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Forebrain noradrenaline and metrazol-induced seizures
Lits Sciences Vol . 23, pp . 167-172 Printed is the U.S .A .
Pergamon Press
FOREBRAIN NORADRENALINE AND METRAZOL-INDUCED SEIZURES I Stephen T. Mason and Michael E . Corcoran2 Division of Neurological Sciences Department of Psychiatry University of British Columbia Vancouver, B .C ., Canada V6T 1W5 (Received is final form May 30, 1978) Summary The role of forebrain noradreaaline in seizures induced by the convulsant drug Metrazol was examined in animals pretreated with injections of 6-hydrozydopamine into the fibers of the ascending noradrenergic bundles . A consistent potentiation of the duration and intensity of the seizures was found in the noradrenalinedepleted animals . Ia recent years there has been a great deal of interest in the functions of the central catecholamines noradrenaline (NA) and dopamine (DA), particularly is such phenomena ae reinforcement and learning (1,2,3) . Attention has also been directed to the possible role of NA and DA in seizures, and a number of experiments have reported that pharmacologically induced depletion of catecholamines results in as enhancement of susceptibility to seizures (4,5) . This suggests that one or both of the catecholamines may act to suppress or retard seizures 1n certain cases . Intraventricular injections of 6-hydroxydopamine (6-OHDA), a neurotoain that selectively destroys catecholaminergic neurons (6), were previously observed (7,8) to produce a marked potentiation of seizures induced by subcutaneous injection of the convulsant drug pentylenetetrazol (Metrazol) . Rats pretreated with 6-OHDA displayed seizures that were significantly longer in duration than those of the control animals and were characterized by episodes of profound tonic extension, in contrast to the solely clonic manifestations of control rate . Although this potentiation of Metrazol-induced seizures seemed better correlated with depletion of NA than DA (8), it was not possible to draw a firm conclusion, because significant depletion of both amines was observed in all rats treated with 6-OHDA . We now report the effects oa Metrazol-induced seizures of snlactlve depletion of forebrain NA, produced by intracerebral injectioae of 6-OHDA into the ascending NA pathways (9) .
1Supported by MRC Grants awarded to H.C . Fibiger and J .A . Wade . S .T . Mason is a MRC Fellow . The able technical assistance of Betty Richter is gratefully acknowledged . ZNow at Department of Psychology, University of Victoria, Victoria, B .C .
0300-9653/78/0710-167$02 .00/0 Copynght © 1978 Pergamon Pros
16 8
Noradrenaliae and Seizures
Vol . 23, No . 2, 1978
Methode Eighteen male Wiatar rate were used . The rata weighed 200-250 g at the start of the experiment and were housed individually with free access to food and water . Under pentobarbital (50 mg/kg) a:~esthesia the experimental rats (n ~ 10) received stereotaxically placed bilateral injections of 6-OHDA hydrobromide (4 ug, dosage expressed as free base, in 2 ul of 0 .9% saline containing 0.3 mg/ml ascorbic acid) into the meseacephalic trajectory of the ascending NA bundles (10,11) . The rate of injection was 1 ul per min, and the coordinates from etereotaxic zero were AP + 2 .6 mm from interaural line, ML _+ 1 .1 mm from midline suture at bregma, and DV + 3 .7 mm from interaural line . Control rats (n S) received iatracerebral injections of the same volume of ascorbic-saline vehicle without 6-OHDA, Two weeks after the injéctions of 6-OHDA or vehicle, the rats were challenged with an injection of Metrazol given eubcutaneously into the flank . The dosage administered was 70 mg/kg, which produces clonic convulsions in upwards of 90X of normal rats (7,8) . Each rat was then placed in a testing cage, and the occurrence of behavioral seizures was observed for 1 hour . The latencies to the first myoclonic jerk and to onset of the generalized seizure were recorded, se