Journal of Comparative and Physiological Psychology 1975, Vol. 88, No. 1, 128-H6

ELECTROPHYSIOLOGICAL AND BEHAVIORAL REACTIVITY TO PHOTIC STIMULI FOLLOWING SEPTAL LESIONS AND PHARMACOLOGICAL TREATMENTS IN RATS1 J. S. SCHWARTZBAUM2 AND CAROL J. KREINICK University of Rochester Analysis of behavioral reactivity and cortical visual evoked response (VER) to photic stimulation revealed 2 patterns of lesion-induced changes. One pattern of VERs reflected a /ij/poarousal electrophysiological condition. This pattern, present initially under all conditions, could be simulated with administration of scopolamine. A second pattern of VERs developed gradually and appeared to reflect a %peraroused electrophysiological condition. This pattern could be simulated with ti-amphetamine. While both lesion-induced electrophysiological patterns were associated with augmented behavioral reactivity to flashes, the hyperarousal pattern related to more intense conditions of stimulation and more sustained behavioral reactivity, Scopolamine, as opposed to d-amphetamine, reproduced the heightened behavioral reactivity to the flashes. These results were interpreted in terms of a "hypoarousal hypothesis" of sensory hyperreactivity.

In earlier work dealing with the electrophysiological correlates of heightened behavioral reactivity to photic stimuli induced by septal lesions, a pattern emerged which suggested that the heightened behavioral response might relate to disruption of an ascending cholinergic arousal system (Schwartzbaum, DiLorenzo, Mello, & Kreinick, 1972; Schwartzbaum, Kreinick, & Levine, 1972). Analysis of averaged visual evoked responses (VERs) recorded at the visual cortex in the freely moving preparation revealed lesion-induced changes suggestive of such electrophysiological hypoarousal. Subsequent studies with scopolamine, an anticholinergic blocking agent, demonstrated significant similarities in behavioral and electrophysiological patterns to those produced by the lesion (Mello & Schwartzbaum, 1973; Schwartzbaum, Ide-Johanson, & Belgrade, 1974). These patterns stood in sharp contrast to those produced by stimulants such as amphetamine (Schwartzbaum et al., 1974). While the above findings with noncontingent photic stimulation pointed to hypoarousal electrophysiological reactions by septal preparations, an entirely different pattern emerged during appetitive behavior 1

(Schwartzbaum & Kreinick, 1974). Analysis of VERs to flashes utilized as probe stimuli during different phases of appetitive behavior and withholding of reinforcement revealed evidence of hyperaroused conditions in septal preparations. In effect, the lesion appeared to produce either hypoarousal or hyperarousal electrophysiological patterns depending upon behavioral conditions. However, the essential properties of these different behavioral conditions could not be clearly specified. Moreover, some unaccountable variation in VER patterns was also found in the original tests on behavioral reactivity to photic stimuli (Schwartzbaum, Kreinick, & Levine, 1972). In the present study, we sought to reexamine lesion-induced changes in reactivity to photic stimuli in an effort (a) to define more clearly the variation in behavioral and electrophysiological patterns of response, (6) to identify pharmacological properties of these varied patterns by utilizing drugs under the same test conditions. The results reveal 2 distinct lesion-induced electrophysiologioal patterns of reactivity and they suggest behavioral and pharmacological correlates of each of the patterns. EXPERIMENT 1

This study was supported by Grant MH-14594 from the National Institute of Mental Health. Method 2 Requests for reprints should be sent to J. S. Subjects. Eighteen male albino rats (Holtzman) Schwartzbaum, Department of Psychology, Uniserved as subjects. They weighed 250-300 gm. s> versity of Rochester, Rochester, New York 14627. 128

REACTIVITY MECHANISMS FOLLOWING SEPTAL LESIONS the time of surgery and were randomly assigned for surgical treatment (septal n — 9, control n — 9). All animals were housed in individual cages in a room with continuous overhead illumination of low intensity. Food and water were available ad Jib. Surgery and histology. Details of surgical procedures are contained in an earlier report (Schwartzbaum, Kreinick, & Levine, 1972). Stainless steel screw electrodes (0-80, Vs in.) were implanted epidurally over the visual cortex (2 mm. lateral to lambda) and ipsilateral frontal cortex (4 mm. anterior to bregma, 3 mm. lateral to midline) for monopolar recordings of VERs. A similar screw electrode over the contralateral frontal cortex served to ground the animal. Electrolytic lesions of the septal area were made stereotactically by passing 2 ma. anodal dc for 20 sec. through a No. 0 stainless steel insect pin insulated with Epoxylite except for .5 mm. at the tip. Coordinates for the bilateral lesions are given elsewhere (Schwartzbaum, Kreinick & Levine, 1972). Since the earlier work had revealed no effects of electrode tracks through the overlying cortex, this control procedure was omitted here; other work with amygdaloid lesions (Schaefer, Kreinick, & Schwartzbaum, 1974) furnishes additional "controls" to assess specificity of effects. Recording leads (.008-in. insulated stainless steel wire soldered to the screws) were crimped to connecting pins that were inserted into an Amphenol strip plug. The entire assembly was secured to the skull by additional screws and acrylic cement. The end holes of the strip plug were tapped so that the recording cable could be firmly attached to the animal with bolts during all behavioral tests. Following completion of the tests, animals were killed and standard histological procedures were utilized to verify placement of the lesions (Schwartzbaum, Kreinick, & Levine, 1972). Alternate series of sections were stained with cresyl violet and oil red 0. The histological findings conformed closely to earlier observations (Schwartzbaum, Kreinick, & Levine, 1972) and require no additional description. Apparatus. All tests were carried out in a Lucite activity chamber described in earlier studies (Schwartzbaum, DiLorenzo, Mello, & Kreinick, 1972). Mirrors surrounded the chamber on 3 sides and beneath the wire-mesh floor. The flashlamp of a Grass PS-2 photic stimulator was centered against the remaining wall. Behavioral activity was measured by 2 intersecting infrared photocell beams that were directed diagonally across the chamber. A count was registered for each interruption of alternate beams. Precautions were taken to preclude spurious counts resulting from flash stimuli. The test chamber was housed in a Lehigh Valley Model 1317 enclosure provided with dim background illumination (S.62 ftL. at the source) and moderately intense white noise (87 db. re .0002 dynes/cm2) to mask clicks associated with the flashes. Programming of events and recording of behavioral activity were controlled by BRS logic modules and Tektronix waveform and pulse generators. Electrophysiological recordings utilized a Micro-

