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Dopamine agonists produce functional recovery from septal lesions which affect hypothalamic defensive attack in cats
381
Brain Research, 407 (1987) 381-385 Elsevier BRE 22132
Dopamine agonists produce functional recovery from septal lesions which affect hypothalamic defensive attack in cats Hisao Maeda and Seiko Maki Department of Psychiatry, Saga Medical School, Nabeshima, (Japan) (Accepted 2 December 1986)
Key words: Recovery of function; Dopamine; Ventromedial hypothalamic nucleus; Defensive attack; Lateral septum; Gating mechanism
Effects of lesions of the lateral septum and subsequent administration of methamphetamine (MAT, 1 mg/kg, i.p.) or apomorphine (APO, 1 mg/kg, i.p.) on thresholds for defensive attack elicited by electrical stimulation of the ventromedial hypothalamic nucleus (VM) were examined. Hissing and directed attack were selected for threshold determination. Thresholds were measured under two situations: one with provocation by a human and the other without it. Electrolytic lesions of the lateral septum enhanced the facilitative influences exerted by the provocation on the thresholds, however, subsequent administration of MAT or APO abolished or tended to abolish the enhancement. The rapid recovery of function was interpreted to have taken place due to excessive dopaminergic inputs to the spared tissue of the lateral septum, and a gating mechanism of neuronal information by dopamine was suggested.
Defensive attack elicited by electrical stimulation of the ventromedial hypothalamic nucleus (VM) consists of 3 e l e m e n t a r y responses, i.e., directed attack, threat, and sympathetic autonomic responses ~1'j9'2°. The minimal current intensity of hypothalamic stimulation required to elicit these e l e m e n t a r y responses (threshold) can be reduced m a r k e d l y by the concurrent presence of environmental stimuli such as a barking dog or provocation by humans 11'2°. Electrolytic lesions of the amygdala attenuate or abolish the facilitative environmental influences o n the hypothalamic defensive attack, but the effects of amygdaloid lesions d i s a p p e a r e d by subsequent administration of d o p a m i n e ( D A ) agonists such as m e t h a m p h e t a m i n e ( M A T , a presynaptic D A releaser 2'3) or a p o m o r p h i n e ( A P O , a D A receptor stimulant2'4). The rapid recovery of the amygdaloid function was interpreted as the result of excessive dopaminergic inputs to the remaining intact tissue of the amygdala. The D A agonists themselves, however, are known to lower thresholds for the hypothalamic defensive attack, possibly by increasing excitability of the V U 16. Therefore, it was neccesary to
see if a similar recovery of function would take place by D A agonists in the direction of elevation of thresholds for the hypothalamic defensive attack. Hence, the influences of D A agonists on the effects of septal lesions were examined in the present study, since lesions of the lateral septum are known to enhance the facilitative environmental influences on thresholds for hypothalamic defensive attack by lowering the thresholds 12, contrary to amygdaloid lesion 13'14. in addition, examinations along these lines may very well yield valuable information concerning the function of dopaminergic inputs to the lateral septum arising in the ventral tegmental area ( V T A , A10) 5,1s. A total of 15 adult cats were used. Electrodes for brain stimulation and electrolytic lesion were implanted chronically in the left medial hypothalamic area and bilateral lateral septum, respectively. A f t e r recovery from the operation, influences of M A T (1 mg/kg, i.p.) or A P O (1 mg/kg, i.p.) on the effects of septal lesions on the hypothalamically elicited defensive attack were studied under an unanesthetized, freely moving condition. The detailed methods for
Corres'pondence: H. Maeda, Department of Psychiatry, Saga Medical School, Nabeshima, Saga 840-0l, Japan. 0006-8993/87/$03.50 © 1987 Elsevier Science Publishers B.V. (Biomedical Division)
