300
Brain Research, 583 (1992) 300-303 © 1992 Elsevier Science Publishers B.V. All rights reserved 0006-8993/92/$05 .00
BRES 25256
Neurochemical effects of vagus nerve stimulation in humans Edward J. Hammond a
a,
B.M. Uthman a, B.J. Wilder a, E. Ben-Menachem T. Hedner d and R. Ekman d
b,
A. Hamberger C,
Neurology Service, Veterans Affairs Medical Center, Gainesville, FL 32608-1197 (USA) and Departments of b Neurology, C Histology and d Pharmacology, University of Gothenburg, Gothenburg (Sweden) (Accepted 7 April 1982)
Key words: Vagus nerve; Serotonin; Dopamine; Aspartate; Neurotransmitter
An implanted stimulating device chronically stimulated the left cervical vagus nerve in epileptic patients. Cerebrospinal fluid concentrations of free and total j-amincbutyric acid , homovanillic acid, 5-hydroxyindoleacetic acid, aspartate, glutamate, aspargine, serine, glutamine, glycine, phosphoethanolamine, taurine, alanine, tyrosine, ethanolamine, valine , phenylalanine, isoleucine, vasoactive intestinal peptide, {3-endorphin, and somatostatin were measured before and after 2 months of chronic stimulation in six patients. Significant increases were seen in homovanillic acid and 5-hydroxyindoleacetic acid in three patients, and significant decreases in aspartate were seen in five patients. These changes were associated with a decrease in seizure frequency.
Electrical stimulation of the vagus nerve is known to produce changes in the electroencephalogram of experimental animals'v" and also to interrupt epileptic seizures in several animal models of epil epsy 23,24,27,28. Afferent fibers of the vagus nerve project to the nucleus tractus solitarius and area postrema, and these areas have widespread connections to many parts of the brain I3•14,19, including the reticular formation, hypothalamus, amygdala, and hippocampus. Accordingly, we implanted a programmable device for stimulating the vagus nerve" in fifteen medically intractable epileptic patients. Results concerning clinical efficacy are reported elsewhere". The mechanism of the antiepileptic effect of vagus nerve stimulation is unknown. One possible mechanism of antiepileptic action is that the electrical stimulation of the vagus nerve causes some anticonvulsant neurochemical to be released at its projection site. To study this possibility, we analyzed cerebrospinal fluid taken from six patients before and after 2 months of chronic intermittent vagus nerve stimulation. We studied patients with medically intractable complex partial seizures, aged 21-58 years. All patients
gave written informed consent for participation in this study. The implanted vagus nerve stimulator (Cyberonics, Inc., Webster TX, Model 100) is a programmable pulse generator that delivers electric pulses to the vagus nerve. It is implanted subcutaneously in the upper chest, and bipolar stimulating electrodes were tunneled to it from the stimulation site in the left side of the neck. The system is programmed with an IBMcompatible personal computer with a specially constructed interface unit. The stimulus current, pulse width, frequency, and duty cycle can be non-invasively adjusted. In these patients stimulus parameters were adjusted to be the maximal which could be comfortably tolerated by each patient. The parameters were in the range of 1.25-3.0 rnA at 10-30 Hz (one patient was stimulated at 2 Hz) with pulse duration of 500 J,LS. Twenty-six 1-ml aliquots of cerebrospinal fluid were taken from the patients who fasted for at least 10 h. Samples were not drawn if the patient had experienced a seizure within the previous 24 h. The chronic intermittent vagus nerve stimulation was suspended during the collection of CSF samples; the period of the last vagal stimulation was approximately 20 min. Aliquots
Correspondence: EJ . Hammond, Neurology Service (127), V.A. Medical Center. Gainesville, FL 32608-1197, USA.
301 were frozen in liquid nitrogen within seconds of being drawn and kept at -70cC until analysis. High-pressure liquid chromatography measurements were made of levels of free and total v-aminobutyric acid, homovanillic acid, 5-hydroxyindoleacetic acid, aspartate, aspargine, glutamate, glutamine, glycine, phenylethalanoamine, taurine, alanine, tyrosine, ethanolamine, methionine, valine, phosphoethanolarnine, and isoleucine; techniques have been published elsewhere", VasointestinaI peptide, somatostatin, and {3-endorphin were analyzed using immunoreactive techniques previously published 7,18,2o. Only levels of
5-hydroxyindoleacetic acid (5-HIAA) and homovanillic acid (HVA) were significantly increased after vagus nerve stimulation. 5-HIAA and HVA are metabolites of the neurotransmitters serotonin and dopamine, respectively. 5-HIAA increased in three patients by 51, 99, and 172% (mean 107%) (see Fig. 1). HVA was increased (by 12, 13, and 78%, mean 68%) in three patients but to a lesser extent than 5-HIAA. Decreased levels, averaging 25%, of the excitatory neurotransmitter aspartate (ASP) were seen in five of the six patients. Only insignificant and/or sporadic changes were seen in the many other substances analyzed (Fig. 1).
