Effect of tetanus toxin on noradrenalin liberation from rat brain synaptosomes

A purified preparation of tetanus toxin (TT) (80–800 MLD/mg protein) was shown to induce liberation of both endogenous and exogenous (labeled with¹⁴C) noradrenalin (NA) from isolated nerve endings (synaptosomes) of the rat brain. Within the range of concentrations studied TT does not inhibit secretion of NA evoked by depolarization of synaptosomes by different methods in vitro.Laboratory of General Pathology of the Nervous System, Institute of General Pathology and Pathological Physiology, Academy of Medical Sciences of the USSR, Moscow. Translated from Byulleten' Éksperimental'noi Biologii i Meditsiny, Vol. 89, No. 2, pp. 148–150, February, 1980.     

Photogenic epilepsy with excitation generator located in the lateral geniculate body (the so-called determinant dispatch station phenomenon)

In experiments on rats and cats a photogenic seizure syndrome was produced by injecting purified tetanus toxin into the lateral geniculate body. Seizures appeared both in response to a photic stimulus and spontaneously. In the period between seizures, flashes evoked photomotor spasms. It is concluded that as a result of disturbance of the mechanisms of inhibition by tetanus toxin a generator of pathologically enhanced excitation arises in the lateral geniculate body and forms the basis of a hyperactive so-called determinant dispatch station, that causes the appearance of the photogenic epilepsy described.Laboratory of General Pathology of the Nervous System, Institute of General Pathology and Pathological Physiology, Academy of Medical Sciences of the USSR, Moscow. Translated from Byulleten' Éksperimental'noi Biologii i Meditsiny, Vol. 81, No. 1, pp. 22–25, January, 1976.     

Analysis of analgesia evoked by creation of an excitation generator in dorsal raphe nucleus

An excitation generator was created in the dorsal raphe nucleus of the mesencephalon in experiments on albino rats by microinjection of tetanus toxin into the nucleus. During formation of the excitation generator electrical activity was found to change in this nucleus, with a sharp increase in the primary negative component (N₁) and a change in the general configuration of the evoked potentials (EP), and an increase in the frequency of spontaneous paroxysmal activity. These changes in EP coincide in time with the appearance of deep and increasing analgesia. The type of analgesia described is not abolished by naloxone.Laboratory of General Pathology of the Nervous System, Institute of General Pathology and Pathological Physiology, Academy of Medical Sciences of the USSR, Moscow. Translated from Byulleten' Éksperimental'noi Biologii i Meditsiny, Vol. 88, No. 9, pp. 278–281, September, 1979.     

Neuropathological effects of injection of tetanus toxin into certain structures of the rat brain

The neuropathological effects of local injection of tetanus toxin (TT) into various structures of the brain were studied in experiments on rats. Definite neuropathological changes were observed in the animals, different from those found after injection of TT elsewhere. As a rule the action of TT in a given region of the brain was local. The experiments confirm the theory of generator mechanisms of neuropathological syndromes, according to which specific manifestations of the corresponding syndrome are determined by the location of a generator of pathologically enhanced excitation in a certain brain structure.Laboratory of General Pathology of the Nervous System, Institute of General Pathology and Pathological Physiology, Academy of Medical Sciences of the USSR, Moscow. (Presented by Academician of the Academy of Medical Sciences of the USSR A. M. Chernukh.) Translated from Byulleten' Éksperimental'noi Biologii i Meditsiny, Vol. 87, No. 2, pp. 124–126, February, 1979.     

Analgesia caused by an excitation generator formed in the mesencephalon

In experiments on albino rats an excitation generator was formed with tetanus toxin in the dorsal nucleus of the midbrain raphe. The formation of an excitation generator in this nucleus was shown to produce general analgesia manifested against physiological (nociceptive stimulation) and central pathological pain (a pain syndrome of spinal origin). It is concluded that prolonged analgesia arising during activation of certain brain structures is due to the appearance of excitation generators in them, which cause prolonged activation of those structures.Laboratory of General Pathology of the Nervous System, Institute of General Pathology and Pathological Physiology, Academy of Medical Sciences of the USSR, Moscow. Translated from Byulleten' Éksperimental'noi Biologii i Meditsiny, Vol. 85, No. 2, pp. 145–148, February, 1977.     

