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Changes in side preference during unilateral electrical stimulation of the caudate nucleus in rats
Brain Research, 86 (1975) 335-338
335
© Elsevier Scientific Publishing Company, Amsterdam - Printed in The Netherlands
Short Communications
Changes in side preference during unilateral electrical stimulation of the caudate nucleus in rats
BETTY ZIMMERBERG AND STANLEY D. GLICK Department of Pharmacology, Mount Sinai School of Medicine, City University of New York, New York, N.Y. 10029 (U.S.A.)
(Accepted December 4th, 1974)
Previous studies have indicated a relationship between side preference and an induced or intrinsic asymmetry of the nigrostriatal system. Unilateral lesions of the substantia nigra, nigrostriatal bundle, or caudate nucleus cause circling, or rotation, towards the side of the lesion, and this rotation can be re-elicited after recovery from surgery by administration of drugs (e.g. D-amphetamine) which release dopamine from neurons in the intact caudate nucleus1,4,15. Similarly, unilateral lesions of the caudate nucleus result in a side preference towards the side of the lesion when rats are tested in a T-maze is. This laboratory has shown that normal, nonlesioned rats will rotate spontaneously after administration of D-amphetamine 9. In normal rats, the dopamine contents of the left and right striata were found to be imbalanced, and this imbalance was potentiated by administration of D-amphetamine 7. The striatum that was higher in dopamine levels was opposite to the direction of rotation; thus normal rats will rotate towards the side of the lower dopamine levels just as rats with unilateral nigrostriatal lesions will rotate towards the side deficient in dopamine neurons. Similarly, normal rats were shown to exhibit stable side preferences in a T-maze, the preference was enhanced by D-amphetamine, and the direction of side preference was opposite to the side of higher dopamine levels in the left or right striatum is. Unilateral electrical stimulation of the nigrostriatal system has been reported to result in rotation away from the side of the stimulation2,a, 17. This paper is an examination of the effects of unilateral electrical stimulation o f the caudate nucleus on side preference, as an attempt to further strengthen the argument that rotation and side preference are both subserved by the nigrostriatal system and reflect, in different magnitudes, the intrinsic asymmetry of the system. Seven rats (female Sprague-Dawley albinos weighing 250 g) were trained to bar-press for water reinforcement on a continuous reinforcement schedule. Testing was conducted in a Lehigh Valley operant test cage with 2 levers (left and right of
336 center reward spout) and responses on either lever were reinforced 5. Rats were trained for 4 weeks in daily half-hour sessions followed by 15 rain of free water in the home cage. All rats showed consistent side preferences. The rats were then bilaterally implanted under methohexital anesthesia with bipolar electrodes in the caudate nucleus; coordinates were 2.0 mm anterior to bregma, 3.0 mm lateral on either side of the midline, and 5.5 mm below the base of the skull with the skull inclined 5 mm (ref. 13). After a one week recovery period, the implanted rats were tested for rotation with unilateral electrical stimulation o f either electrode. The stimulus was a pulse train of 2 sec duration; pulses were monopolar, 5 msec wide, 100 Hz, and pulse amplitude was varied from 10 to 300 #A, at constant current, delivered from a Grass $48 stimulator. Threshold for rotation was defined as that current which elicited a 180° turn of the head and body. As expected 17, unilateral stimulation elicited contralateral rotation for the duration of the stimulation. The rats were then water deprived for 2 days, and retested for 2 weeks in the test cage. There were no significant changes in performance (response rate) or side preference as a result of the electrode implantation. The effect of unilateral stimulation of the caudate nucleus on side preference was observed via a closed circuit video monitor while the subject was bar-pressing, and responses on left and right levers were recorded on an event recorder and on digital counters. Unilateral stimulation was delivered through a connecting cable from a constant voltage sine wave stimulator (0.7 sec pulses, 2 sec apart) at currents 10 ~ below rotation threshold, determined again with the new stimulation parameters. No disruptive motor behavior was observed during stimulation testing. The stimulation test was conducted as follows: the subject was allowed to emit 150 responses with no stimulation, 150 responses during stimulation, and 150 responses with no stimulation. Each subject received this stimulation test for at least 3 sessions. Lastly, contralateral rotation was observed at the same threshold currents, as determined earlier, when the bar-pressing experiment was concluded. The sites of implantation were then verified histologically for each subject. TABLE I EFFECT OF IPSILATERAL CAUDATE STIMULATION ON SIDE PREFERENCES
Subject (preference)
1 (left) 2 (right) 3 (right) 4 (left) 5 (right) 6 (left) 7 (right) Combined means
Mean % responses on preferred bar Training
Pre-stimulation
Stimulation
Post-stimulation
75 67 95 99 98 99 91 89
73 62 71 92 100 100 60 80
26 16 10 18 56 86 03 31 *
68 83 21 100 90 100 55 74
* Significantly different from pre-stimulation and post-stimulation at P < 0.001, t-test.