B
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I
Fig. lA-D. Effect of chronic cervical vagus nerve stimulation on various neurochemicals measured in cerebrospinal fluid. Cerebrospinal fluid was taken prior to and 2 months after chronic vagus nerve stimulation and analyzed with high-pressure liquid chromatography. Data from each individual patient are shown as well as mean values from all patients. Data are presented as per cent change from baseline. Histograms also show per cent change from baseline of seizure frequency for each patient. Abbreviations: F-GABA, free y-aminobutyric acid; T-GABA, total y-aminobutyric acid; HVA, homovanillic acid; HIAA, 5-hydroxyindoleacetic acid; ASP, aspartate; ASN, aspargine; GLV, glutamate; SER, serine; GLN, glutamine; GLY, glycine; PEA, phosphoethanolamine; TAU, taurine; ALA, alanine; TRY, tyrosine; EA, ethanolamine; MET, methionine; VAL, valine; PHE, phenylalanine; ISO, isoleucine; VIP, vasoactive intestinal peptide; SOM, somatostatin, END, p-endorphin; and SZ FREQ, seizure frequency during the month prior to CSF collection. At the base of the histograms, data concerning the patient number and stimulus parameters are given.
302
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I
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It§1 Pt COg: 1.5mA at 30Hz I Fig. 1 (continued ).
Further rese arch is needed to determine whether the selective increases in 5-HIAA and HVA and decreases in ASP reported here are epiphenomena or are directly related to the vagus nerve stimulation. It is possible that these changes are related to an anticonvulsant effect since serotonergic and to a lesser extent dopaminergic mechani sms have been found to have anticonvulsant effects in animal and human studies of various types of epilepsy (see refs. 7 and 19 for reviews). Anticonvulsant dopaminergic mechanisms have also been implicated in experimental seizure models 1,21. Anatomical":" and physiological studies 3,5,10,17 indicate that serotonergic mechanisms are active in the cervical vagus nerve and nucleus tractus solitarius. For example the data of Meller and colleagues'? indicated that 5-hydroxytryptamine (5-HT) stimulates vagal affer-
ents which project centrally and then activate descending inhibitory systems from the brainstem. In their studies 5-HT-mediated vagal stimulation inhibited the nociceptive tail-flick reflex in rats. Descending pathways inhibitory to flexion reflex afferents as well as exerting postsynaptic inhibition of flexion motoneurons have been described in some detail", The studies of Browning (reviewed in ref. 8) demonstrated that the pontine reticular formation plays a key role in the generation and expression of tonic convulsions and that this area contains critical serotonergic neurons involved in giving an antiextensor effect in experimental maximal electric shock seizures. Such descending pathways into the spinal cord have been implicated in the motor aspects of expression of some types of seizures 8,12. Although we are mainly measuring complex partial seizures in our human patients,
303 clonic and tonic-clonic convulsive activities in experimental animals are considered to be a model for human generalized seizures. Aspartate levels also correlated with seizure control. For example, the only patient (COl) who showed increased ASP levels after vagus nerve stimulation, was the only patient who reported no beneficial effect of the stimulator, and the patients (C03 and C06) with the largest decrease in ASP reported the best seizure control (see Fig. 1). Aspartate has been implicated in experimental and human seizure mechanisms. In particular, the N-methyl-D-aspartate receptor is thought to playa critical role in epileptogenesis 2,15,22 . There are