were the number and duration of seizures . Each seizure was characterized as containing only clonic or both tonic and clonic componeata . Two weeks after testing, the rats were killed by cervical fracture . With a epectrophotofluorometric technique (12) concentrations of DA were measured in the caudate-putamen, and concentrations of NA were measured in the hippocampuscortea, the hypothalamus, the cerebellum, and the spinal cord . It is known that the 6-OHDA treatment used here produces a severe and permanent depletion of NA . No recovery occurs from this lesion either is terms of amine concentrations (6) or in terms of behavioral function (9) . Amine depletions remain stable from two weeks to two years after the operation . Results One rat in each group failed to display a generalized seizure after injection of Metrazol, and their data were omitted from analysis . It is evident from Table 1 that pretreatment with 6-OHDA resulted in a significant potentiation of several aspects of the convulsive effects of Metrazol . Although the groups did not differ is latencies to either the first myoclonic jerk or generalized seizure, the 6-OHDA-treated rata displayed generalized seizures of significantly greater duration (Mann-Whitney U ~ 4 .5, p < 0 .02, two-tailed) . Furthermore, none of the controls had more than one seizure during the 1 hr session, whereas 5 of the 9 6-OHDA-treated rats had 2 seizures (Fisher's exact probability test, p - 0 .03, two-tailed) . Finally, and perhaps most significant, the seizures of the 2 groups differed quantitâtively . The seizure displayed by all 7 control rats consisted ... of a aeries of intermittent myoclonic jerks, emerging into an episode of violent generalized clonic jerking of the forelimbs and facial musculature . The 6-OHDA-treated rats displayed a similar seizure, but with the addition that 5 of the 9 rate displayed an episode of tonic extension of the forelimbs (Fisher's test, p ' 0 .03, two-tailed) . However, it may be significant that only one of these 5 rata displayed a fully generalized tonic seizure that also involved extension of the hiadlimba, similar to the seizure induced by maximal electroshock . The The effects of 6-OHDA oa concentrations of NA and DA are shown in Table 2 . injections of 6-OHDA produced large and significant depletion of hypothalamic and hippocampal-cortical NA no significant depletion of DA in the caudateputamen or cerebellur and spinal NA .
Vol . 23, No . 2, 1978
Noradrenaline and Seizures
lbq
It is known from assay data on other animals that amygdaloid NA is depleted to 15X and .septal NA to 45X of control values . No sigpificaat lose of DA occurs in hypothalamus, septum, amygdala or frontal torte: with this lesion . TABLE 1 Metrazol-Induced Seizures in .Control .and .6-OHDA-Treated .Rat e Latency to first jerk (min) controls (n~7)
8 .7 + 1 .2
Latency Duration No . of rata to first of first with multiple seizure (min) seizure (sec) seizures
14 .9 + 1 .6
NS 6-OHDA (n-9)
8 .2 + 1 .4
32 .9 + 3 .0
NS
**
14 .8 + 2 .3
113 .2 + 11 .7
No . of rata with tonic seizures
0/7
0/7
5/9
5/9
The data on latencies and duration are presented as plus and minus the standard error of the mesa . The control and 6-OHDA-treate~ groups are significantly different at the following levels : ** p < 0 .02, p ~ 0 .03, NS ~ not significant . TABLE 2 Levels of Catecholamiaea in Control sad 6-OHDA-Treated Rata Region
Control (n=5)
Treated (n=5)
X
t
p
0 .001 0 .001 NS NS
NORADRENALINE Hippocampus-cortex Hypothalamus Cerebellum Spinal cord
0 .264 2 .240 0 .219 0 .255
+ + + +
0 .006 0 .077 0 .012 0 .006
+ 0 .001 + 0 .087 + 0 .008 + 0 .012
2 26 124 120
5 .26 6 .87 0 .62 0 .65
11 .570 + 1 .190
88
1 .89
0 .006 0 .590 0 .271 0 .307
DOPAMINE Striatum
13 .170 + 0 .570
NS