Experimental pain and itch syndromes of thalamic origin

Syndromes of pain and itch of thalamic origin were produced in experiments on rats by inducing generators of pathologically increased excitation in the nucleus gelatinosus of the thalamus by means of a local disturbance of inhibitory processes in that nucleus caused by injection of tetanus toxin. The toxin was injected into the nucleus in microvolumes by a stereotaxic method. The results of the investigations agree with the concept of generator mechanisms of neuropathological syndromes which the authors have developed on the basis of the theory of the role of determinant dispatch stations in the activity of the nervous system.Laboratory of General Pathology of the Nervous System, Institute of General Pathology and Pathological Physiology, Academy of Medical Sciences of the USSR, Moscow. Translated from Byulleten' Éksperimental'noi Biologii i Meditsiny, Vol. 81, No. 6, pp. 651–653, June, 1976.     

Effect of diazepam on epileptic activity in rats with experimental photogenic epilepsy

The effect of diazepam (in a dose of 4 mg/kg body weight) on the specific and nonspecific mechanisms of formation of experimental photogenic epilepsy, produced by injection of tetanus toxin into the lateral geniculate body (LGB), and the formation of a generator of pathologically enhanced excitation (GPEE) in that nucleus, was studied in chronic experiments on rats. In the above dose diazepam was found to have a relatively weak action on the degree of pathological enhancement of sensory visual stimuli in LGB in which a GPEE was formed, it facilitated the appearance of focal interictal discharges in LGB, and for 1 h it completely suppressed generalized epileptic activity in the experimental animals.Laboratory of General Pathology of the Nervous System, Institute of General Pathology and Pathological Physiology, Academy of Medical Sciences of the USSR, Moscow. Translated from Byulleten' Éksperimental'noi Biologii i Meditsiny, Vol. 87, No. 2, pp. 160–164, February, 1979.     

Action of tetanus toxin and colchicine on synaptic membranes of the rat cerebral cortex

Purified tetanus toxin (TT), in experiments in vitro, was shown to affect neither the Na,K-ATPase activity of the synaptic membrane fraction of the rat cerebral cortex nor the inhibition of Na,K-ATPase activity produced by electrical stimulation of a suspension of synaptic membranes, nor the binding of GABA-³H by synaptosomes. TT and colchicine (1 mM) reduced the osmotic sensitivity of the nerve endings. Colchicine, in low concentrations (10^–5 to 10^–3 M), does not affect Mg- and Na,K-ATPase but, in higher concentrations (10^–2 M), it inhibits the activity of both ATPases considerably.Laboratory of General Pathology of the Nervous System, Institute of General Pathology and Pathological Physiology, Academy of Sciences of the USSR, Moscow. Translated from Byulleten' Éksperimental'noi Biologii i Meditsiny, Vol. 83, No. 2, pp. 139–142, February, 1977.     

Pathogenetic factors of experimental photogenic epilepsy

The character of formation of an experimental syndrome of photogenic epilepsy, obtained by creating a generator of pathologically enhanced excitation in the lateral geniculate body by local injection of tetanus toxin, was studied in chronic experiments on rats. The initial manifestations appearing in the animals were shown to be due to pathological enhancement of specific sensory excitation in the lateral geniculate body and to be accompanied by a marked increase in amplitude of the evoked potential in the visual cortex. The subsequent development of a neuropathological syndrome was connected with diffuse disturbances of rhythmic electrical activity of the brain, characteristic of a state of increased epileptic predisposition in the experimental animals. The results of these experiments indicate an important role of specific and nonspecific factors of epileptogenesis in the formation of experimental photogenic epilepsy.Laboratory of General Pathology of the Nervous System, Institute of General Pathology and Pathological Physiology, Academy of Medical Sciences of the USSR, Moscow. Translated from Byulleten' Eksperimental'noi Biologii i Meditsiny, Vol. 87, No. 1, pp. 8–12, January, 1979.     