several limitations to this study. Although Ben-Menachem and colleagues" have shown that dayto-day variability in neurochemical levels measured in CSF is minimal, this still could playa role in individual subjects. Also, at the present time the effects of different stimulus parameters on vagal presynaptic release of neurochemicals is unknown. Although the stimulus parameters varied slightly in our patients (see Fig. I), they are similar enough to warrant conclusions about the resultant CSF levels. These initial data need to be extended in further studies in human epileptic patients and experimental animals to further study these possible variables. The authors are grateful to Janet Wootten and Anne Crawford for manuscript preparation, and to L.K Holder for graph construction. This research was supported by the Medical Research Service of the Veterans Affairs Medical Center, and the Epilepsy Research Foundation of Florida. 1 Anlezark, G.M. and Meldrum, B.S., Effects of apomorphine, ergocornine, and piribedil on audiogenic seizures in DBA/2 mice, Br. J. Pharmacol., 53 (1975) 419-426. 2 Avoli, M. and Olivier, A, Bursting in human epileptogenic neocortex is depressed by an N-methyl-D-aspartate antagonist, Neurosci. Lett.. 76 (1987) 249-254. 3 Bachman, D.S., Hallowitz, R.A and MacLean, P.D., Effects of vagal volleys and serotonin on units of cingulate cortex in monkeys, Brain Res., 130 (1977) 253-269. 4 Ben-Menachem, E., Persson, L.L, Schechter, P.J., Haegele, KD., Hurbert, N. and Hardenberg, J., Cerebrospinal fluid parameters in healthy volunteers during serial lumbar punctures, 1. Neurochem., 53 (1989) 632-635. 5 Beck, P.W. and Handwerker, H.O., Bradykinin and serotonin effects on various types of cutaneous nerve fibers, Pfliigers Arch., 347 (1974) 207-222. 6 Bowker, R.M., Westlund, KN., Sullivan, M.C. and Coulter, J.D., Organization of descending serotonergic projections to the spinal cord, Prog. Brain Res., 57 (1982) 239-265. 7 Brammert, M., Ekman, R, Larsson, I. and Thorell, J., Characterization and application of a radioimmunoassay for ,a-endorphin using an antiserum with negative cross-reactivity against ,a-lipotropin, Regul. Pept., 5 (1982) 65-75. 8 Browning, RA, Role of the brain-stem reticular formation in tonic-clonic seizures: lesion and pharmacological studies, Fed. Proc., 44 (1985) 2425-2431.
9 Chase, M.H., Nakamura, Y. and Clemente, C.D., Afferent vagal stimulation: neurographic correlates of induced EEG synchronization and desynchronization, Brain Res., 5 (1967) 236-249. 10 Fozard, J.R., Neuronal 5-HT receptors in the periphery, Neuropharmacology, 23 (1984) 1473-1486. 11 Fuxe, K and Owman, C, Cellular localization of monoamines in the area postrema of certain mammals, J. Camp. Neurol., 125 (1965) 337-347. 12 Jacobs, B.L., Motor activity and the brain serotonin system, Adv. Neurol., 43 (1986) 481-491. 13 Kalia, M. and Mesularn, M.-M., Brain stem projections of afferent and efferent fibers of the vagus nerve in the cat: I. The cervical vagus and nodose ganglion, J. Comp. Neurol., 193 (1980) 523-553. 14 Kalia, M. and Mesulam, M.-M., Brain stem projections of sensory and motor components of the vagus complex in the cat: II. Laryngeal, tracheobronchial, pulmonary, cardiac and gastrointestinal branches, 1. Camp. Neurol., 193 (1980) 467-508. 15 Kish, S.J., Dixon, L.M. and Sherwin, AL., Aspartic acid aminotransferase activity is increased in actively spiking compared with non-spiking human epileptogenic cortex, J. Neural. Neurosurg. Psychiatry, 51 (1988) 552-556. 16 Leslie, RA, Neuroactive substances in the dorsal vagal complex of the medulla oblongata: nucleus of the tractus solitarius, area postrema, and dorsal motor nucleus of the vagus, Neurochem. Int., 7 (1985) 191-211. 