Striatal dopamine and the interface between orienting and ingestive functions

Physiology & Behavior, Vol. 44, pp. 469--471.Copyright©Pergamon Press plc, 1988. Primed in the U.S.A.

0031-9384/88 $3.00 + .00

Striatal Dopamine and the Interface Between Orienting and Ingestive Functions STUART HALL AND TIMOTHY

SCHALLERT 1

Department o f Psychology and Institute for Neurological Science University o f Texas at Austin, Austin, T X 78712

HALL, S. AND T. SCHALLERT. Striatal dopamine and the interface between orienting and ingestivefunctions. PHYSIOL BEHAV 44(4/5) 469--471, 1988.--Recent lesion experiments have implicated forebrain catecholaminergic projections in a unique switching mechanism that enables sensory orientation to occur during ongoing feeding behavior. Unit recording studies indicate that there is a population of neurons in the striatum that respond to tactile stimulation only while an animal is eating. These sensory-related cells may serve as part of a system that diverts attention away from ingestive behavior. In the present study, 6-hydroxydopamine was infused directly into the striatum in rats to eliminate the dopaminergic input specifically to this region. The animals were tested for their reactions to tactile stimulation of the vibrissae during or in the absence of eating. During noneating trials, orienting was rapid and reliable to stimuli presented on either side of the body midline. While eating, contralateral orienting never occurred, even when the stimulation was intense, whereas ipsilateral orienting was unaffected. It was suggested that the capacity to disengage from ingestive behavior may depend importantly on the integrity of dopaminergic input to the striatum. Striatai dopamine

Ingestive behavior

6-Hydroxydopamine

P O S N E R et al. (5) defined three primary operations involved in shifting attention: disengaging from the current focus of attention, moving attention to the location of the target, and engaging the target. They found that patients with severe unilateral parietal lobe injuries have a deficit in the disengage operation when the target is in the contralateral hemifield. Recently we reported what might be an analogous sensorimotor impairment in rats that occurs after unilateral microinjections of 6-hydroxydopamine (6-OHDA; a dopaminedepleting neurotoxin) into the medial forebrain bundle (6). When these rats are engaged in eating behavior they fail to orient to contralateral tactile stimulation o f the perioral region. They instantly disengage from eating in response to ipsilateral stimulation, and when not eating, contralateral orienting is rapid and reliable. Normal animals disengage from eating readily in response to stimulation of either side o f the body. The disengage deficit appears to be qualitatively different from previously described sensorimotor asymmetries, such as the inattention (neglect) syndrome detailed by Marshall et al. (2,3). Moreover, the deficit continues to occur long after recovery, as measured using a battery o f other sensorimotor tests. We hypothesized that the striatum might be a critical component to an inter-

Orienting

face between subsystems of the brain involved in feeding behavior and subsystems involved in orienting to external stimuli (6). Although dopamine was depleted in several cortical and subcortical areas, we focussed on the striatal projections. First, hemidecorticate rats (tested 4 weeks after surgery) do not show the disengage deficit (8). Second, the striatum contains a class of cells that may function in a manner consistent with the disengage operation (1,11). These neurons, termed " c o m p l e x sensory cells," do not respond when the vibrissae contralateral to the recording site receive tactile stimulation, yet respond dramatically when the vibrissae are stimulated while the animal is lapping milk. No response occurs while the animal laps milk in the absence of vibrissae stimulation. It is possible that dopaminergic input to the striatum is necessary to maintain the normal function of these cells, which may serve to redirect attention from ingestive behavior to external stimulation. The present experiment examined further the role of the striatum in the disengage deficit. As noted above, in our original study 6-OHDA was infused into the medial forebrain bundle, which depleted DA in nonstriatal areas (6). To determine whether damage to striatal dopaminergic input alone is capable of yielding the disengage deficit, 6-OHDA was

tRequests for reprints should be addressed to T. Schallert, Department of Psychology, University of Texas at Austin, Austin, TX 78712.

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infused directly into the striatum. METHOD

Animals Six female Long-Evans hooded rats, 4-5 months old and weighing 250-305 grams, were individually housed and maintained on a 12:12 hr light/dark cycle with free access to lab chow and water. The cages were made of metal and consisted of a wire mesh front and 3 solid walls with small holes drilled in them to allow access to the rats regardless of their location in the cage (6). Prior to surgery, all animals were regularly handled and periodically fed chocolate until they would readily eat this food. At no time were the animals deprived of food. Preoperative orientation training was conducted so that the rats responded vigorously whenever they received tactile stimulation to the perioral region.