Generators of pathologically enhanced excitation as determinant structures in the spinal cord

With the aid of tetanus toxin, which disturbs various types of inhibition, generators of excitation were created in the left and right anterior horns of the lumbar spinal cord in rats. The regimes of activity of the generators differed: the left-sided generator, formed during the longer action of the toxin, in response to activation by trigger stimulation first produced tonic, and then intermittent activity, or individual spontaneous discharges, whereas the righ-sided generator produced only tonic activity. If one generator was blocked by glycine, the other continued to operate as before. Activation of one generator led to concomitant depression of the effects of the other. During separate activation of each generator, all the spinal and supraspinal motoneuron pools synchronously reproduced the character of activity of the generator functioning at that particular moment. The generator thus played the role of a determinant structure, determining the behavior of the system. The results are examined from the standpoint of the general concept of the role of determinant structures in the activity of the nervous system and the theory of generator mechanisms of neuropathological syndromes characterized by hyperactivity of systems.Laboratory of General Pathology of the Nervous System, Institute of General Pathology and Pathological Physiology, Academy of Medical Sciences of the USSR, Moscow. Translated from Byulleten' Éksperimental'noi Biologii i Meditsiny, Vol. 83, No. 5, pp. 515–519, May, 1977.     

Effect of tetanus toxin on contractility of the actomyosin-like protein of rat brain

Preparation of purified actomyosin-like protein (ALP) was isolated from the coarse fraction of rat brain mitochondria. The ALP preparation contained Mg(Ca)-ATPase activity, inhibited by 0.1% deoxycholate, together with acetylcholinesterase activity and contractility (superprecipitation reaction). The contraction of ALP and ATPase activity were considerably reduced by tetanus toxin. Inactivated toxin had no effect. The possible functional role of ALP in the maintenance and secretion of mediators by nerve endings is discussed.Laboratory of General Pathology of the Nervous System, Institute of Normal and Pathological Physiology, Academy of Medical Sciences of the USSR, Moscow. Translated from Byulleten' Éksperimental'noi Biologii i Meditsiny, Vol. 78, No. 12, pp. 24–27, December, 1974.     

Some properties of low-molecular-weight tetanus antitoxin

After intravenous injection of tetanus antitoxin obtained by tryptic digestion of Diaferm-3 horse immunoglobulin, purification, and concentration of the active fragments, the antitoxin was excreted by rabbits 3 times faster than after injection of the original Diaferm-3 antitoxin. After injection of the fragmented antitoxin its excretion continued until the 6th days, whereas after injection of Diaferm-3 antitoxin its excretion continued until the 19th day; in the first case much less antitoxin was excreted than in the second (2% and 3.5% respectively). In both cases the antitoxin excreted in the urine consisted of monovalent Fab' fragments which caused delay of precipitation in the cross reaction in agar gel between tetanus toxoid and antitetanus serum. The Fab' gragment obtained by this method possessed anaphylactogenic properties.L'vov Medical Institute. Institute of General Pathology and Pathological Physiology, Academy of Medical Sciences of the USSR, Moscow. Translated from Byulleten' Éksperimental'noi Biologii i Meditsiny, Vol. 81, No. 3, pp. 331–333, March, 1976.     

Food hypermotivation syndromes in rabbits with hyperactivity of lateral hypothalamic structures

A focus of hyperactivity in the initiating centers for food motivation was created in experiments on unrestrained rabbits by blocking inhibitory mechanisms in the lateral hypothalamus (LH) by injection of tetanus toxin (group 1) or by chronic electrical stimulation of the same region of the brain (group 2). The syndromes thus evoked differed in the intensity of food hypermotivation. The syndrome evoked by injection of tetanus toxin was characterized by very rapid development, clear symptoms of hyperphagia, and a severe course. Marked epileptiform activity was recorded in LH, evidence of the formation of a generator of pathologically enhanced excitation in the pacemaker of food motivation. Mechanisms of adequate correction of behavior depending on the result obtained were completely disturbed in the animals. The syndrome evoked by chronic electrical stimulation of LH was characterized by slower formation and a more favorable course. Relatively weak epileptiform activity was recorded in LH. Enhanced food-getting activity of the rabbits also was observed in the late periods after the beginning of electrical stimulation, but the animals' behavior did not lose its adaptive character in this case. The formation of the two syndromes of food hypermotivation described above was connected with the formation of two excitation generators, differing in the intensity of excitation produced by them.Laboratory of General Pathology of the Nervous System, Institute of General Pathology and Pathological Physiology, Academy of Medical Sciences of the USSR, Moscow. Department of Pathological Physiology, Leningrad San.-Gig. Medical Institute. Group for Neurophysiology of Motivations, Institute of Normal Physiology, Academy of Medical Sciences of the USSR, Moscow. Translated from Byulleten' Éksperimental'noi Biologii i Meditsiny, Vol. 89, No. 3, pp. 281–284, March, 1980.     