382 under 50/xA, 10 ~tA between 50 and 100 uA, and 21) uA between 100 and 200 ~ A was used for the threshold determination. Stimulation of a given current intensity was administered for 10 s. each stimulation trial being 50 s apart, and the threshold was represented by the lowest current intensity which elicited the same response on two consecutive stimulation reals. Such thresholds were measured hourly, and MAT or APO was administered 3 h after septal lesions which were made at one stage by passing a cathodal DC current of 5 mA for 20 s. Typical changes in the thresholds produced by septal lesions and subsequent administration of MAT are illustrated in Fig. 1. Usually, the thresholds for hissing was lowered by provocation by up to 50% before the lesions. Septal lesions enhanced the facilitative influence exerted by the provocation without altering the hissing thresholds under the non-provocative situation, but the enhancement disappeared after the administration of MAT and did not reappear on the following day. Changes In thresholds for directed attack paralleled those in hissing thresholds under the provocative situation. The observed find-
surgery, electrical stimulation, electrolytic lesion. behavioral observation, and histology have been mentioned previously TM. Briefly, 6 stainless-steel stimulation electrodes in a linear array were implanted stereotaxically in the left medial hypothalamic area (A 13.0, L 1.0, H 5.0 from the interaural zero point for the most rostral electrode) and another stainless-steel electrode for electrolytic lesion in the lateral septum bilaterally ~A 15.0, L 1.0, H 11.0). One electrode which could elicit defensive attack was used in the experiment. Stimulation was carried out monopolarly with 60 Hz biphasic square-wave train pulses (pulse duration 1 ms. pulse intensity 0-200 #A). Directed attack and hissing were selected for threshold determination from the elementary responses as constituting the defensive attack. Thresholds for hissing were measured under two situations: one in which the cat was simultaneously stimulated electrically and provoked visually by the experimenter, and the other without such provocation. Thresholds for directed attack were determined only under the provocative situation. An ascending series of currents with increments of 5 ~A
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Fig. 1. Typical examples (2 cats) of threshold changes in electrically elicited hypothalamicdefensive attack induced by bilateral electrolytic lesions of the lateral septum and subsequent administration of MAT (1 mg/kg, i.p.): Open circles indicate thresholds for hissing under the non-provocativesituation; closed circles and squares indicate thresholds for hissing and directed attack; respeCtively. under the provocative situation. Numbers on the right of each graph are the identification numbers of cats. Lesions and injections were made at arrows under an unanesthetized, freely movingcondition.
383 ings were verified further as group means shown in Fig. 2. Similar functional recovery from septal lesions: were observed following the injection of APO (Fig. 3). The tips of stimulation electrodes used were all located in the VM and areas just rostral to it. The extent of septal lesions maximal in each cat are shown as reconstructions in Fig. 4. The lateral septum was destroyed in 14 cats, however, some parts of the lateral septum remained undamaged because its structural characteristics elongated along the anterior-posterior axis (A 14.0-A 18.0). Lesions of the lateral septum lowered thresholds for hissing and directed attack under the provocative situation without changing thresholds for hissing under the non-provocative situation. This indicates that the facilitative influences exerted by the environment, i.e., the provocation, were enhanced further by the septal lesions, confirming previous results 12'~5. This behavioral change was contrary to that induced by amygdaloid lesions 13-15. Subsequent administration of MAT or APO elevated the lowered thresholds to the prelesion level, thus abolishing the effects of septal lesions. The direction of the threshold change
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Fig. 2. Threshold changes induced by septal lesions and subsequent administration of M A T (1 mg/kg, i.p.), presented as group means (n = 10). The ordinate indicates the number of increment steps by which thresholds differ from the prelesion level. Thresholds differing from the prelesion level by more than 5 steps were dealt with as differing by 5 steps. Vertical bars show the standard deviations. Lesions and injections were performed at arrows. Symbols are the same as in Fig. 1. *** P < 0.005 (U-test).
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< 0.05 (U-test).