Surgery All rats were anesthetized with equithesin (0.3 cc/100 g) and given unilateral lesions of the lateral striatum. Lesions were produced by infusing an 8/zg//zl solution of 6-OHDA in a vehicle of artificial cerebrospinal fluid with 0.1% ascorbic acid into 3 areas of the lateral striatum. The infusion volume was 1/~1, which was delivered at the rate of 1/zl/min. In all instances the cannula was left in place for 4 min after the infusion in order to allow for complete diffusion of the toxin. The animals were pretreated with a noradrenergic uptake blocker, desipramine (15 mg/kg), 15 min prior to the 6-OHDA infusion to help protect noradrenergic neurons (10). The coordinates for the 3 placements were: 1) 1.4 mm anterior and 3.2 mm lateral to bregma, and 5.0 below dura; 2) 0.5 mm anterior and 3.2 mm lateral to bregma, and 5.5 mm below dura; and 3) - 0 . 4 mm posterior and 3.7 mm lateral to bregma, and 5.5 mm below dura (the skull surface was horizontal between bregma and lamda landmarks). All rats received cannula penetrations in the hemisphere opposite the lesion to control for cortical damage or other nonspecific effects. This consisted of lowering the cannula through the cortex at the coordinates given above, but stopping short of the corpus ca]losum.

Behavioral Tests Behavioral tests were conducted preoperatively and on postoperative Days 3, 5, 7 and 14. These measures were carded out in the home cage where responsivity is optimal (7). Three animals were tested for an additional 49 days. The rats were tested for their ability to orient to tactile stimulation o f the perioral area. A solid wooden probe (23 cm long, 3 mm in diameter) was used to provide unilateral stimulation to the left and right perioral region at 2-sec intervals until the animal either oriented or 60 sec had elapsed. Timing began with the first contact of the probe to the perioral region and the latency to respond (in sec) was recorded for each animal (6). Behavior was examined during and in the absence of eating behavior. During eating trials, a rectangular piece of chocolate (3.4 g) was placed in the home cage, Approximately 2 sec after the rat actively began to eat, perioral stimulation was applied as described above.

Apomorphine Rotation Test Animals that have unilateral DA depletions of approximately 85% or greater rotate in a contra]ateral direction when

TABLE 1 MEAN LATENCY (IN SEC) TO ORIENT TO CONTRALATERALVS. IPSILATERALPERIORAL STIMULATION Days

0

3

5

7

14

1.1 <1

1.4 <1

1.4 <1

46.4 <1

60 <1

60 <1

6-OHDA: Not Eating Contralateral Ipsilateral

<1 <1

1.7 <1

6-OHDA: Eating Contralateral Ipsilateral

<1 <1

46.1 <1

administered the DA agonist apomorphine (4,14). Unlike the present experiment, these data were obtained from animals that received infusions of 6-OHDA into the nigrostriatal bundle or substantia nigra. It is not known that DA depletion caused by intrastriatal 6-OHDA yields comparable data. Therefore, an apomorphine challenge was used to determine whether a significant level of DA depletion had been achieved. All 6-OHDA-treated animals were administered 0.5 mg/kg apomorphine subcutaneously and placed i n a Plexiglas bowl having a diameter of 50 cm. After a 5-min habituation period, the number and direction of 360 ° rotations made by an animal in three consecutive 5 min periods were recorded. RESULTS

Behavioral Tests Noneating trials. Preoperatively, all animals had orientation latencies of <1 sec to stimulation of either the left or right perioral region. Following unilateral 6-OHDA infusions, the rats occasionally showed slight delays in orienting to contralateral periorai stimulation. These delays, however, were very short (e.g., 2 sec) and not significantly different (p>0.05) from their ipsilateral latencies, which were < 1 sec on all test days (see Table 1). Eating trials. Preoperatively during eating, all rats had orientation latencies of < 1 sec to stimulation of either the left or right perioral region. Postoperatively during eating, contralateral orienting behavior was completely eliminated while ipsilateral orienting occurred in < 1 sec on all test days (see Table 1). A N O V A indicated that the contralateral orienting latencies were significantly different from ipsilatera] orienting latencies, F(I,12)= 154.84, p<0.001. This disengage deficit continued through 7 weeks. Apomorphine Rotation Test All 6-OHDA-treated rats showed exclusive contra]ateral rotation in response to the apomorphine (0.5 mg/kg) drug challenge. In the first 5-rain period these rats made a mean (---SE) of 21.0--- 3.8 complete 360° contralateral rotations and no ipsilateral rotations. During the second and third 5-rain periods they continued to rotate contralaterally, making a mean of 2 4 . 0+- 1.7 and 25.0---7.5 contralateral rotations respectively with no ipsilateral rotations. DISCUSSION Unilateral DA depletion restricted to the striatum was sufficient to yield the disengage deficit. Following unilateral