Regional amine assay values on control and 6-OHDA-treated rata . Values are means of five randomly selected controls and five treated rata in micrograms of amine per gram wet weight of tissue with standard errors of the mean . X column is the percentage of control concentrations remaining is lesioned tissues . Discussion It seems well established that central catecholaminergic neurone can suppress various forms of seizure activity (4,5) . The relative antiseizure activity of NA and DA, and particularly of the forebrain projections of these neurons, is
170
Noradrenaline and Seizurea
Vol . 23, No . 2, 1978
less clear . It can be stated With some certainty that spinal NA playa a role in inhibiting the postdecapitation reflex (13, 14) . The picture is less certain with other forms of seizure activity, however, because the ezperimeatal techniques used in the relevant studies depleted either peripheral ae well as central catecholamiaes (15,16), both DA and NA (7,8,17,18,19,20), or, when central NA was implicated, cerebellar and spinal as well ae forebrain levels of NA (8,21) . In contrast to previous work, the present experiment made use of intracerebral injections of 6-OHDA to produce a selective depletion of NA in the diencephalic and telencephalic terminals of the ascending noradrenergic pathways . Rather than producing a general depletion of NA throughout the CNS, our injections of 6-0HDA resulted in essentially intact concentrations of NA in the cerebellum and spinal cord . The results thus demonstrate that selective depletion of forebrain NA results in a significant potentiation of Metrazol-induced seizures, measured quantitatively as increases in the duration and number of evoked seizures and qualitatively as induction of mild tonic episodes in many of the 6OHDA-treated rats . One possible ezplanation of these results is that 6-OHDA-induced depletion of NA produced increased penetration of Metrazol into the brain . Although we did not test this hypothesis directly, we believe that it can be eliminated, because 1t would predict that all measures of the convulsant effects of Metrazol, including latencies to the first jerk and the first seizure, should have shown similar potentiation in the 6-0HDA-treated rats . This clearly was not the case . It is interesting that depletion of forebrain NA did not consistently result in induction of generalized ionic seizures, including extension of the hindlimba, as was previously observed in rate receiving 6-OHDA intraventricularly (7,8) . This suggests that depletion of forebrain NA alone cannot fully account for the marked potentiation of Metrazol-induced seizures induced by intravemtricular injections of 6-ONDA . We are at present attempting to determine whether other aspects of Metrazol-induced seizures areFatentiated by selective depletion of DA, cerebellar NA, .or spinal NA . In summary, selective depletion of forebrain NA potentiated nartaia aspects of the seizure induced by Matrazol . This suggests that NA in the intact brain may act to reduce the intensity and duration of seizure activity . Whether suppreaaion of seizures is a specific function of NA or merely a byproduct of its largely inhibitory synaptic action (22,23) cannot be determined on the basis of the present results . Complex roles is normal behavior have beeq ascribed to NA (24,25,26,27), and so it seems unlikely that suppression of seizures could be its sole or even primary function is the CNS . Depletion of forebrain NA does nonetheless result in a potentiation of seizures, however, and it may be the case that in pathological states such ae epilepsy a deficiency in NA plays a causal role .
References 1. 2. 3. 4. 5. 6.
T .J . CROW, Peychol. lied . 2 414-417 (1972) . T .J . CROW, Peychol. Med . 105 (1973) . S .S . RETY, The Neurosciences, p . 324, Rockefeller University Preae, New York (1970) . R . LOVELL, Hapdbook of Neurochemistry , Vol . 6, p . 63, Plenum Press, New York (1971) . E.W . MAYNERT, EpilBpaia 10 145-162 (1969) . N.J . IIRETSRY sad L.L . IVERSEN, Nature 221 557-559 (1969) .
3
Vol . 23, No . 2, 1978 7. 8. 9. 10 . 11 . 12 . 13 . 14 . 15 . 16 . 17 . 18 . 19 . 20 . 21 . 22 . 23 . 24 . 25 . 26 . 27 .
