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Lesions of the locus coeruleus system aggravate ischemic damage in the rat brain
Neuroscience Letters, 58 (1985) 353-358
353
Elsevier Scientific Publishers Ireland Ltd.
NSL 03438
LESIONS OF THE LOCUS COERULEUS SYSTEM AGGRAVATE ISCHEMIC DAMAGE IN THE RAT BRAIN
PHOTJANEE BLOMQVIST j, OLLE LINDVALL 2 and TADEUSZ WIELOCH I.*
1Laboratory for Experimental Brain Research, University of Lund, Lurid Hospital, S-22l 85 Lund, and :Department of Histology, University of Lund, Biskopsgatan 5, S-223 62 Lund (Sweden) (Received April 22nd, 1985; Accepted May 7th, 1985)
Key words: noradrenaline - locus coeruleus - ischemia - neuronal damage - hippocampus - rat
The possibility that the noradrenergic locus coeruleus system influences brain damage following ischemia was explored in rats. Bilateral lesions of the locus coeruleus projections to the forebrain aggravated the neuronal necrosis in the hippocampal CA I region and neocortex following complete cerebral isehemia induced by transient cardiac arrest. These findings provide evidence that the postischemic activation of the inhibitory locus coeruleus system could counteract a possible detrimental neuronal hyperexcitation, thereby limiting neuronal necrosis.
Transient ischemia causes selective neuronal necrosis in certain vulnerable regions of the brain such as the hippocampus [5, 14, 21,]. Although the mechanisms of selective neuronal necrosis still remain elusive, recent evidence indicates that uncontrolled release of excitatory amino acids in vulnerable areas could be a critical factor in the pathogenesis of ischemic brain damage [16, 19, 22]. The possible influence of inhibitory neuronal systems on the development of neuronal necrosis has not yet been investigated. The noradrenergic locus coeruleus (LC) system, a principal inhibitory system [18], innervates most regions of the brain [10] and its seizure-suppressant properties have been clearly demonstrated [13]. In the first few minutes after the onset of ischemia this neuronal system is activated [8] and an increased turnover of noradrenaline (NA) has been reported in the recirculation period following ischemia [6]. The objective of this study was to clarify if this activation of the NA system could influence the ischemia-induced neuronal necrosis. Our experimental animals consisted of 7 NA-lesioned, 7 sham-lesioned and 6 control rats. Bilateral lesions of the LC projection to the forebrain were carried out by 6-hydroxydopamine (6-OHDA) injection (8 ttg in 4/~1 saline) into the dorsal catecholamine bundle in the caudal mesencephalon [7]. In the sham-operated animals, the cannula was lowered to the same coordinates but no injection was made. After 14-21 days the animals were subjected to 5-7 min of complete cerebral ischemia induced by cardiac arrest [5]. Following one week recovery, the animals were reanesthetized *Author for correspondence. 0304-3940/85/$ 03.30 © 1985 Elsevier Scientific Publishers Ireland Ltd.
354 100
_L
80
-
60
-
v
u •" U) tO
c
40
_1_
0
b,.
z
20
0 Control (n=12) NA l e v e l Ischemic
time
(ng/g) (min)
245+-12 5.7+-0.2
Sham (n.14) 204"-19 5.6-'0.2
NA-lesion (n=14) 8-+1 5.9-*0.3
Fig. 1. Density of necrotic pyramidal cells in the CAI region of the dorsal hippocampus (levels 2 5, see Fig. 2) in percent of the total pyramidal cell population. The ischemic time (min) and the NA content (ng/g tissue) in the frontal cortex for the different experimental groups are given. The values are means _+S.E.M., n - number of hemispheres. Asterisks denote statistical difference from control or sham groups, P< 0.01. Statistical differences were calculated using one-way analysis of variance (ANOVA) with the Newman-Keul's test for assessment of differences between groups.