17 Meller, S.T., Lewis, S.1., Ness, T.1., Brody, M.1. and Gebhart, G.F., Vagal afferent-mediated inhibition of a nociceptive reflex by intravenous serotonin in the rat. I. Characterization, Brain Res., 524 (1990) 90-100. 18 Minthon, L., Edvinsson, L., Ekman, R. and Gustafson, L., Neuropeptide levels in Alzheimer's disease and dementia with frontotemporal degeneration, J. Neural Trans., Suppl. 30 (1990) 57-67. 19 Morest, D.K., Experimental studies of the projections of the nucleus of the tractus solitarius and the area postrema of the cat, 1. Camp. Neurol., 130 (1967) 277-300. 20 Nilson, Ekman, R., Lindvall-Axelsson, M. and Owman, C., Distribution of peptidergic nerves in the choroid plexus, focusing on coexistence of neuropeptide Y, vasoactive intestinal polypeptide and peptide histidine isoleucine, Regul. Pept., 27 (1990) 11-26. 21 Snead, O.c., On the sacred disease: the neurochemistry of epilepsy, Int. Rev. Neurobiol., 24 (1983) 93-180. 22 Stasheff, S.F., Anderson, W.W., Clark, S. and Wilson, W.A., NMDA antagonists differentiate epileptogenesis from seizure expression in an in vitro model, Science, 245 (1989) 648-651. 23 Stoica, L and Tudor, I., Effects of vagus afferents on strychninic focus of coronal gyrus, Rev. Raum. Neurol., 4 (1967) 287-295. 24 Stoica, I. and Tudor, I., Vagal trunk stimulation influences on epileptic spiking focus activity, Rev. Raum. Neurol., 5 (1968) 203-210. 25 Terry, R, Tarver, W.B. and Zabara, J., An implantable neurocybernetic prosthesis system, Epilepsia, 31 (Suppl, 2) (1990) S33S37. 26 Wilder, B.J., Uthman, B.M. and Hammond, E.J., Vagal stimulation for control of complex partial seizures in medically refractory epileptic patients, Pacing Clin. Electrophysiol., 14 (1991) 108-115. 27 Woodbury, D.M. and Woodbury, J.W., Effects of vagal stimulation on experimentally induced seizures in rats, Epilepsia, 31 (Suppl, 2) (1990) S7-S19. 28 Woodbury, J.W. and Woodbury, D.M., Vagal stimulation reduces the severity of maximal electroshock seizures in intact rats: use of a cuff electrode for stimulating and recording, Pacing Clin. Electrophysiol., 14 (1991) 94-107. 29 Zabara, J., Peripheral control of hypersynchronous discharge in epilepsy, Electroencephalogr. Clin. Neurophysiol., 61 (1985) S162. 30 Zanchetti, A, Wang, S.c. and Moruzzi, G., The effect of vagal stimulation on the EEG pattern of the cat, Electroencephalogr. Clin. Neurophysiol., 4 (1952) 357-361.
c.
Brain Research, 583 (1992) 300-303 © 1992 Elsevier Science Publishers B.V. All rights reserved 0006-8993/92/$05 .00
BRES 25256
Neurochemical effects of vagus nerve stimulation in humans Edward J. Hammond a
a,
B.M. Uthman a, B.J. Wilder a, E. Ben-Menachem T. Hedner d and R. Ekman d
b,
A. Hamberger C,
Neurology Service, Veterans Affairs Medical Center, Gainesville, FL 32608-1197 (USA) and Departments of b Neurology, C Histology and d Pharmacology, University of Gothenburg, Gothenburg (Sweden) (Accepted 7 April 1982)
Key words: Vagus nerve; Serotonin; Dopamine; Aspartate; Neurotransmitter
An implanted stimulating device chronically stimulated the left cervical vagus nerve in epileptic patients. Cerebrospinal fluid concentrations of free and total j-amincbutyric acid , homovanillic acid, 5-hydroxyindoleacetic acid, aspartate, glutamate, aspargine, serine, glutamine, glycine, phosphoethanolamine, taurine, alanine, tyrosine, ethanolamine, valine , phenylalanine, isoleucine, vasoactive intestinal peptide, {3-endorphin, and somatostatin were measured before and after 2 months of chronic stimulation in six patients. Significant increases were seen in homovanillic acid and 5-hydroxyindoleacetic acid in three patients, and significant decreases in aspartate were seen in five patients. These changes were associated with a decrease in seizure frequency.