Noradrenaliae and Seiaures
171
M .E . CORCORAN, H .C . FIBIGER, E .G . MCGEER, and J .A . WADA, J . Pharm . Pharmac . _25 497-499 (1973) . M .E . CORCORAN, H .C . FIBIGER, J .A . McCAUGHRAN, and J .A . WADA, ERp . Neurol . 45 118-133 (1974) . S.T . MASON aad S .D . IVERS$N, NBtûYA 258 422-424 (1975) . U . UNGERSTEDT, Acts" Ptiysi0l : 5t~d . sûppl. . _367 1-49 (1971) . 0 . LINDVALL and A . BJORKLUND, AttA Phyéidl . Stàbd . suppl . 412 1-48 (1974) . E .G . McGEER and P .L . McGEER, Cad . J . Biothem . _40 1141-1151(1962) . W .M . BOURN, P .F . GEIGER, and P .C . JOBE, Rés . COthm . YBythol . Psyrthiat . Behav . 2 9-20 (1977) . N . SUENAGA, K . YAMADA, and T . FUKUDA, Brain Res . 122 165-169 (1977) . W .M . BOURN, L . CHIN, and A .L . PICCIONI, Lifa Sci .21 701-706 (1977) . G .M . McRENZIE and F .E . SOROKO, J . Pharm . Pharmac . 25 76-77 (1973) . P .S .~ARNOLD, R .J . RACINE, and R .A . WISE, Exp . Neurol . _40 457-470 (1973) . I .H . AYHAN, Arch . Int . Pharmacodya . 223 282-286 (1976) R .A . BROWNING and E .W . MAYNERT, fled .Proc . 29 417 (1970) . A . QUATTRONE and R . SAMANIN, Eur . J . Pharmacôl . _41 333-336 (1977) . A . LEHMANN, Life Sci . 20 2047-2060 (1977) . M . SEGAL and F .E . BLOOM, Brain Res . 72 79-97 (1974) . B .J . HOFFBR, G .R . SIGGENS, A .P . OLIVgR, and F .E . BLOOM, J . Pharmac . ExP . Therap . 184 553-569 (1973) . S .T . MASONand S .D . IVERSEN, J . Comp . Physiol . Pevcho] . . 91 165-173 (1977) . S .T . MASON aad 5 .D . IVERSEN, Brain Res . 134 513-527 (1977) . S .T . MASON ead S .D . IVERSEN, Pharmac . Bioche~n . Behav . _7 373-379 (1977) . S .T . MASON and H .C . FIBIGER, Nature 269 704-705 (1977)
Pergamon Press
FOREBRAIN NORADRENALINE AND METRAZOL-INDUCED SEIZURES I Stephen T. Mason and Michael E . Corcoran2 Division of Neurological Sciences Department of Psychiatry University of British Columbia Vancouver, B .C ., Canada V6T 1W5 (Received is final form May 30, 1978) Summary The role of forebrain noradreaaline in seizures induced by the convulsant drug Metrazol was examined in animals pretreated with injections of 6-hydrozydopamine into the fibers of the ascending noradrenergic bundles . A consistent potentiation of the duration and intensity of the seizures was found in the noradrenalinedepleted animals . Ia recent years there has been a great deal of interest in the functions of the central catecholamines noradrenaline (NA) and dopamine (DA), particularly is such phenomena ae reinforcement and learning (1,2,3) . Attention has also been directed to the possible role of NA and DA in seizures, and a number of experiments have reported that pharmacologically induced depletion of catecholamines results in as enhancement of susceptibility to seizures (4,5) . This suggests that one or both of the catecholamines may act to suppress or retard seizures 1n certain cases . Intraventricular injections of 6-hydroxydopamine (6-OHDA), a neurotoain that selectively destroys catecholaminergic neurons (6), were previously observed (7,8) to produce a marked potentiation of seizures induced by subcutaneous injection of the convulsant drug pentylenetetrazol (Metrazol) . Rats pretreated with 6-OHDA displayed seizures that were significantly longer in duration than those of the control animals and were characterized by episodes of profound tonic extension, in contrast to the solely clonic manifestations of control rate . Although this potentiation of Metrazol-induced seizures seemed better correlated with depletion of NA than DA (8), it was not possible to draw a firm conclusion, because significant depletion of both amines was observed in all rats treated with 6-OHDA . We now report the effects oa Metrazol-induced seizures of snlactlve depletion of forebrain NA, produced by intracerebral injectioae of 6-OHDA into the ascending NA pathways (9) .