produced by MAT or APO was contrary to that expected from the threshold lowering action of the DA agonists themselves 16. Hence, it is reasonable to conclude that the recovery of the septal function was produced by the DA agonists, independently of the direct action of the drugs on thresholds for hypothalamic defensive attack. Generally, recovery of function after brain damage is mediated by the spared tissue of the damaged system 4,1°. Therefore, it is most likely that the observed rapid recovery of the septal function occurred as a result of excessive dopaminergic inputs produced directly by the DA agonists to the spared tissue of the lateral septum. Usually, the effects of electrolytic lesions of the septum disappear within 7-10 days without DA agonists ~2. Similar results have been obtained in rats. Hyperirritability or hyperreactivity induced by septal lesions was reported to be abolished by administration of L-DOPA, APO, or amphetamine 6.17, and on the other hand, the duration of hyperirritability was prolonged substantially by dopaminergic depletion from the brain with intraventricular pretreatment of 6-hydroxydopamine 9. These findings complement the resuits in the present study. The lateral septum is the area where the descending efferents of the hippocampus terminate solely2~. The hippocampus, in turn, receives convergent multisynaptic inputs of transcortical multimodal sensory
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Fig. 4. Reconstructionof septal lesions. The extent of lesions maximal in each cat is depicted by thicker lines on the coronal drawings7. Numbers below the drawings indicate the numbers of the coronal plane and numbers at the shoulder are the identification numbers of the animals. A: MAT injection. B: APO injection. AC, anterior commissure; Acb, Nucleus accumbens; CC; corpus catlosum; Cd, caudate nucleus; Ch, chiasma; DBB, diagonal band of Broca; S, septum. information, along with the amygdala and the prefrontal cortex 8,23,24. The lateral septum then projects to the hypothalamus and the brainstem 1,22. Thus, the lateral septum can be considered to be a pivotal structure which relays sensory information coming from the environment through the cortex and the hippocampus to the hypothalamus and the brainstem. The sensory information appears to suppress the hypothalamic defensive attack, since lesions of the lateral septum resulted in enhancement of the facilitative influences from the environment. The suppressive inputs to the VM which had been blocked by the septal lesions were thought to be reinstated by the D A agonists. Again it is possible that dopaminergic
The authors express appreciation to Dr. M. Takeichi for his comments and to Dr. R.J.K. Uehara for correction of the English.
1 Blume, H.W., Pittman, QJ., Lafontaine, S. and Renaud, L.P., Lateral septum-medial hypothalamic connections - an electrophysiological study in the rat, Neuroscience, 7 (I982) 2783-2792. 2 Bunney, B.S., Aghajanian, G.K. and Roth, R.H., Com-
parison of effects of L-DOPA, amphetamine and apomorphine on firing rate of rat dopaminergic neurons, Nature (London), 245 (i973) 123-1251 3 Costa, E:, Groppetti, A. and Naimzada, M.K., Effects of amphetamine on the turnover rate of brain catecholamines
inputs to the lateral septum which arise in the VTA may gate the passage of neuronal information through the lateral septum, coming from the environment via the cerebral cortex en route to the VM, which are suppressive to the hypothalamic defensive attack function, It is also noteworthy that the direction of the behavioral changes produced by DA agonists was contrary for lesions of the lateral septum and the amygdala, suggesting non-specific action of DA.
385 and motor activity, Br. J. Pharmacol., 44 (1972) 742-757. 4 Crutcher, K.A., Kesner, R.P. and Novak, J,M., Medial septal lesions, radial arm maze performance, and sympathetic sprouting; a study of recovery of function, Brain Research, 262 (1983) 91-98. 5 Dahlstr6m, A. and Fuxe, K., Evidence for the existence of monoamine containing neurons in the central nervous system. I. Demonstration of monoamines in the cell bodies of brain stem neurons, Acta Physiol. Scand., 62 (Suppl. 232) (1964) 1-55. 6 Gage, F.H. and Olton, D.S., L-Dopa reduces hyperreactivity induced by septal lesions in rats, Behav. Biol., 17 (1976) 213-218. 7 Jasper, H.H. and Ajmone-Marsan, C., A Stereotaxic Atlas of the Diencephalon of the Cat, National Research Council of Canada, Ottawa, 1954. 8 Jones, E.G. and Powell, T.P.S., An anatomical study of converging sensory pathways within the cerebral cortex of the monkey, Brain, 93 (1970) 793-820. 9 Kurumiya, S. and Umemoto, M., Prolonged hyperreactivity of septal rats with intraventricular pretreatment of 6-hydroxydopamine, Physiol. Psychol., 9 (1981) 347-350. 10 LeVere, N.D. and LeVere, T.E., Recovery of function after brain damage; support for the compensation theory of the behavioral deficit, Physiol. Psychol., 10 (1982) 165-174. 11 Maeda, H., Behavioral construction of hypothalamic rage in cats, I Fukuoka Acta Med., 67 (1976) 364-373 (in Japanese). 12 Maeda£ H., Effects of septal lesions on electrically elicited hypothalamic rage in cats, Physiol. Behav., 21 (1978) 339-343. 13 Maeda, H. and Hirata, K., Two-stage amygdaloid lesions and hypothalamic rage: a method useful for detecting functional localization, Physiol. Behav., 21 (1978) 529-530.