and a b o u t 5 mg of frontal cortex tissue were removed on each side. The N A c o n t e n t was determined using a r a d i o e n z y m a t i c method o n an acidic extract [17]. The rats were then perfusion-fixed with buffered formalin, e m b e d d e d in paraffin, sectioned (8/~m) a n d stained with acid fuchsin and cresyl violet [2]. The N A depletion in the neocortex of the 6 - O H D A - i n j e c t e d a n i m a l s a m o u n t e d to 9 6 ~o o f the c o n t r o l values which signifies a nearly complete removal of LC axons in the forebrain [10]. Fig. 1 shows the density of necrotic n e u r o n s in the CA1 p y r a m i d a l cell layer of the dorsal h i p p o c a m p u s in the different experimental groups. N o significant difference was f o u n d between control and s h a m - o p e r a t e d a n i m a l s (40 a n d 43~o n e u r o n a l necrosis, respectively, of the total n e u r o n a l p o p u l a t i o n in the CA1 p y r a m i d a l cell layer). In
355
Fig. 2. Schematic representation of the distribution and density of hippoeampal.CA1 damage at 7 levels along the septo-temporal axis. The black dots represent the relative proportion of pyramidal cell necrosis after 5-7 min of ischemia followedby one week recovery.A: pooled data from control and sham groups (26 hemispheres). B: NA lesion group (14 hemispheres). The borders of the CA1 region are indicated by bars. the NA-lesioned group the damage increased to 83~o. The damage in the ventral part of the hippocampus was also more extensive in NA-lesioned animals than in sham-operated and control rats (Fig. 2). Removal of the N A input seemed to cause a more pronounced increase of neuronal necrosis in the ventral than in the dorsal hippocampus. The CA3 region showed no signs of neuronal necrosis in any experimental group. No necrotic neurons were found in the neocortex of control or sham-operated animals. In contrast, in 5 out of 7 NAlesioned animals, numerous necrotic neurons were observed in layers I I I - V of the parietal neocortex. Selective neuronal necrosis following short periods (5-7 min) of ischemia is confined to certain regions of the brain including hippocampus, dorsolateral septum, amygdala, entorhinal cortex [5, 21]. A similar distribution of morphological changes has been observed in rats subjected to limbic seizures, such as sustained amygdala
356 kindling [12] or perforant path stimulation [20]. Thus, a seizure-related pathogenic mechanism, possibly triggered by excessive release of excitotoxic amino acids, may also prevail in ischemic brain damage [23]. The magnitude of neuronal necrosis may therefore depend on the balance between excitatory and inhibitory receptor stimulation during and after the ischemia. We have previously shown that unilateral transection of the perforant path, a major excitatory input, reduces neuronal necrosis by 70~ in the ipsilateral CA1 region following 5-7 min of cardiac arrest [22]. In agreement with this, intrahippocampal injection of a glutamate receptor antagonist has been reported to be protective against the acute morphological changes following 30 min of cerebral ischemia [19]. The present study shows that lesions of an inhibitory input (the LC projection to the forebrain) increases the density of neuronal necrosis in the hippocampus and causes cell damage in the neocortex. It seems likely that the activation of the NA system has a depressant effect on neuronal excitability both during and following ischemia. The NA lesion eliminates this inhibition which probably leads to a predominance of excitatory synaptic mechanisms thereby aggravating neuronal necrosis. In control and sham-operated animals, the CA1 region shows much less cell damage in the ventral than in the dorsal part of the hippocampus (Fig. 2). In view of the possible protective role of the NA system in ischemia it is interesting that the ventral part of the hippocampus has a higher NA content than the dorsal part and is more densely innervated by NA-containing fibers [11]. However, even after removal of the NA input no necrotic neurons were observed in the CA3 region, which is more densely innervated by LC fibers than the CA 1 region. The difference between CA1 and CA3 pyramidal neurons in sensitivity to an ischemic insult is thus due to other factors than differences in NA terminal densities. Other possible mechanisms by which LC lesions could aggravate ischemic brain damage should, however, also be considered. The LC system has been proposed to participate in the regulation of cerebral blood flow via a direct vasoconstrictory action [15]. The postischemic activation of the NA system could thus aggravate the damage incurred by impairing cerebral perfusion following ischemia. However, the present data indicate a protective action of LC and furthermore postischemic hypoperfusion is not affected by LC lesions [4]. It might also be argued that the LC lesions could affect the restitution of the brain energy metabolism [9] during the recovery period following ischemia. No difference was however noted in the postischemic levels of labile phosphate compounds between LC lesioned and sham-operated animals [3]. The action of the noradrenergic LC system in cerebral ischemia, as indicated by the present investigation, agrees well with the proposed role of the LC system as a protective, 'stress dampening' system in the brain [1]. In our opinion, it seems most likely that the LC minimizes neuronal necrosis in the brain by an inhibitory action thereby counteracting a detrimental neuronal excitability. The results imply that administration of drugs which impair central NA transmission during the recovery period following transient cerebral ischemia could aggravate brain damage in patients. Conversely, NA agonists might prove to be protective against ischemic neuronal necrosis.