1Supported by MRC Grants awarded to H.C . Fibiger and J .A . Wade . S .T . Mason is a MRC Fellow . The able technical assistance of Betty Richter is gratefully acknowledged . ZNow at Department of Psychology, University of Victoria, Victoria, B .C .
0300-9653/78/0710-167$02 .00/0 Copynght © 1978 Pergamon Pros
16 8
Noradrenaliae and Seizures
Vol . 23, No . 2, 1978
Methode Eighteen male Wiatar rate were used . The rata weighed 200-250 g at the start of the experiment and were housed individually with free access to food and water . Under pentobarbital (50 mg/kg) a:~esthesia the experimental rats (n ~ 10) received stereotaxically placed bilateral injections of 6-OHDA hydrobromide (4 ug, dosage expressed as free base, in 2 ul of 0 .9% saline containing 0.3 mg/ml ascorbic acid) into the meseacephalic trajectory of the ascending NA bundles (10,11) . The rate of injection was 1 ul per min, and the coordinates from etereotaxic zero were AP + 2 .6 mm from interaural line, ML _+ 1 .1 mm from midline suture at bregma, and DV + 3 .7 mm from interaural line . Control rats (n S) received iatracerebral injections of the same volume of ascorbic-saline vehicle without 6-OHDA, Two weeks after the injéctions of 6-OHDA or vehicle, the rats were challenged with an injection of Metrazol given eubcutaneously into the flank . The dosage administered was 70 mg/kg, which produces clonic convulsions in upwards of 90X of normal rats (7,8) . Each rat was then placed in a testing cage, and the occurrence of behavioral seizures was observed for 1 hour . The latencies to the first myoclonic jerk and to onset of the generalized seizure were recorded, se were the number and duration of seizures . Each seizure was characterized as containing only clonic or both tonic and clonic componeata . Two weeks after testing, the rats were killed by cervical fracture . With a epectrophotofluorometric technique (12) concentrations of DA were measured in the caudate-putamen, and concentrations of NA were measured in the hippocampuscortea, the hypothalamus, the cerebellum, and the spinal cord . It is known that the 6-OHDA treatment used here produces a severe and permanent depletion of NA . No recovery occurs from this lesion either is terms of amine concentrations (6) or in terms of behavioral function (9) . Amine depletions remain stable from two weeks to two years after the operation . Results One rat in each group failed to display a generalized seizure after injection of Metrazol, and their data were omitted from analysis . It is evident from Table 1 that pretreatment with 6-OHDA resulted in a significant potentiation of several aspects of the convulsive effects of Metrazol . Although the groups did not differ is latencies to either the first myoclonic jerk or generalized seizure, the 6-OHDA-treated rata displayed generalized seizures of significantly greater duration (Mann-Whitney U ~ 4 .5, p < 0 .02, two-tailed) . Furthermore, none of the controls had more than one seizure during the 1 hr session, whereas 5 of the 9 6-OHDA-treated rats had 2 seizures (Fisher's exact probability test, p - 0 .03, two-tailed) . Finally, and perhaps most significant, the seizures of the 2 groups differed quantitâtively . The seizure displayed by all 7 control rats consisted ... of a aeries of intermittent myoclonic jerks, emerging into an episode of violent generalized clonic jerking of the forelimbs and facial musculature . The 6-OHDA-treated rats displayed a similar seizure, but with the addition that 5 of the 9 rate displayed an episode of tonic extension of the forelimbs (Fisher's test, p ' 0 .03, two-tailed) . However, it may be significant that only one of these 5 rata displayed a fully generalized tonic seizure that also involved extension of the hiadlimba, similar to the seizure induced by maximal electroshock . The The effects of 6-OHDA oa concentrations of NA and DA are shown in Table 2 . injections of 6-OHDA produced large and significant depletion of hypothalamic and hippocampal-cortical NA no significant depletion of DA in the caudateputamen or cerebellur and spinal NA .