337
S
Fig. 1. Representative event recording showing the effect of unilateral caudate stimulation on barpressing; stimulation was administered to the caudate ipsilateral to the initial (pre-stimulation) side preference, t, time with 15 see between markers; L, left lever; S, stimulation; R, right lever. The results of the experiment are shown in Table I. Stimulation o f the caudate nucleus on the same side as the side preference caused a reversal of side preference to the opposite lever, as illustrated in Fig. 1. Stimulation of the caudate nucieus on the side opposite to the preferred lever had no effect on side preference. Thus, an electrically-induced increase in activity in one half o f the nigrostriatal system results in a preference for the opposite side. The results of this experiment suggest that an intrinsic asymmetry of the nigrostriatal system, expressed in rotation and in a T-maze side preference, may also be responsible for a spontaneous side preference in a 2 lever Skinner box, as proposed earlierS, 8. Two studies, by Hansing et al. 8 and Levine et al. 1°, in which unilateral lesions of the caudate nucleus or the globus pallidus selectively blocked lever pressing with the forepaw contralateral to the lesion, support this view. In addition, Ungerstedt 16 has reported unilateral sensory neglect in several modalities on the contralateral side after unilateral destruction of the nigrostriatal system by 6-hydroxydopamine. Contralateral sensory neglect is also seen after unilateral lateral hypothalamic lesionsll,lz, 14 which might include damage to the nigrostriatal system, and after ablation of the ansa lenticularis, an efferent projection of the caudate nucleus via the globus pallidus 11. Perhaps the reversal of side preference after unilateral stimulation of the caudate nucleus in the present experiment can be seen as sensory 'overattention' to the opposite side. With increased attentiveness to stimuli present on the contralateral side, the animal presses the lever on that side more frequently. A side preference exhibited spontaneously may be the result of a normal imbalance between the left and right nigrostriatal systems, with the greater activity in one system producing greater attention to the opposite side. This research was supported by N I M H Grant MH25644 and N I M H Research Scientist Development Award (Type 2) DA70082 to S. D. Glick. We thank Alison Crane for technical assistance.
1 ANDt~N,N. E., DAHLSTRGM,A., FuxE, K., ANDLARSSON,K., Functional role of the nigroneostriatal dopamine neurons, Aeta pharmacol. (Kbh.), 24 (1966) 263-274. 2 ARaUTHNOTT,G. W., AND CROW,T. J., Relation of contraversive turning to unilateral release of dopamine from the nigrostriatal pathway in rats, Exp. Neurol., 30 (1971) 484-491. 3 ARBUTHNOTT, G. W., AND UNGERSTEDT,U., Locomotor behavior after electrical stimulation of dopamine containing neurones, Acta physiol, scand., Suppl. 330 (1969) 117. 4 CHRISTIE, J. E., AND CROW, T. J., Turning behavior as an index of the action of amphetamines and ephedrines on central dopamine-containing neurones, Brit. J. PharmacoL, 43 (1971) 658-667.