Prolongation of sleep as the result of the creation of a generator of pathologically enhanced excitation in the orbital cortex

In acute experiments on cats injection of tetanus toxin, which disturbs various types of inhibition, into the orbital cortex caused the formation of a local generator of pathologically enhanced excitation in that region. In chronic experiments on cats with such a generator in the orbital cortex pathological changes of sleep appeared: a decrease in the duration of wakefulness and the development of a prolonged sleep state, while the normal ratio between slow-wave and paradoxical stages in the sleep continuum was preserved. The results confirm the view that the orbitofrontal cortex participates in the induction of sleep and they develop the general concept of the role of determinant structures in the activity of the nervous system and the theory of generator mechanisms of neuropathological syndromes characterized by hyperactivity of its systems.Laboratory of General Pathology and Pathological Physiology, Academy of Medical Sciences of the USSR, Moscow. Department of Pathological Physiology, N. I. Pirogov Odessa Medical Institute. Translated from Byulleten' Éksperimental'noi Biologii i Meditsiny, Vol. 84, No. 11, pp. 531–534, November, 1977.     

Creation of hyperactive determinant dispatch stations in the caudate nucleus in experimental neuropathological syndromes caused by tetanus toxin

Generators of pathologically enhanced excitation, playing the role of hyperactive determinant dispatch stations (DDS) were created with the aid of tetanus toxin, which disturbs various types of inhibition in rats, in the rostral part of both caudate nuclei. The formation of these DDS generators in the structures specified led to the formation of stereotypes, impulsive seizure movements, and catalepsy.Laboratory of General Pathology of the Nervous System, Institute of General Pathology and Pathological Physiology, Academy of Medical Sciences of the USSR, Moscow. Translated from Byulleten' Éksperimental'noi Biologii i Meditsiny, Vol. 81, No. 4, pp. 397–399, April, 1976.     

Experimental simulation of neuropathological syndromes by creating pathologically enhanced excitation generators in the rabbit hypothalamus

Experiments on rabbits under free behavior conditions showed that injection of tetanus toxin into motivation-emotiogenic pacemaker regions of the hypothalamus, with the object of producing generators of pathologically enhanced excitation in those regions gives rise to stable and prolonged disturbances of the animals' motivational-emotional behavior. These changes were expressed as a marked increase in foodgetting activity by the animals, including an increase in secondary motivational responses, increased motor activity, the appearance of an excessive number of automated chewing movements, aggressiveness, a fear reaction, and the corresponding autonomic changes. The character of these responses depended on the region into which the toxin was injected and on its dose. Investigations showed that the formation of long-acting generators of pathologically enhanced excitation in motivation-emotiogenic pacemaker centers of the hypothalamus with the aid of tetanus toxin can be used to simulate psychopathological states in animals. The results confirm, by the use of this new model, the theory of generator mechanisms of neuropathological syndromes characterized by hyperactivity of systems.Laboratory of General Pathology of the Nervous System, Institute of General Pathology and Pathological Physiology, Academy of Medical Sciences of the USSR. Laboratory of Emotions and Emotional Stresses, P. K. Anokhin Institute of Normal Physiology, Academy of Medical Sciences of the USSR, Moscow. Translated from Byulleten' Éksperimental'noi Biologii i Meditsiny, Vol. 84, No. 10, pp. 405–408, October, 1977.     

Analgesia on electrical stimulation of mesencephalic nuclei in rats with a pain syndrome of spinal origin

Effects of electrical stimulation of the periventricular gray matter and dorsal nucleus raphe in the midbrain on physiological pain induced by nociceptive stimulation (crushing the tail or skin of the limbs with forceps) and on pathological pain (a pain syndrome of spinal origin) were studied in experiments on albino rats. This last pain syndrome was produced by creating a generator of pathologically enhanced excitation in the posterior horns of the spinal cord with the aid of tetanus toxin, which disturbs various types of inhibition. Electrical stimulation of the above structure was shown to depress both physiological and pathological pain. It is concluded that analgesia during electrical stimulation of brain structures is connected not only with the strengthening of descending inhibition in the spinal cord, as in the case of physiological pain caused by peripheral nociceptive stimulation (as several workers have shown), but also with blocking the spread of excitation at the supraspinal level. This mechanism must play the decisive role in the production of analgesia in pain syndromes of central origin, including those arising under natural conditions.Laboratory of General Pathology of the Nervous System, Institute of General Pathology and Pathological Physiology, Academy of Medical Sciences of the USSR, Moscow. Translated from Byulleten' Éksperimental'noi Biologii i Meditsiny, Vol. 84, No. 7, pp. 16–19, July, 1977.     