Vol . 23, No . 2, 1978
Noradrenaline and Seizures
lbq
It is known from assay data on other animals that amygdaloid NA is depleted to 15X and .septal NA to 45X of control values . No sigpificaat lose of DA occurs in hypothalamus, septum, amygdala or frontal torte: with this lesion . TABLE 1 Metrazol-Induced Seizures in .Control .and .6-OHDA-Treated .Rat e Latency to first jerk (min) controls (n~7)
8 .7 + 1 .2
Latency Duration No . of rata to first of first with multiple seizure (min) seizure (sec) seizures
14 .9 + 1 .6
NS 6-OHDA (n-9)
8 .2 + 1 .4
32 .9 + 3 .0
NS
**
14 .8 + 2 .3
113 .2 + 11 .7
No . of rata with tonic seizures
0/7
0/7
5/9
5/9
The data on latencies and duration are presented as plus and minus the standard error of the mesa . The control and 6-OHDA-treate~ groups are significantly different at the following levels : ** p < 0 .02, p ~ 0 .03, NS ~ not significant . TABLE 2 Levels of Catecholamiaea in Control sad 6-OHDA-Treated Rata Region
Control (n=5)
Treated (n=5)
X
t
p
0 .001 0 .001 NS NS
NORADRENALINE Hippocampus-cortex Hypothalamus Cerebellum Spinal cord
0 .264 2 .240 0 .219 0 .255
+ + + +
0 .006 0 .077 0 .012 0 .006
+ 0 .001 + 0 .087 + 0 .008 + 0 .012
2 26 124 120
5 .26 6 .87 0 .62 0 .65
11 .570 + 1 .190
88
1 .89
0 .006 0 .590 0 .271 0 .307
DOPAMINE Striatum
13 .170 + 0 .570
NS
Regional amine assay values on control and 6-OHDA-treated rata . Values are means of five randomly selected controls and five treated rata in micrograms of amine per gram wet weight of tissue with standard errors of the mean . X column is the percentage of control concentrations remaining is lesioned tissues . Discussion It seems well established that central catecholaminergic neurone can suppress various forms of seizure activity (4,5) . The relative antiseizure activity of NA and DA, and particularly of the forebrain projections of these neurons, is
170
Noradrenaline and Seizurea
Vol . 23, No . 2, 1978
less clear . It can be stated With some certainty that spinal NA playa a role in inhibiting the postdecapitation reflex (13, 14) . The picture is less certain with other forms of seizure activity, however, because the ezperimeatal techniques used in the relevant studies depleted either peripheral ae well as central catecholamiaes (15,16), both DA and NA (7,8,17,18,19,20), or, when central NA was implicated, cerebellar and spinal as well ae forebrain levels of NA (8,21) . In contrast to previous work, the present experiment made use of intracerebral injections of 6-OHDA to produce a selective depletion of NA in the diencephalic and telencephalic terminals of the ascending noradrenergic pathways . Rather than producing a general depletion of NA throughout the CNS, our injections of 6-0HDA resulted in essentially intact concentrations of NA in the cerebellum and spinal cord . The results thus demonstrate that selective depletion of forebrain NA results in a significant potentiation of Metrazol-induced seizures, measured quantitatively as increases in the duration and number of evoked seizures and qualitatively as induction of mild tonic episodes in many of the 6OHDA-treated rats . One possible ezplanation of these results is that 6-OHDA-induced depletion of NA produced increased penetration of Metrazol into the brain . Although we did not test this hypothesis directly, we believe that it can be eliminated, because 1t would predict that all measures of the convulsant effects of Metrazol, including latencies to the first jerk and the first seizure, should have shown similar potentiation in the 6-0HDA-treated rats . This clearly was not the case . It is interesting that depletion of forebrain NA did not consistently result in induction of generalized ionic seizures, including extension of the hindlimba, as was previously observed in rate receiving 6-OHDA intraventricularly (7,8) . This suggests that depletion of forebrain NA alone cannot fully account for the marked potentiation of Metrazol-induced seizures induced by intravemtricular injections of 6-ONDA . We are at present attempting to determine whether other aspects of Metrazol-induced seizures areFatentiated by selective depletion of DA, cerebellar NA, .or spinal NA . In summary, selective depletion of forebrain NA potentiated nartaia aspects of the seizure induced by Matrazol . This suggests that NA in the intact brain may act to reduce the intensity and duration of seizure activity . Whether suppreaaion of seizures is a specific function of NA or merely a byproduct of its largely inhibitory synaptic action (22,23) cannot be determined on the basis of the present results . Complex roles is normal behavior have beeq ascribed to NA (24,25,26,27), and so it seems unlikely that suppression of seizures could be its sole or even primary function is the CNS . Depletion of forebrain NA does nonetheless result in a potentiation of seizures, however, and it may be the case that in pathological states such ae epilepsy a deficiency in NA plays a causal role .