338 5 GLICK, S.D., Enhancement of spatial preferences by (-]-)-amphetamine, Neuropharmacology, 12 (1973) 43-47. 6 GLICK,S. D., AND JERUSSl, T. P,, Spatial and paw preferences in rats: their relationship to ratedependent effects of D-amphetamine, J. Pharmacol. exp. Ther., 188 (1974) 714-725. 7 GLlCK, S. D., JERUSSI, T. P., WATERS,D. H., AND GREEN,J. P., Amphetamine-induced changes in striatal dopamine and acetylcholine levels and relationship to rotation (circling behavior) in rats, Biochem. Pharmacol., 23 (1974) 3223-3225. 8 HANSING,R. A., SCHWARTZBAUM,J. S., AND TrtOMVSON,J. B., Operant behavior following unilateral and bilateral caudate lesions in the rat, J. comp. physiol. Psychol., 66 (1968) 378-388. 9 JERUSSX,T. P., AND GLICK, S. D., Amphetamine-induced rotation in rats without lesions, Neuropharmacology, 13 (1974) 283-286. 10 LEVINE, M. S., FERGUSON,N., KREINICK,C.J., GUSTAFSON,J. W., AND SCHWARTZBAUM,J. S., Sensorimotor dysfunctions and aphagia and adipsia following pallidal lesions in rats, J. comp. physiol. Psychol., 77 (1971) 282-293. 11 MARSHALL,J. F., AND TEITELnAUM,P., Further analysis of sensory inattention following lateral hypothalamic damage in rats, J. comp. physiol. Psychol., 86 (1974) 375-395. 12 MARSHALL,J. F., TURNER,B. H., ANDTEITELBAUM,P., Sensory neglect produced by lateral hypothalamic damage, Science, 174 (1971) 523-525. 13 PELEGRINO,L.J., AND CUSHMAN,A.J., Stereotaxic Atlas of the Rat Brain, Appleton-CenturyCrofts, New York, 1967. 14 TURNER, B. H., Sensorimotor syndrome produced by lesions of the amygdala and lateral hypothalamus, J. comp. physiol. Psychol., 82 (1973) 37-47. 15 UNGERSTEDT,U., Striatal dopamine release after amphetamine or nerve degeneration revealed by rotational behavior, Acta physiol, scand., Suppl. 367 (1971) 49-68. 16 UNGERSTEDT,U., Brain dopamine neurons and behavior. In F. O. SCHMITTAND F. G. WORDEN (Eds.), The Neurosciences,Third Study Program, MIT Press, Cambridge, Mass., 1974, pp. 695-703. 17 ZIMMERBER6,B., AND GLICK, S. D., Rotation and stereotypy during electrical stimulation of the caudate nucleus, Res. Commun. chem. Path. Pharmacol., 8 (1974) 195-196. 18 ZIMMERBERG,B., GLICK,S. D., ANDJERUSSI,T. P., Neurochemical correlate of a spatial preference in rats, Science, 185 (1974) 623-625.
335
© Elsevier Scientific Publishing Company, Amsterdam - Printed in The Netherlands
Short Communications
Changes in side preference during unilateral electrical stimulation of the caudate nucleus in rats
BETTY ZIMMERBERG AND STANLEY D. GLICK Department of Pharmacology, Mount Sinai School of Medicine, City University of New York, New York, N.Y. 10029 (U.S.A.)
(Accepted December 4th, 1974)
Previous studies have indicated a relationship between side preference and an induced or intrinsic asymmetry of the nigrostriatal system. Unilateral lesions of the substantia nigra, nigrostriatal bundle, or caudate nucleus cause circling, or rotation, towards the side of the lesion, and this rotation can be re-elicited after recovery from surgery by administration of drugs (e.g. D-amphetamine) which release dopamine from neurons in the intact caudate nucleus1,4,15. Similarly, unilateral lesions of the caudate nucleus result in a side preference towards the side of the lesion when rats are tested in a T-maze is. This laboratory has shown that normal, nonlesioned rats will rotate spontaneously after administration of D-amphetamine 9. In normal rats, the dopamine contents of the left and right striata were found to be imbalanced, and this imbalance was potentiated by administration of D-amphetamine 7. The striatum that was higher in dopamine levels was opposite to the direction of rotation; thus normal rats will rotate towards the side of the lower dopamine levels just as rats with unilateral nigrostriatal lesions will rotate towards the side deficient in dopamine neurons. Similarly, normal rats were shown to exhibit stable side preferences in a T-maze, the preference was enhanced by D-amphetamine, and the direction of side preference was opposite to the side of higher dopamine levels in the left or right striatum is. Unilateral electrical stimulation of the nigrostriatal system has been reported to result in rotation away from the side of the stimulation2,a, 17. This paper is an examination of the effects of unilateral electrical stimulation o f the caudate nucleus on side preference, as an attempt to further strengthen the argument that rotation and side preference are both subserved by the nigrostriatal system and reflect, in different magnitudes, the intrinsic asymmetry of the system. Seven rats (female Sprague-Dawley albinos weighing 250 g) were trained to bar-press for water reinforcement on a continuous reinforcement schedule. Testing was conducted in a Lehigh Valley operant test cage with 2 levers (left and right of