357
The authors thank A.-M. Andersson, G. Stridsberg, K. Fogelstrfm, L.-M. Lindestrrm, S. Hammarstedt and B. Olsson for technical assistance, and E. Bjrrkengren for secretarial work. We thank Anders Bjrrklund, Fred H. Gage and Bo K. Siesj6 for helpful comments on the manuscript. This study was supported by grants from the Swedish Medical Research Council (Projects 04X-263 and 04X-4493), and the USPHS (Grant 2 R01 NS-07838). 1 Amarat, D.G. and Sinnamon, H.M., The locus coeruleus: neurobiology of a central noradrenergic nucleus, Prog. Neurobiol., 9 (1977) 147-196. 2 Auer, R.N., Olsson, Y. and Siesj6, B.K., Hypoglycemic brain injury in the rat, Diabetes, 33 (1984) 1090-1098. 3 Blomqvist, P., Lindvall, O. and Wieloch, T., Cyclic AMP concentrations in rat neocortex and hippocampus during and following incomplete ischemia: influence of central noradrenergic neurons, prostaglandins and adenosine, J. Neurochem., 44 (1985) 1345-1353. 4 Blomqvist, P., Lindvall, O. and Wieloch, T., Delayed postischemic hypoperfusion: evidence against involvement of the noradrenergic locus coeruleus system, J. Cereb. Blood Flow Metabol., 4 (1984) 425-429. 5 Blomqvist, P. and Wieloch, T., Ischemic brain damage in the rat following cardiac arrest using a longterm recovery model, J. Cereb. Blood Flow Metabol., in press. 6 Calderini, C., Carlsson, A. and Nordstr6m, C.-H., Influence of transient ischemia on monoamine metabolism in the rat brain during nitrous oxide and phenobarbitone anesthesia, Brain Res., 157 (1978) 303-310. 7 Dahlgren, N., Lindvall, O., Sakabe, T., Stenevi, U., and Siesjr, B.K., Cerebral blood flow and oxygen consumption in the rat brain after lesions of the noradrenergic locus coeruleus system, Brain Res., 209 (1981) 11-23. 8 Harik, S.I., Busto, R. and Martinez, E., Norepinephrine regulation of cerebral glycogen utilization during seizures and ischemia, J. Neurosci., 2 (1982) 409-414. 9 La Manna, J.C., Harik, S.I., Light, A.I. and Rosenthal, M., Norepinephrine depletion alters cerebral oxidative metabolism in the active state, Brain Res., 204 (1981) 87-101. 10 Lindvall, O. and Bjrrkland, A., Organization of catecholamine neurons in the rat central nervous system. In L.L. Iversen, S.D. Iversen, S.H. Snyder (Eds.), Handbook of Psychopharmacology, Vol. 9, Plenum, New York, 1978, pp. 139-231. 11 Loy, R., Koziell, D.A., Lindsey, J.D. and Moore, R.Y., Noradrenergic innervation of the adult rat hippocampal formation, J. Comp. Neurol., 189 (1980) 699-710. 12 Mclntyre, D.C., Nathanson, D. and Edson, N., A new model of partial status epilepticus based on kindling, Brain Res., 250 (1982) 53-63. 13 Peterson, S.L. and Albertson, T.E., Neurotransmitter and neuromodulator function in the kindled seizure and state, Prog. Neurobiol., 19 (1982) 237-270. 14 Pulsinelli, W.A., Brierley, J.B. and Plum, F., Temporal profile of neuronal damage in a model of transient forebrain ischemia, Ann. Neurol., 11 (1982) 491-499. 