References 1. 2. 3. 4. 5. 6.
T .J . CROW, Peychol. lied . 2 414-417 (1972) . T .J . CROW, Peychol. Med . 105 (1973) . S .S . RETY, The Neurosciences, p . 324, Rockefeller University Preae, New York (1970) . R . LOVELL, Hapdbook of Neurochemistry , Vol . 6, p . 63, Plenum Press, New York (1971) . E.W . MAYNERT, EpilBpaia 10 145-162 (1969) . N.J . IIRETSRY sad L.L . IVERSEN, Nature 221 557-559 (1969) .
3
Vol . 23, No . 2, 1978 7. 8. 9. 10 . 11 . 12 . 13 . 14 . 15 . 16 . 17 . 18 . 19 . 20 . 21 . 22 . 23 . 24 . 25 . 26 . 27 .
Noradrenaliae and Seiaures
171
M .E . CORCORAN, H .C . FIBIGER, E .G . MCGEER, and J .A . WADA, J . Pharm . Pharmac . _25 497-499 (1973) . M .E . CORCORAN, H .C . FIBIGER, J .A . McCAUGHRAN, and J .A . WADA, ERp . Neurol . 45 118-133 (1974) . S.T . MASON aad S .D . IVERS$N, NBtûYA 258 422-424 (1975) . U . UNGERSTEDT, Acts" Ptiysi0l : 5t~d . sûppl. . _367 1-49 (1971) . 0 . LINDVALL and A . BJORKLUND, AttA Phyéidl . Stàbd . suppl . 412 1-48 (1974) . E .G . McGEER and P .L . McGEER, Cad . J . Biothem . _40 1141-1151(1962) . W .M . BOURN, P .F . GEIGER, and P .C . JOBE, Rés . COthm . YBythol . Psyrthiat . Behav . 2 9-20 (1977) . N . SUENAGA, K . YAMADA, and T . FUKUDA, Brain Res . 122 165-169 (1977) . W .M . BOURN, L . CHIN, and A .L . PICCIONI, Lifa Sci .21 701-706 (1977) . G .M . McRENZIE and F .E . SOROKO, J . Pharm . Pharmac . 25 76-77 (1973) . P .S .~ARNOLD, R .J . RACINE, and R .A . WISE, Exp . Neurol . _40 457-470 (1973) . I .H . AYHAN, Arch . Int . Pharmacodya . 223 282-286 (1976) R .A . BROWNING and E .W . MAYNERT, fled .Proc . 29 417 (1970) . A . QUATTRONE and R . SAMANIN, Eur . J . Pharmacôl . _41 333-336 (1977) . A . LEHMANN, Life Sci . 20 2047-2060 (1977) . M . SEGAL and F .E . BLOOM, Brain Res . 72 79-97 (1974) . B .J . HOFFBR, G .R . SIGGENS, A .P . OLIVgR, and F .E . BLOOM, J . Pharmac . ExP . Therap . 184 553-569 (1973) . S .T . MASONand S .D . IVERSEN, J . Comp . Physiol . Pevcho] . . 91 165-173 (1977) . S .T . MASON aad 5 .D . IVERSEN, Brain Res . 134 513-527 (1977) . S .T . MASON ead S .D . IVERSEN, Pharmac . Bioche~n . Behav . _7 373-379 (1977) . S .T . MASON and H .C . FIBIGER, Nature 269 704-705 (1977)