336 center reward spout) and responses on either lever were reinforced 5. Rats were trained for 4 weeks in daily half-hour sessions followed by 15 rain of free water in the home cage. All rats showed consistent side preferences. The rats were then bilaterally implanted under methohexital anesthesia with bipolar electrodes in the caudate nucleus; coordinates were 2.0 mm anterior to bregma, 3.0 mm lateral on either side of the midline, and 5.5 mm below the base of the skull with the skull inclined 5 mm (ref. 13). After a one week recovery period, the implanted rats were tested for rotation with unilateral electrical stimulation o f either electrode. The stimulus was a pulse train of 2 sec duration; pulses were monopolar, 5 msec wide, 100 Hz, and pulse amplitude was varied from 10 to 300 #A, at constant current, delivered from a Grass $48 stimulator. Threshold for rotation was defined as that current which elicited a 180° turn of the head and body. As expected 17, unilateral stimulation elicited contralateral rotation for the duration of the stimulation. The rats were then water deprived for 2 days, and retested for 2 weeks in the test cage. There were no significant changes in performance (response rate) or side preference as a result of the electrode implantation. The effect of unilateral stimulation of the caudate nucleus on side preference was observed via a closed circuit video monitor while the subject was bar-pressing, and responses on left and right levers were recorded on an event recorder and on digital counters. Unilateral stimulation was delivered through a connecting cable from a constant voltage sine wave stimulator (0.7 sec pulses, 2 sec apart) at currents 10 ~ below rotation threshold, determined again with the new stimulation parameters. No disruptive motor behavior was observed during stimulation testing. The stimulation test was conducted as follows: the subject was allowed to emit 150 responses with no stimulation, 150 responses during stimulation, and 150 responses with no stimulation. Each subject received this stimulation test for at least 3 sessions. Lastly, contralateral rotation was observed at the same threshold currents, as determined earlier, when the bar-pressing experiment was concluded. The sites of implantation were then verified histologically for each subject. TABLE I EFFECT OF IPSILATERAL CAUDATE STIMULATION ON SIDE PREFERENCES
Subject (preference)
1 (left) 2 (right) 3 (right) 4 (left) 5 (right) 6 (left) 7 (right) Combined means
Mean % responses on preferred bar Training
Pre-stimulation
Stimulation
Post-stimulation
75 67 95 99 98 99 91 89
73 62 71 92 100 100 60 80
26 16 10 18 56 86 03 31 *
68 83 21 100 90 100 55 74
* Significantly different from pre-stimulation and post-stimulation at P < 0.001, t-test.
337
S
Fig. 1. Representative event recording showing the effect of unilateral caudate stimulation on barpressing; stimulation was administered to the caudate ipsilateral to the initial (pre-stimulation) side preference, t, time with 15 see between markers; L, left lever; S, stimulation; R, right lever. The results of the experiment are shown in Table I. Stimulation o f the caudate nucleus on the same side as the side preference caused a reversal of side preference to the opposite lever, as illustrated in Fig. 1. Stimulation of the caudate nucieus on the side opposite to the preferred lever had no effect on side preference. Thus, an electrically-induced increase in activity in one half o f the nigrostriatal system results in a preference for the opposite side. The results of this experiment suggest that an intrinsic asymmetry of the nigrostriatal system, expressed in rotation and in a T-maze side preference, may also be responsible for a spontaneous side preference in a 2 lever Skinner box, as proposed earlierS, 8. Two studies, by Hansing et al. 8 and Levine et al. 1°, in which unilateral lesions of the caudate nucleus or the globus pallidus selectively blocked lever pressing with the forepaw contralateral to the lesion, support this view. In addition, Ungerstedt 16 has reported unilateral sensory neglect in several modalities on the contralateral side after unilateral destruction of the nigrostriatal system by 6-hydroxydopamine. Contralateral sensory neglect is also seen after unilateral lateral hypothalamic lesionsll,lz, 14 which might include damage to the nigrostriatal system, and after ablation of the ansa lenticularis, an efferent projection of the caudate nucleus via the globus pallidus 11. Perhaps the reversal of side preference after unilateral stimulation of the caudate nucleus in the present experiment can be seen as sensory 'overattention' to the opposite side. With increased attentiveness to stimuli present on the contralateral side, the animal presses the lever on that side more frequently. A side preference exhibited spontaneously may be the result of a normal imbalance between the left and right nigrostriatal systems, with the greater activity in one system producing greater attention to the opposite side. This research was supported by N I M H Grant MH25644 and N I M H Research Scientist Development Award (Type 2) DA70082 to S. D. Glick. We thank Alison Crane for technical assistance.