Electrical stimulation of the vagus nerve is known to produce changes in the electroencephalogram of experimental animals'v" and also to interrupt epileptic seizures in several animal models of epil epsy 23,24,27,28. Afferent fibers of the vagus nerve project to the nucleus tractus solitarius and area postrema, and these areas have widespread connections to many parts of the brain I3•14,19, including the reticular formation, hypothalamus, amygdala, and hippocampus. Accordingly, we implanted a programmable device for stimulating the vagus nerve" in fifteen medically intractable epileptic patients. Results concerning clinical efficacy are reported elsewhere". The mechanism of the antiepileptic effect of vagus nerve stimulation is unknown. One possible mechanism of antiepileptic action is that the electrical stimulation of the vagus nerve causes some anticonvulsant neurochemical to be released at its projection site. To study this possibility, we analyzed cerebrospinal fluid taken from six patients before and after 2 months of chronic intermittent vagus nerve stimulation. We studied patients with medically intractable complex partial seizures, aged 21-58 years. All patients
gave written informed consent for participation in this study. The implanted vagus nerve stimulator (Cyberonics, Inc., Webster TX, Model 100) is a programmable pulse generator that delivers electric pulses to the vagus nerve. It is implanted subcutaneously in the upper chest, and bipolar stimulating electrodes were tunneled to it from the stimulation site in the left side of the neck. The system is programmed with an IBMcompatible personal computer with a specially constructed interface unit. The stimulus current, pulse width, frequency, and duty cycle can be non-invasively adjusted. In these patients stimulus parameters were adjusted to be the maximal which could be comfortably tolerated by each patient. The parameters were in the range of 1.25-3.0 rnA at 10-30 Hz (one patient was stimulated at 2 Hz) with pulse duration of 500 J,LS. Twenty-six 1-ml aliquots of cerebrospinal fluid were taken from the patients who fasted for at least 10 h. Samples were not drawn if the patient had experienced a seizure within the previous 24 h. The chronic intermittent vagus nerve stimulation was suspended during the collection of CSF samples; the period of the last vagal stimulation was approximately 20 min. Aliquots
Correspondence: EJ . Hammond, Neurology Service (127), V.A. Medical Center. Gainesville, FL 32608-1197, USA.
301 were frozen in liquid nitrogen within seconds of being drawn and kept at -70cC until analysis. High-pressure liquid chromatography measurements were made of levels of free and total v-aminobutyric acid, homovanillic acid, 5-hydroxyindoleacetic acid, aspartate, aspargine, glutamate, glutamine, glycine, phenylethalanoamine, taurine, alanine, tyrosine, ethanolamine, methionine, valine, phosphoethanolarnine, and isoleucine; techniques have been published elsewhere", VasointestinaI peptide, somatostatin, and {3-endorphin were analyzed using immunoreactive techniques previously published 7,18,2o. Only levels of
5-hydroxyindoleacetic acid (5-HIAA) and homovanillic acid (HVA) were significantly increased after vagus nerve stimulation. 5-HIAA and HVA are metabolites of the neurotransmitters serotonin and dopamine, respectively. 5-HIAA increased in three patients by 51, 99, and 172% (mean 107%) (see Fig. 1). HVA was increased (by 12, 13, and 78%, mean 68%) in three patients but to a lesser extent than 5-HIAA. Decreased levels, averaging 25%, of the excitatory neurotransmitter aspartate (ASP) were seen in five of the six patients. Only insignificant and/or sporadic changes were seen in the many other substances analyzed (Fig. 1).
B
Neurochemical Changes in CSF
..
A
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.
..,PATIENT COt .
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I~ Pt C03: 2.0mA at 10Hz I
Il§l Pt COl: 3.0mA at 2Hz I 40.---------------------,
.E
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Neurochemical.
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I
Fig. lA-D. Effect of chronic cervical vagus nerve stimulation on various neurochemicals measured in cerebrospinal fluid. Cerebrospinal fluid was taken prior to and 2 months after chronic vagus nerve stimulation and analyzed with high-pressure liquid chromatography. Data from each individual patient are shown as well as mean values from all patients. Data are presented as per cent change from baseline. Histograms also show per cent change from baseline of seizure frequency for each patient. Abbreviations: F-GABA, free y-aminobutyric acid; T-GABA, total y-aminobutyric acid; HVA, homovanillic acid; HIAA, 5-hydroxyindoleacetic acid; ASP, aspartate; ASN, aspargine; GLV, glutamate; SER, serine; GLN, glutamine; GLY, glycine; PEA, phosphoethanolamine; TAU, taurine; ALA, alanine; TRY, tyrosine; EA, ethanolamine; MET, methionine; VAL, valine; PHE, phenylalanine; ISO, isoleucine; VIP, vasoactive intestinal peptide; SOM, somatostatin, END, p-endorphin; and SZ FREQ, seizure frequency during the month prior to CSF collection. At the base of the histograms, data concerning the patient number and stimulus parameters are given.
302
c
75 - r - - - - - - - - - - - - - - - - - - - - - - ,
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~ 60
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It§1 Pt COg: 1.5mA at 30Hz I Fig. 1 (continued ).