S T R I A T A L DA A N D D I S E N G A G E D E F I C I T

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microinfusions of 6-OHDA directly into the striatum, rats did not orient to intense tactile stimulation of the vibrissae contralateral to the damaged hemisphere during eating, but readily oriented to ipsilateral stimulation. At no time did the animals neglect contralateral perioral stimulation during noneating trials. This can be contrasted with the behavior of animals that have sustained 6-OHDA infusions of the medial forebrain bundle (3, 4, 6) which show orienting impairment during at Mast the first few postoperative weeks. It may be necessary to deplete other brain regions in addition to the striatum in order to obtain neglect in the absence of eating behavior. On the other hand, perhaps the depletion of dopamine was not severe enough or widespread enough within the striatum. In either case, the disengage test appears to be a highly sensitive and specific marker of striatal dopamine depletion. In recent work, Schneider and Markham (12) found that after DA depletions in cats, produced by peripheral administration of the dopaminergic neurotoxin, MPTP, there was a dramatic reduction in the sensory responsiveness of caudate neurons which was accompanied by somatosensory neglect and movement initiation deficits (akinesia). However,

chronic unit activity following recovery from neglect and akinesia was not examined, nor was the effect of MPTP specifically on " c o m p l e x sensory cells." It would be interesting in future work to determine the effects of 6-OHDA on the activity of the various types of sensory related caudate neurons and their relation to behavior. The failure of striatal dopamine-depleted rats to disengage from eating may seem paradoxical. It is well known that forebrain dopamine depletion severely interferes with eating (3, 9, 13, 15). Instead, we found that relative to control animals, in the presence of sensory input, eating behavior was profoundly resistant to disruption. However, the lesions were unilateral and thus did not yield the aphagia expected from bilateral lesions. Perhaps the disengage deficit would emerge in bilaterally-depleted animals following recovery from aphagia.

ACKNOWLEDGEMENTS Supported by NIH grant NS-23964 to T. Schallert. We thank Kelly Thorstad and Javaid Shad for assistance in data collection.

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9. Schallert, T.; Whishaw, I. Q.; Ramirez, V. D.; Teitelbaum, P. Compulsive, abnormal walking caused by anticholinergics in akinetic, 6-hydroxydopamine-treated rats. Science 199:14611463; 1978. 10. Schallert, T.; Wilcox, R. E. Neurotransmitter-selective brain lesions. In: Boulton, A. A.; Baker, G. B., eds. Neuromethods: Neurochemistry, general techniques. Clifton, NJ: Humana Press; 1985:343--387. 11. Schneider, J. S.; Levine, M. S.; Hull, C. D.; Buchwald, N. A. Development of somatosensory responsiveness in the basal ganglia in awake cats. Neurophysiology 54:143-154; 1985. 12. Schneider, J. S.; Markham, C. H. MPTP-induced dopamine depletions alter sensory processing in the caudate nucleus in the awake cat. Soc. Neurosci. Abstr. 13:1362; 1987. 13. Stricker, E. M. Brain neurochemistry and the control of food intake. In: Satinoff, E.; Teitelbaum, P., eds. Handbook of behavioral neurobiology, vol. 6. New York: Plenum Press; 1983. 14. Ungerstedt, U. Postsynaptic supersensitivity to dopamine agonists following unilateral 6-hydroxydopamine induced degeneration of the nigro-striatal dopamine system. Acta Physiol. Scand. [Suppl.] 367:69-93; 1971. 15. Ungerstedt, U. Adipsia and aphagia after 6-hydroxydopamine induced degeneration of the nigro-striatal dopamine system. Acta Physiol. Scand. 82:95-122; 1971.