15 Raichle, M.E., Hartman, B.K., Eichling, J.O. and Sharpe, L.G., Central noradrenergic regulation of cerebral blood flow and vascular permeability, Proc. Natl. Acad. Sci. USA, 72 (1975) 3726-3730. 16 Rothman, S., Synaptic release of excitatory amino acid neurotransmitter mediates anoxic neuronal death, J. Neurosci., 4 (1984) 1884-1891. 17 Schmidt, R.H., Ingvar, M., Lindvall, O., Stenevi, U. and Bj6rklund, A., Functional activity of substantia nigra grafts reinnervating the striatum: neurotransmitter metabolism and [t4C]-2-deoxy-D-glucose autoradiography, J. Neurochem., 38 (1982) 737-748. 18 Segal, M. and Bloom, F.E., The action of norepinephrine in the rat hippocampus. III. Hippocampal cellular responses to locus coeruleus stimulation in the awake rat, Brain Res., 107 (1976) 499-511. 19 Simon, R.P., Swan, J.H., Griffith, T. and Meldrum, B.S., Blockade of N-methyl-o-aspartate receptors may protect against ischemic damage in the brain, Science, 226 (1984) 850-852.
358 20 Sloviter, R.S. and Damiano, B.P., Sustained electrical stimulation of the perforant path duplicates kainate-induced electrophysiological effects and hippocampal damage in rats, Neurosci. Lett., 24 (1981 ) 279-284. 21 Smith, M.-U, Auer, R.N. and Siesj6, B.K., The density and distribution of ischemic brain injury in the rat following 2-10 min of forebrain ischemia, Acta Ncuropathol. (Bed.), 64 (1984) 319-332. 22 Wieloch, T., Lindvall, O., Blomqvist, P. and Gage, F.H., Evidence for amelioration ofiscbemic neuronal damage in the hippocampal formation by lesions of the perforant path, Neurol. Res., 7 (1985) 24-26. 23 Wieloch, T., Neurochemical correlates to selective neuronal vulnerability, Prog. Brain Res., 63 (1985) in press.
353
Elsevier Scientific Publishers Ireland Ltd.
NSL 03438
LESIONS OF THE LOCUS COERULEUS SYSTEM AGGRAVATE ISCHEMIC DAMAGE IN THE RAT BRAIN
PHOTJANEE BLOMQVIST j, OLLE LINDVALL 2 and TADEUSZ WIELOCH I.*
1Laboratory for Experimental Brain Research, University of Lund, Lurid Hospital, S-22l 85 Lund, and :Department of Histology, University of Lund, Biskopsgatan 5, S-223 62 Lund (Sweden) (Received April 22nd, 1985; Accepted May 7th, 1985)
Key words: noradrenaline - locus coeruleus - ischemia - neuronal damage - hippocampus - rat
The possibility that the noradrenergic locus coeruleus system influences brain damage following ischemia was explored in rats. Bilateral lesions of the locus coeruleus projections to the forebrain aggravated the neuronal necrosis in the hippocampal CA I region and neocortex following complete cerebral isehemia induced by transient cardiac arrest. These findings provide evidence that the postischemic activation of the inhibitory locus coeruleus system could counteract a possible detrimental neuronal hyperexcitation, thereby limiting neuronal necrosis.
