistar male rats, bipolar electrodes were implanted in the lateral hypothalamus to study self-stimulation reaction in the Skinner box. Simultaneously, the microcannules were implanted into the bed nucleus of stria terminalis to inject the drugs under study. Some drugs, xycaine, or lidocain, a blocker of sodium influx ionic currents, antagonists of GABAA receptors bicuculline, D1 dopamine receptors SCH23390 and D2 dopamine receptors sulpiride which were administered intrastructurally into the bed nucleus of stria terminalis, were used for pharmacological analysis. Xycaine > SCH23390 = bicuculline inhibited self-stimulation of the lateral hypothalamus. The reinforcing properties of a number of psychoactive drugs (amphetamine, Fentanyl, sodium ethaminal and leuenkephaline) were changed on the background of their action. It is concluded that the bed nucleus of stria terminalis controls the hypothalamic self-stimulation via GABA- and dopaminergic mechanisms. GABA realizes the negative (inhibitory) action. The direct positive (activating) effect on the lateral hypothalamus is realized through D1 dopamine receptors, and D2 dopamine receptors of the bed nucleus of stria terminalis limit the positive effects of narcogenic drugs.     

Effect of chronic administration of lithium chloride on the development of dopamine receptor sensitivity during morphine withdrawal in rats

The morphine withdrawal syndrome was studied in male Wistar rats. Spontaneous aggressiveness, enhanced apomorphine aggressiveness, lowered pain threshold and decreased dopamine turnover were observed after withdrawal of 10-day treatment with the increasing doses of morphine (30-300 mg/kg). These changes attested to the increased sensitivity of dopamine receptors. Administration of morphine in conjunction with lithium chloride in a dose of 2 mekv/kg prevented the development of dopamine receptor hypersensitivity. Also, this method did not produce the increased spontaneous and apomorphine aggressiveness or the decreased dopamine turnover. Meanwhile the pain threshold remained lowered.     

Conditioned-reflex activation of electrical self-stimulation of the brain: a model of a situational craving for narcotics]

Rats with electrodes implanted into lateral hypothalamus were trained to press a lever to obtain electrical stimulation of the brain. After elaboration of self-stimulation (SS) conditioning of morphine-induced activation of SS-response was carried out. Five pairings were performed of morphine (3 mg/kg, i.p.) administration and SS in the box with distinct environmental cues (brightness, color, floor texture, background noise). After morphine withdrawal activation of SS was reproduced after simple placing of the animal in "conditioned" chamber. This effect was naloxone-sensitive. The observed effect is considered to be the adequate model of addictive substances craving.     

Role of tricyclic antidepressants in the central regulation of hyperalgesia and stress analgesia

The effect of hypophysectomy (HE) on pain thresholds was studied in female noninbred rats. Hyperalgesia was observed after HE since the first till the sixth day of the observation period. Droperidol (1 mg/kg i.p.) and amitryptyline (5 mg/kg i.p.) produced hyperalgesia in sham-operated rats, which was potentiated in hypophysectomized animals. In rats taken into the experiment 3 days after operation, no increase in the pain threshold was recordable during the 30-minute painful stress, and poststress autoanalgesia did not develop subsequently. The opposing data were obtained in sham-operated animals. On intraperitoneal administration of phentanyl (25 micrograms/kg) after the 30-minute painful stress hypophysectomized rats did not manifest any potentiation of its analgesic effect in contradistinction to sham-operated animals. Simultaneous administration of phentanyl at the same dose and melipramine (5 mg/kg i.p.) produced considerable potentiation of analgesia if administered after stress. In hypophysectomized rats, that effect was somewhat reduced.     

The effects of pituitary adenylate cyclase-activating polypeptide on acute and chronic morphine actions in mice

The effects of pituitary adenylate cyclase-activating polypeptide (PACAP) on pain sensitivity, on morphine analgesia, on morphine tolerance and withdrawal were investigated in mice. The heat-radiant tail-flick test was used to assess antinociceptive threshold. Intracerebroventricular (i.c.v.) administration of PACAP alone had no effect on pain sensitivity but in a dose of 500 ng, it significantly diminished the analgesic effect of a single dose of morphine (2.25 mg/kg, s.c.). PACAP (500 ng, i.c.v.) significantly increased the chronic tolerance to morphine and enhanced the naloxone (1 mg/kg, s.c.)-precipitated withdrawal jumping. Theophylline (1 mg/kg, i.p.) pretreatment significantly enhanced the effect of PACAP on morphine analgesia but the effects of PACAP on tolerance and withdrawal were unaffected upon theophylline administration. On the grounds of our previous studies with vasoactive intestinal polypeptide (VIP), it appears that different receptors are involved in the effects of PACAP in acute and chronic morphine actions. Our results indicate that PACAP-induced actions likely participate in acute and chronic effects of morphine and suggest a potential role of PACAP in opioid analgesia, tolerance and withdrawal.     

Pain threshold and morphine activity in vitamin D-deficient rats

In rats, vitamin D-deficiency increases basal pain threshold and the analgesic effect of morphine (hot plate test). Cholecalciferol (1000 I.U./Kg/day s.c.x 5 days) restores pain sensitivity in vitamin D-deficient rats and brings the analgesic effect of morphine back to normal. On the other hand, tolerance to morphine develops faster in vitamin D-deficient rats, this effect too being prevented by cholecalciferol treatment. These data suggest a role for vitamin D status in pain sensitivity and opiate activity.