14 Maeda, H. and Maki, S., Dopaminergic facilitation of recovery from amygdaloid lesions which affect hypothalamic defensive attack in cats, Brain Research, 363 (1986) 135-140. 15 Maeda, H. and Nakao, H., Effects of sequential destruction of amygdala and septum on hypothalamic rage in cats. In M. Ito, N. Tsukahara, K. Kubota and K. Yagi (Eds.), In-
tegrative Control of Functions of the Brain, Vol. 1, Kodansha, Tokyo, 1978, pp. 370-372. 16 Maeda, H., Sato, T. and Maki, S., Effects of dopamine agonists on hypothalamic defensive attack in cats, Physiol. Behav., 35 (1985) 89-92. 17 Marotta, R.F., Logan, N., Potegal, M., Glusman, M. and Gardner, E.L., Dopamine agonists induce recovery from surgically induced septal rage, Nature (London), 269 (1977) 513-515. 18 Moore, R.Y. and Bloom, F.E., Central catecholamine neuron systems: anatomy and physiology of the dopamine systems, Annu. Rev. Neurosci., 1 (1978) 129-169. 19 Nakao, H., Emotional behavior produced by hypothalamic stimulation, Am. J. Physiol., 194 (1958) 411-418. 20 Nakao, H., Brain Stimulation and Learning. Switch-Off Behavior, Fisher, Jena, 1971. 21 Swanson, L.W., The hippocampus - - new anatomical insight, TINS, 2 (1979) 9-12. 22 Swanson, L.W. and Cowan, W.M., The connections of the septal region in the rat, J. Comp. Neurol., 186 (1979) 621-656. 23 Turner, B.H., Mishkin, M. and Knapp, M., Organization of the amygdalopetal projections from modality-specific cortical association areas in the monkey, J. Comp. Neurol., 191 (1980) 515-544. 24 vanHoesen, G.W., The parahippocampal gyrus. New observations regarding its cortical connections in the monkey, TINS, 5 (1982) 345-350.
Brain Research, 407 (1987) 381-385 Elsevier BRE 22132
Dopamine agonists produce functional recovery from septal lesions which affect hypothalamic defensive attack in cats Hisao Maeda and Seiko Maki Department of Psychiatry, Saga Medical School, Nabeshima, (Japan) (Accepted 2 December 1986)
Key words: Recovery of function; Dopamine; Ventromedial hypothalamic nucleus; Defensive attack; Lateral septum; Gating mechanism
Effects of lesions of the lateral septum and subsequent administration of methamphetamine (MAT, 1 mg/kg, i.p.) or apomorphine (APO, 1 mg/kg, i.p.) on thresholds for defensive attack elicited by electrical stimulation of the ventromedial hypothalamic nucleus (VM) were examined. Hissing and directed attack were selected for threshold determination. Thresholds were measured under two situations: one with provocation by a human and the other without it. Electrolytic lesions of the lateral septum enhanced the facilitative influences exerted by the provocation on the thresholds, however, subsequent administration of MAT or APO abolished or tended to abolish the enhancement. The rapid recovery of function was interpreted to have taken place due to excessive dopaminergic inputs to the spared tissue of the lateral septum, and a gating mechanism of neuronal information by dopamine was suggested.