Further rese arch is needed to determine whether the selective increases in 5-HIAA and HVA and decreases in ASP reported here are epiphenomena or are directly related to the vagus nerve stimulation. It is possible that these changes are related to an anticonvulsant effect since serotonergic and to a lesser extent dopaminergic mechani sms have been found to have anticonvulsant effects in animal and human studies of various types of epilepsy (see refs. 7 and 19 for reviews). Anticonvulsant dopaminergic mechanisms have also been implicated in experimental seizure models 1,21. Anatomical":" and physiological studies 3,5,10,17 indicate that serotonergic mechanisms are active in the cervical vagus nerve and nucleus tractus solitarius. For example the data of Meller and colleagues'? indicated that 5-hydroxytryptamine (5-HT) stimulates vagal affer-
ents which project centrally and then activate descending inhibitory systems from the brainstem. In their studies 5-HT-mediated vagal stimulation inhibited the nociceptive tail-flick reflex in rats. Descending pathways inhibitory to flexion reflex afferents as well as exerting postsynaptic inhibition of flexion motoneurons have been described in some detail", The studies of Browning (reviewed in ref. 8) demonstrated that the pontine reticular formation plays a key role in the generation and expression of tonic convulsions and that this area contains critical serotonergic neurons involved in giving an antiextensor effect in experimental maximal electric shock seizures. Such descending pathways into the spinal cord have been implicated in the motor aspects of expression of some types of seizures 8,12. Although we are mainly measuring complex partial seizures in our human patients,
303 clonic and tonic-clonic convulsive activities in experimental animals are considered to be a model for human generalized seizures. Aspartate levels also correlated with seizure control. For example, the only patient (COl) who showed increased ASP levels after vagus nerve stimulation, was the only patient who reported no beneficial effect of the stimulator, and the patients (C03 and C06) with the largest decrease in ASP reported the best seizure control (see Fig. 1). Aspartate has been implicated in experimental and human seizure mechanisms. In particular, the N-methyl-D-aspartate receptor is thought to playa critical role in epileptogenesis 2,15,22 . There are several limitations to this study. Although Ben-Menachem and colleagues" have shown that dayto-day variability in neurochemical levels measured in CSF is minimal, this still could playa role in individual subjects. Also, at the present time the effects of different stimulus parameters on vagal presynaptic release of neurochemicals is unknown. Although the stimulus parameters varied slightly in our patients (see Fig. I), they are similar enough to warrant conclusions about the resultant CSF levels. These initial data need to be extended in further studies in human epileptic patients and experimental animals to further study these possible variables. The authors are grateful to Janet Wootten and Anne Crawford for manuscript preparation, and to L.K Holder for graph construction. This research was supported by the Medical Research Service of the Veterans Affairs Medical Center, and the Epilepsy Research Foundation of Florida. 1 Anlezark, G.M. and Meldrum, B.S., Effects of apomorphine, ergocornine, and piribedil on audiogenic seizures in DBA/2 mice, Br. J. Pharmacol., 53 (1975) 419-426. 2 Avoli, M. and Olivier, A, Bursting in human epileptogenic neocortex is depressed by an N-methyl-D-aspartate antagonist, Neurosci. Lett.. 76 (1987) 249-254. 3 Bachman, D.S., Hallowitz, R.A and MacLean, P.D., Effects of vagal volleys and serotonin on units of cingulate cortex in monkeys, Brain Res., 130 (1977) 253-269. 4 Ben-Menachem, E., Persson, L.L, Schechter, P.J., Haegele, KD., Hurbert, N. and Hardenberg, J., Cerebrospinal fluid parameters in healthy volunteers during serial lumbar punctures, 1. Neurochem., 53 (1989) 632-635. 5 Beck, P.W. and Handwerker, H.O., Bradykinin and serotonin effects on various types of cutaneous nerve fibers, Pfliigers Arch., 347 (1974) 207-222. 6 Bowker, R.M., Westlund, KN., Sullivan, M.C. and Coulter, J.D., Organization of descending serotonergic projections to the spinal cord, Prog. Brain Res., 57 (1982) 239-265. 7 Brammert, M., Ekman, R, Larsson, I. and Thorell, J., Characterization and application of a radioimmunoassay for ,a-endorphin using an antiserum with negative cross-reactivity against ,a-lipotropin, Regul. Pept., 5 (1982) 65-75. 8 Browning, RA, Role of the brain-stem reticular formation in tonic-clonic seizures: lesion and pharmacological studies, Fed. Proc., 44 (1985) 2425-2431.
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