Transient ischemia causes selective neuronal necrosis in certain vulnerable regions of the brain such as the hippocampus [5, 14, 21,]. Although the mechanisms of selective neuronal necrosis still remain elusive, recent evidence indicates that uncontrolled release of excitatory amino acids in vulnerable areas could be a critical factor in the pathogenesis of ischemic brain damage [16, 19, 22]. The possible influence of inhibitory neuronal systems on the development of neuronal necrosis has not yet been investigated. The noradrenergic locus coeruleus (LC) system, a principal inhibitory system [18], innervates most regions of the brain [10] and its seizure-suppressant properties have been clearly demonstrated [13]. In the first few minutes after the onset of ischemia this neuronal system is activated [8] and an increased turnover of noradrenaline (NA) has been reported in the recirculation period following ischemia [6]. The objective of this study was to clarify if this activation of the NA system could influence the ischemia-induced neuronal necrosis. Our experimental animals consisted of 7 NA-lesioned, 7 sham-lesioned and 6 control rats. Bilateral lesions of the LC projection to the forebrain were carried out by 6-hydroxydopamine (6-OHDA) injection (8 ttg in 4/~1 saline) into the dorsal catecholamine bundle in the caudal mesencephalon [7]. In the sham-operated animals, the cannula was lowered to the same coordinates but no injection was made. After 14-21 days the animals were subjected to 5-7 min of complete cerebral ischemia induced by cardiac arrest [5]. Following one week recovery, the animals were reanesthetized *Author for correspondence. 0304-3940/85/$ 03.30 © 1985 Elsevier Scientific Publishers Ireland Ltd.
354 100
_L
80
-
60
-
v
u •" U) tO
c
40
_1_
0
b,.
z
20
0 Control (n=12) NA l e v e l Ischemic
time
(ng/g) (min)
245+-12 5.7+-0.2
Sham (n.14) 204"-19 5.6-'0.2
NA-lesion (n=14) 8-+1 5.9-*0.3
Fig. 1. Density of necrotic pyramidal cells in the CAI region of the dorsal hippocampus (levels 2 5, see Fig. 2) in percent of the total pyramidal cell population. The ischemic time (min) and the NA content (ng/g tissue) in the frontal cortex for the different experimental groups are given. The values are means _+S.E.M., n - number of hemispheres. Asterisks denote statistical difference from control or sham groups, P< 0.01. Statistical differences were calculated using one-way analysis of variance (ANOVA) with the Newman-Keul's test for assessment of differences between groups.
and a b o u t 5 mg of frontal cortex tissue were removed on each side. The N A c o n t e n t was determined using a r a d i o e n z y m a t i c method o n an acidic extract [17]. The rats were then perfusion-fixed with buffered formalin, e m b e d d e d in paraffin, sectioned (8/~m) a n d stained with acid fuchsin and cresyl violet [2]. The N A depletion in the neocortex of the 6 - O H D A - i n j e c t e d a n i m a l s a m o u n t e d to 9 6 ~o o f the c o n t r o l values which signifies a nearly complete removal of LC axons in the forebrain [10]. Fig. 1 shows the density of necrotic n e u r o n s in the CA1 p y r a m i d a l cell layer of the dorsal h i p p o c a m p u s in the different experimental groups. N o significant difference was f o u n d between control and s h a m - o p e r a t e d a n i m a l s (40 a n d 43~o n e u r o n a l necrosis, respectively, of the total n e u r o n a l p o p u l a t i o n in the CA1 p y r a m i d a l cell layer). In
355
Fig. 2. Schematic representation of the distribution and density of hippoeampal.CA1 damage at 7 levels along the septo-temporal axis. The black dots represent the relative proportion of pyramidal cell necrosis after 5-7 min of ischemia followedby one week recovery.A: pooled data from control and sham groups (26 hemispheres). B: NA lesion group (14 hemispheres). The borders of the CA1 region are indicated by bars. the NA-lesioned group the damage increased to 83~o. The damage in the ventral part of the hippocampus was also more extensive in NA-lesioned animals than in sham-operated and control rats (Fig. 2). Removal of the N A input seemed to cause a more pronounced increase of neuronal necrosis in the ventral than in the dorsal hippocampus. The CA3 region showed no signs of neuronal necrosis in any experimental group. No necrotic neurons were found in the neocortex of control or sham-operated animals. In contrast, in 5 out of 7 NAlesioned animals, numerous necrotic neurons were observed in layers I I I - V of the parietal neocortex. Selective neuronal necrosis following short periods (5-7 min) of ischemia is confined to certain regions of the brain including hippocampus, dorsolateral septum, amygdala, entorhinal cortex [5, 21]. A similar distribution of morphological changes has been observed in rats subjected to limbic seizures, such as sustained amygdala