1 ANDt~N,N. E., DAHLSTRGM,A., FuxE, K., ANDLARSSON,K., Functional role of the nigroneostriatal dopamine neurons, Aeta pharmacol. (Kbh.), 24 (1966) 263-274. 2 ARaUTHNOTT,G. W., AND CROW,T. J., Relation of contraversive turning to unilateral release of dopamine from the nigrostriatal pathway in rats, Exp. Neurol., 30 (1971) 484-491. 3 ARBUTHNOTT, G. W., AND UNGERSTEDT,U., Locomotor behavior after electrical stimulation of dopamine containing neurones, Acta physiol, scand., Suppl. 330 (1969) 117. 4 CHRISTIE, J. E., AND CROW, T. J., Turning behavior as an index of the action of amphetamines and ephedrines on central dopamine-containing neurones, Brit. J. PharmacoL, 43 (1971) 658-667.
338 5 GLICK, S.D., Enhancement of spatial preferences by (-]-)-amphetamine, Neuropharmacology, 12 (1973) 43-47. 6 GLICK,S. D., AND JERUSSl, T. P,, Spatial and paw preferences in rats: their relationship to ratedependent effects of D-amphetamine, J. Pharmacol. exp. Ther., 188 (1974) 714-725. 7 GLlCK, S. D., JERUSSI, T. P., WATERS,D. H., AND GREEN,J. P., Amphetamine-induced changes in striatal dopamine and acetylcholine levels and relationship to rotation (circling behavior) in rats, Biochem. Pharmacol., 23 (1974) 3223-3225. 8 HANSING,R. A., SCHWARTZBAUM,J. S., AND TrtOMVSON,J. B., Operant behavior following unilateral and bilateral caudate lesions in the rat, J. comp. physiol. Psychol., 66 (1968) 378-388. 9 JERUSSX,T. P., AND GLICK, S. D., Amphetamine-induced rotation in rats without lesions, Neuropharmacology, 13 (1974) 283-286. 10 LEVINE, M. S., FERGUSON,N., KREINICK,C.J., GUSTAFSON,J. W., AND SCHWARTZBAUM,J. S., Sensorimotor dysfunctions and aphagia and adipsia following pallidal lesions in rats, J. comp. physiol. Psychol., 77 (1971) 282-293. 11 MARSHALL,J. F., AND TEITELnAUM,P., Further analysis of sensory inattention following lateral hypothalamic damage in rats, J. comp. physiol. Psychol., 86 (1974) 375-395. 12 MARSHALL,J. F., TURNER,B. H., ANDTEITELBAUM,P., Sensory neglect produced by lateral hypothalamic damage, Science, 174 (1971) 523-525. 13 PELEGRINO,L.J., AND CUSHMAN,A.J., Stereotaxic Atlas of the Rat Brain, Appleton-CenturyCrofts, New York, 1967. 14 TURNER, B. H., Sensorimotor syndrome produced by lesions of the amygdala and lateral hypothalamus, J. comp. physiol. Psychol., 82 (1973) 37-47. 15 UNGERSTEDT,U., Striatal dopamine release after amphetamine or nerve degeneration revealed by rotational behavior, Acta physiol, scand., Suppl. 367 (1971) 49-68. 16 UNGERSTEDT,U., Brain dopamine neurons and behavior. In F. O. SCHMITTAND F. G. WORDEN (Eds.), The Neurosciences,Third Study Program, MIT Press, Cambridge, Mass., 1974, pp. 695-703. 17 ZIMMERBER6,B., AND GLICK, S. D., Rotation and stereotypy during electrical stimulation of the caudate nucleus, Res. Commun. chem. Path. Pharmacol., 8 (1974) 195-196. 18 ZIMMERBERG,B., GLICK,S. D., ANDJERUSSI,T. P., Neurochemical correlate of a spatial preference in rats, Science, 185 (1974) 623-625.