An experimental vestibulopathy produced by formation of a pathologically enhanced excitation generator in the vestibular nucleus (the determinant dispatch station phenomenon)

The possibility of formation of a pathologically enhanced excitation generator in the vestibular nucleus of the medulla through a disturbance of inhibition in that nucleus was demonstrated and, as a result, the animals developed rotatory movements toward the opposite side. Experimental electrical stimulation or coagulation of the lateral vestibular nucleus showed that the pathologically enhanced excitation generator is based on a system of vestibular neurons which organizes a synchronous volley along the vestibulo-spinal tracts. It is concluded that the pathologically enhanced excitation generator formed in the lateral vestibular nucleus as a result of disturbance of inhibition lies at the basis of the hyperactive determinant dispatch station responsible for the syndrome of vestibulopathy.Laboratory of General Pathology of the Nervous System, Institute of General Pathology and Pathological Physiology, Academy of Medical Sciences of the USSR, Moscow. Translated from Byulleten' Éksperimental'noi Biologii i Meditsiny, Vol. 81, No. 2, pp. 147–150, February, 1976.     

Experimental stereotypy induced by disturbance of GABA-ergic mechanisms in the caudate nuclei

Stereotypy was produced in rats by the formation of generators of pathologically enhanced excitation (GPEE) during local disturbance of inhibitory mechanisms in the rostral part of the caudate nuclei (CN) as a result of bilateral, injection of tetanus toxin. Microinjections of gamma-aminobutyric acid (GABA) into the region of GPEE and systemic administration of haloperidol suppressed the stereotyped behavior of the animals. It is concluded that the stereotypy may be based on the formation of a GPEE as a result of disturbances in the presynaptic component of the GABA-ergic system of CN, the operant part of which consists of dopaminergic neurons.Laboratory of General Pathology of the Nervous System, Institute of General Pathology and Pathological Physiology, Academy of Medical Sciences of the USSR, Moscow. Translated from Buylleten' Éksperimental'noi Biologii i Meditsiny, Vol. 87, No. 4, pp. 314–317, April, 1979.     

Analgesic effects of inhibitory mediators in a pain syndrome of spinal origin

A pain syndrome of spinal origin was induced by creating a generator of pathologically enhanced excitation (GPEE) in the dorsal horn of the lumbosacral segments of the spinal cord in rats with the aid of tetanus toxin, strychnine, penicillin, KCl, and ouabain. The substances were applied to the dorsal surface of the spinal cord. An agar wafer method was developed to enable local prolonged and dose-dependent effects of the substances applied to be produced and studied in freely behaving animals. The effects of the inhibitory mediators were determined by the nature of the generator produced and, in particular, by the state of the mediator-receptor system of the neuronal membranes of cells forming in GPEE. Glycine prevented the development of the pain syndrome in the case of generators induced with tetanus toxin, penicillin, KCl, and ouabain. GABA was effective in the case of generators produced by tetanus toxin, potassium, and ouabain. Injection of glycine into the region of a generator produced by tetanus toxin at the height of development of the pain syndrome abolished that syndrome for the duration of action of the mediator. The pain syndrome could thus be specifically abolished or prevented for the period of action of the mediator by depressing the GPEE with the appropriate inhibitory mediators, depending on the nature of the GPEE, i.e., on the features distinguishing the state of the mediator apparatus of its neurons. Under these conditions inhibitory mediators, although not analgesics in the pharmacological sense, have a specific analgesic effect.Laboratory of General Pathology of the Nervous System, Institute of General Pathology and Pathological Physiology, Academy of Medical Sciences of the USSR, Moscow. Translated from Byulleten' Éksperimental'noi Biologii i Meditsiny, Vol. 87, No. 6, pp. 525–528, June, 1979.