Defensive attack elicited by electrical stimulation of the ventromedial hypothalamic nucleus (VM) consists of 3 e l e m e n t a r y responses, i.e., directed attack, threat, and sympathetic autonomic responses ~1'j9'2°. The minimal current intensity of hypothalamic stimulation required to elicit these e l e m e n t a r y responses (threshold) can be reduced m a r k e d l y by the concurrent presence of environmental stimuli such as a barking dog or provocation by humans 11'2°. Electrolytic lesions of the amygdala attenuate or abolish the facilitative environmental influences o n the hypothalamic defensive attack, but the effects of amygdaloid lesions d i s a p p e a r e d by subsequent administration of d o p a m i n e ( D A ) agonists such as m e t h a m p h e t a m i n e ( M A T , a presynaptic D A releaser 2'3) or a p o m o r p h i n e ( A P O , a D A receptor stimulant2'4). The rapid recovery of the amygdaloid function was interpreted as the result of excessive dopaminergic inputs to the remaining intact tissue of the amygdala. The D A agonists themselves, however, are known to lower thresholds for the hypothalamic defensive attack, possibly by increasing excitability of the V U 16. Therefore, it was neccesary to
see if a similar recovery of function would take place by D A agonists in the direction of elevation of thresholds for the hypothalamic defensive attack. Hence, the influences of D A agonists on the effects of septal lesions were examined in the present study, since lesions of the lateral septum are known to enhance the facilitative environmental influences on thresholds for hypothalamic defensive attack by lowering the thresholds 12, contrary to amygdaloid lesion 13'14. in addition, examinations along these lines may very well yield valuable information concerning the function of dopaminergic inputs to the lateral septum arising in the ventral tegmental area ( V T A , A10) 5,1s. A total of 15 adult cats were used. Electrodes for brain stimulation and electrolytic lesion were implanted chronically in the left medial hypothalamic area and bilateral lateral septum, respectively. A f t e r recovery from the operation, influences of M A T (1 mg/kg, i.p.) or A P O (1 mg/kg, i.p.) on the effects of septal lesions on the hypothalamically elicited defensive attack were studied under an unanesthetized, freely moving condition. The detailed methods for
Corres'pondence: H. Maeda, Department of Psychiatry, Saga Medical School, Nabeshima, Saga 840-0l, Japan. 0006-8993/87/$03.50 © 1987 Elsevier Science Publishers B.V. (Biomedical Division)
382 under 50/xA, 10 ~tA between 50 and 100 uA, and 21) uA between 100 and 200 ~ A was used for the threshold determination. Stimulation of a given current intensity was administered for 10 s. each stimulation trial being 50 s apart, and the threshold was represented by the lowest current intensity which elicited the same response on two consecutive stimulation reals. Such thresholds were measured hourly, and MAT or APO was administered 3 h after septal lesions which were made at one stage by passing a cathodal DC current of 5 mA for 20 s. Typical changes in the thresholds produced by septal lesions and subsequent administration of MAT are illustrated in Fig. 1. Usually, the thresholds for hissing was lowered by provocation by up to 50% before the lesions. Septal lesions enhanced the facilitative influence exerted by the provocation without altering the hissing thresholds under the non-provocative situation, but the enhancement disappeared after the administration of MAT and did not reappear on the following day. Changes In thresholds for directed attack paralleled those in hissing thresholds under the provocative situation. The observed find-
surgery, electrical stimulation, electrolytic lesion. behavioral observation, and histology have been mentioned previously TM. Briefly, 6 stainless-steel stimulation electrodes in a linear array were implanted stereotaxically in the left medial hypothalamic area (A 13.0, L 1.0, H 5.0 from the interaural zero point for the most rostral electrode) and another stainless-steel electrode for electrolytic lesion in the lateral septum bilaterally ~A 15.0, L 1.0, H 11.0). One electrode which could elicit defensive attack was used in the experiment. Stimulation was carried out monopolarly with 60 Hz biphasic square-wave train pulses (pulse duration 1 ms. pulse intensity 0-200 #A). Directed attack and hissing were selected for threshold determination from the elementary responses as constituting the defensive attack. Thresholds for hissing were measured under two situations: one in which the cat was simultaneously stimulated electrically and provoked visually by the experimenter, and the other without such provocation. Thresholds for directed attack were determined only under the provocative situation. An ascending series of currents with increments of 5 ~A
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Fig. 1. Typical examples (2 cats) of threshold changes in electrically elicited hypothalamicdefensive attack induced by bilateral electrolytic lesions of the lateral septum and subsequent administration of MAT (1 mg/kg, i.p.): Open circles indicate thresholds for hissing under the non-provocativesituation; closed circles and squares indicate thresholds for hissing and directed attack; respeCtively. under the provocative situation. Numbers on the right of each graph are the identification numbers of cats. Lesions and injections were made at arrows under an unanesthetized, freely movingcondition.