356 kindling [12] or perforant path stimulation [20]. Thus, a seizure-related pathogenic mechanism, possibly triggered by excessive release of excitotoxic amino acids, may also prevail in ischemic brain damage [23]. The magnitude of neuronal necrosis may therefore depend on the balance between excitatory and inhibitory receptor stimulation during and after the ischemia. We have previously shown that unilateral transection of the perforant path, a major excitatory input, reduces neuronal necrosis by 70~ in the ipsilateral CA1 region following 5-7 min of cardiac arrest [22]. In agreement with this, intrahippocampal injection of a glutamate receptor antagonist has been reported to be protective against the acute morphological changes following 30 min of cerebral ischemia [19]. The present study shows that lesions of an inhibitory input (the LC projection to the forebrain) increases the density of neuronal necrosis in the hippocampus and causes cell damage in the neocortex. It seems likely that the activation of the NA system has a depressant effect on neuronal excitability both during and following ischemia. The NA lesion eliminates this inhibition which probably leads to a predominance of excitatory synaptic mechanisms thereby aggravating neuronal necrosis. In control and sham-operated animals, the CA1 region shows much less cell damage in the ventral than in the dorsal part of the hippocampus (Fig. 2). In view of the possible protective role of the NA system in ischemia it is interesting that the ventral part of the hippocampus has a higher NA content than the dorsal part and is more densely innervated by NA-containing fibers [11]. However, even after removal of the NA input no necrotic neurons were observed in the CA3 region, which is more densely innervated by LC fibers than the CA 1 region. The difference between CA1 and CA3 pyramidal neurons in sensitivity to an ischemic insult is thus due to other factors than differences in NA terminal densities. Other possible mechanisms by which LC lesions could aggravate ischemic brain damage should, however, also be considered. The LC system has been proposed to participate in the regulation of cerebral blood flow via a direct vasoconstrictory action [15]. The postischemic activation of the NA system could thus aggravate the damage incurred by impairing cerebral perfusion following ischemia. However, the present data indicate a protective action of LC and furthermore postischemic hypoperfusion is not affected by LC lesions [4]. It might also be argued that the LC lesions could affect the restitution of the brain energy metabolism [9] during the recovery period following ischemia. No difference was however noted in the postischemic levels of labile phosphate compounds between LC lesioned and sham-operated animals [3]. The action of the noradrenergic LC system in cerebral ischemia, as indicated by the present investigation, agrees well with the proposed role of the LC system as a protective, 'stress dampening' system in the brain [1]. In our opinion, it seems most likely that the LC minimizes neuronal necrosis in the brain by an inhibitory action thereby counteracting a detrimental neuronal excitability. The results imply that administration of drugs which impair central NA transmission during the recovery period following transient cerebral ischemia could aggravate brain damage in patients. Conversely, NA agonists might prove to be protective against ischemic neuronal necrosis.
357