383 ings were verified further as group means shown in Fig. 2. Similar functional recovery from septal lesions: were observed following the injection of APO (Fig. 3). The tips of stimulation electrodes used were all located in the VM and areas just rostral to it. The extent of septal lesions maximal in each cat are shown as reconstructions in Fig. 4. The lateral septum was destroyed in 14 cats, however, some parts of the lateral septum remained undamaged because its structural characteristics elongated along the anterior-posterior axis (A 14.0-A 18.0). Lesions of the lateral septum lowered thresholds for hissing and directed attack under the provocative situation without changing thresholds for hissing under the non-provocative situation. This indicates that the facilitative influences exerted by the environment, i.e., the provocation, were enhanced further by the septal lesions, confirming previous results 12'~5. This behavioral change was contrary to that induced by amygdaloid lesions 13-15. Subsequent administration of MAT or APO elevated the lowered thresholds to the prelesion level, thus abolishing the effects of septal lesions. The direction of the threshold change
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< 0.05 (U-test).
produced by MAT or APO was contrary to that expected from the threshold lowering action of the DA agonists themselves 16. Hence, it is reasonable to conclude that the recovery of the septal function was produced by the DA agonists, independently of the direct action of the drugs on thresholds for hypothalamic defensive attack. Generally, recovery of function after brain damage is mediated by the spared tissue of the damaged system 4,1°. Therefore, it is most likely that the observed rapid recovery of the septal function occurred as a result of excessive dopaminergic inputs produced directly by the DA agonists to the spared tissue of the lateral septum. Usually, the effects of electrolytic lesions of the septum disappear within 7-10 days without DA agonists ~2. Similar results have been obtained in rats. Hyperirritability or hyperreactivity induced by septal lesions was reported to be abolished by administration of L-DOPA, APO, or amphetamine 6.17, and on the other hand, the duration of hyperirritability was prolonged substantially by dopaminergic depletion from the brain with intraventricular pretreatment of 6-hydroxydopamine 9. These findings complement the resuits in the present study. The lateral septum is the area where the descending efferents of the hippocampus terminate solely2~. The hippocampus, in turn, receives convergent multisynaptic inputs of transcortical multimodal sensory
384 A CC
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121
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Fig. 4. Reconstructionof septal lesions. The extent of lesions maximal in each cat is depicted by thicker lines on the coronal drawings7. Numbers below the drawings indicate the numbers of the coronal plane and numbers at the shoulder are the identification numbers of the animals. A: MAT injection. B: APO injection. AC, anterior commissure; Acb, Nucleus accumbens; CC; corpus catlosum; Cd, caudate nucleus; Ch, chiasma; DBB, diagonal band of Broca; S, septum. information, along with the amygdala and the prefrontal cortex 8,23,24. The lateral septum then projects to the hypothalamus and the brainstem 1,22. Thus, the lateral septum can be considered to be a pivotal structure which relays sensory information coming from the environment through the cortex and the hippocampus to the hypothalamus and the brainstem. The sensory information appears to suppress the hypothalamic defensive attack, since lesions of the lateral septum resulted in enhancement of the facilitative influences from the environment. The suppressive inputs to the VM which had been blocked by the septal lesions were thought to be reinstated by the D A agonists. Again it is possible that dopaminergic
The authors express appreciation to Dr. M. Takeichi for his comments and to Dr. R.J.K. Uehara for correction of the English.
1 Blume, H.W., Pittman, QJ., Lafontaine, S. and Renaud, L.P., Lateral septum-medial hypothalamic connections - an electrophysiological study in the rat, Neuroscience, 7 (I982) 2783-2792. 2 Bunney, B.S., Aghajanian, G.K. and Roth, R.H., Com-
parison of effects of L-DOPA, amphetamine and apomorphine on firing rate of rat dopaminergic neurons, Nature (London), 245 (i973) 123-1251 3 Costa, E:, Groppetti, A. and Naimzada, M.K., Effects of amphetamine on the turnover rate of brain catecholamines
inputs to the lateral septum which arise in the VTA may gate the passage of neuronal information through the lateral septum, coming from the environment via the cerebral cortex en route to the VM, which are suppressive to the hypothalamic defensive attack function, It is also noteworthy that the direction of the behavioral changes produced by DA agonists was contrary for lesions of the lateral septum and the amygdala, suggesting non-specific action of DA.
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