The authors thank A.-M. Andersson, G. Stridsberg, K. Fogelstrfm, L.-M. Lindestrrm, S. Hammarstedt and B. Olsson for technical assistance, and E. Bjrrkengren for secretarial work. We thank Anders Bjrrklund, Fred H. Gage and Bo K. Siesj6 for helpful comments on the manuscript. This study was supported by grants from the Swedish Medical Research Council (Projects 04X-263 and 04X-4493), and the USPHS (Grant 2 R01 NS-07838). 1 Amarat, D.G. and Sinnamon, H.M., The locus coeruleus: neurobiology of a central noradrenergic nucleus, Prog. Neurobiol., 9 (1977) 147-196. 2 Auer, R.N., Olsson, Y. and Siesj6, B.K., Hypoglycemic brain injury in the rat, Diabetes, 33 (1984) 1090-1098. 3 Blomqvist, P., Lindvall, O. and Wieloch, T., Cyclic AMP concentrations in rat neocortex and hippocampus during and following incomplete ischemia: influence of central noradrenergic neurons, prostaglandins and adenosine, J. Neurochem., 44 (1985) 1345-1353. 4 Blomqvist, P., Lindvall, O. and Wieloch, T., Delayed postischemic hypoperfusion: evidence against involvement of the noradrenergic locus coeruleus system, J. Cereb. Blood Flow Metabol., 4 (1984) 425-429. 5 Blomqvist, P. and Wieloch, T., Ischemic brain damage in the rat following cardiac arrest using a longterm recovery model, J. Cereb. Blood Flow Metabol., in press. 6 Calderini, C., Carlsson, A. and Nordstr6m, C.-H., Influence of transient ischemia on monoamine metabolism in the rat brain during nitrous oxide and phenobarbitone anesthesia, Brain Res., 157 (1978) 303-310. 7 Dahlgren, N., Lindvall, O., Sakabe, T., Stenevi, U., and Siesjr, B.K., Cerebral blood flow and oxygen consumption in the rat brain after lesions of the noradrenergic locus coeruleus system, Brain Res., 209 (1981) 11-23. 8 Harik, S.I., Busto, R. and Martinez, E., Norepinephrine regulation of cerebral glycogen utilization during seizures and ischemia, J. Neurosci., 2 (1982) 409-414. 9 La Manna, J.C., Harik, S.I., Light, A.I. and Rosenthal, M., Norepinephrine depletion alters cerebral oxidative metabolism in the active state, Brain Res., 204 (1981) 87-101. 10 Lindvall, O. and Bjrrkland, A., Organization of catecholamine neurons in the rat central nervous system. In L.L. Iversen, S.D. Iversen, S.H. Snyder (Eds.), Handbook of Psychopharmacology, Vol. 9, Plenum, New York, 1978, pp. 139-231. 11 Loy, R., Koziell, D.A., Lindsey, J.D. and Moore, R.Y., Noradrenergic innervation of the adult rat hippocampal formation, J. Comp. Neurol., 189 (1980) 699-710. 12 Mclntyre, D.C., Nathanson, D. and Edson, N., A new model of partial status epilepticus based on kindling, Brain Res., 250 (1982) 53-63. 13 Peterson, S.L. and Albertson, T.E., Neurotransmitter and neuromodulator function in the kindled seizure and state, Prog. Neurobiol., 19 (1982) 237-270. 14 Pulsinelli, W.A., Brierley, J.B. and Plum, F., Temporal profile of neuronal damage in a model of transient forebrain ischemia, Ann. Neurol., 11 (1982) 491-499. 15 Raichle, M.E., Hartman, B.K., Eichling, J.O. and Sharpe, L.G., Central noradrenergic regulation of cerebral blood flow and vascular permeability, Proc. Natl. Acad. Sci. USA, 72 (1975) 3726-3730. 16 Rothman, S., Synaptic release of excitatory amino acid neurotransmitter mediates anoxic neuronal death, J. Neurosci., 4 (1984) 1884-1891. 17 Schmidt, R.H., Ingvar, M., Lindvall, O., Stenevi, U. and Bj6rklund, A., Functional activity of substantia nigra grafts reinnervating the striatum: neurotransmitter metabolism and [t4C]-2-deoxy-D-glucose autoradiography, J. Neurochem., 38 (1982) 737-748. 18 Segal, M. and Bloom, F.E., The action of norepinephrine in the rat hippocampus. III. Hippocampal cellular responses to locus coeruleus stimulation in the awake rat, Brain Res., 107 (1976) 499-511. 19 Simon, R.P., Swan, J.H., Griffith, T. and Meldrum, B.S., Blockade of N-methyl-o-aspartate receptors may protect against ischemic damage in the brain, Science, 226 (1984) 850-852.
358 20 Sloviter, R.S. and Damiano, B.P., Sustained electrical stimulation of the perforant path duplicates kainate-induced electrophysiological effects and hippocampal damage in rats, Neurosci. Lett., 24 (1981 ) 279-284. 21 Smith, M.-U, Auer, R.N. and Siesj6, B.K., The density and distribution of ischemic brain injury in the rat following 2-10 min of forebrain ischemia, Acta Ncuropathol. (Bed.), 64 (1984) 319-332. 22 Wieloch, T., Lindvall, O., Blomqvist, P. and Gage, F.H., Evidence for amelioration ofiscbemic neuronal damage in the hippocampal formation by lesions of the perforant path, Neurol. Res., 7 (1985) 24-26. 23 Wieloch, T., Neurochemical correlates to selective neuronal vulnerability, Prog. Brain Res., 63 (1985) in press.