129

dot cable assembly attached to a 9-channel Lehigh Valley swivel. The signals were fed into Grass 7P511 amplifiers (.5-amp. filters set at 1 and IK Hz) and were monitored on an oscilloscope or by polygraph write-out. A Fabri-tek 1051 signal averager and Hewlett-Packard X-Y plotter provided data on averaged VERs. Procedure. Following 1 wk. of recovery from surgery, on the last 2 days of which the animals were handled briefly, each animal received 5 daily test sessions in the activity chamber. Each session consisted of a 3-min. adaptation period followed by 8 series of flashes at a I/sec frequency and intensity setting of 4 on the photic stimulator. Each series lasted 68 sec. and was preceded by a 68-sec. baseline period without stimulation. Behavioral activity was recorded during each of these periods. A 30-sec. interval separated the end of one flash series from the start of the next baseline period (or approximately 100-sec. intervals between flash series). The first 64 flashes of each series were used to determine averaged VERs in Session 1. In Sessions 2-5, averaged VERs were based on successive pairs of flash series (128 sweeps). Background electrocortical activity was continuously monitored to check for evidence of sleep patterns. In all cases, septal lesions eliminated hippocampal theta rhythms normally recorded with spaced cortical electrodes through volume conduction. It should be noted that relative to earlier work (Schwartzbaum, DiLorenzo, Mello, & Kreinick, 1972), the present test conditions utilized a shorter adaptation period prior to the start of the flash series and a substantially shorter interval between flash series. These differences altered the pattern of reactivity to the stimuli. The analysis of averaged VERs followed earlier test procedures (Schwartzbaum, Kreinick & Levine, 1972) with the exception that baseline level was now always set at the foot of the early negative component even when it was preceded by a small positive deflection; in the earlier work, the midpoint of any such positive deflection was used. This difference in measurement is minor.

Results As shown in the upper panel of Figure 1, septal lesions produced sustained and marked increase in behavioral reactivity to the flashes. An analysis of variance of these these data based on groups, sessions, series (within sessions), and baseline flash conditions revealed significant overall group differences in activity across conditions (F = 31.81, df = 1/16, p < .001) as well as significant interaction between groups and baseline flash conditions (F = 43.22, df = 1/16, p < .001). The latter interaction reflected the differentially enhanced activity of septal preparations during photic stimu-

130

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SESSION FIGURE 1. Mean activity counts for successive pairs of flash series and corresponding baseline periods within each session under various test contitions.

lation as opposed to baseline conditions. Other changes in activity across series and sessions were also reliable but are of lesser importance. Thus, septal preparations (and controls) did show orderly decrements in activity with repeated series within each session (series: F = 65.37, df = 3/48, p < .001), but these were not substantial nor progressive with repeated sessions. The test conditions, in effect, resulted in a lesioninduced heightened reactivity to the flashes

that persisted virtually unabated throughout the tests. The results on VERs are summarized in Figure 2 and illustrated by the examples shown in Figure 3, which also identify the various components that were analyzed. Two basic features of the findings are to be noted. First, in line with earlier observations (Schwartzbaum, DiLorenzo, Mello, & Kreinick, 1972), the lesions increased the amplitude of the early positive (EP) component

REACTIVITY MECHANISMS FOLLOWING SEPTAL LESIONS

DIM BKGND.

131

I/SEC.

12

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2 3 SESSION

FIGURE 2. Mean amplitude of each component of averaged visual evoked responses (VERs) for each flash series in Session 1 and for pairs of flash series in succeeding sessions. (Note negative components are scaled upward and positive components downward to conform to write-out of VERs. EN = early negative; EP = early positive; LN = late negative; LP = late positive.)

of the VER, but, in contrast to the earlier data, the effect did not persist across sessions. Analysis of EP revealed a significant Group x Session intraction (F = 3.90, df = 4/64, p < .01); all analyses were based on pairs of series within each session including Session 1. Other general decrements in EP within and across sessions were also reliable and conformed to earlier findings (Fs = 21.28 and 25.60, respectively; d/s = 3/48 and 4/64; p < .001). Second, the septal lesions produced an unusual within-session decremental pattern in the amplitude of the late negative (LN) wave following elaboration of this component in Session 1. This effect, which contrasts sharply with the lesion-induced enhancement in LN described in earlier work (Schwartzbaum, DiLorenzo, Mello, & Kreinick, 1972), was reflected in a significant Groups X Series interaction (F — 7.12, df — 3/48, p < .001); the Group X Session interaction approached significance (F = 2.34, df = 4/64, p < .10). Further, it can be seen that the decrements in LN, which averaged about 20% of the initial values in the ses-

sion, were not associated with corresponding changes in the early negative (EN) component of the VER. The development of the decremental pattern appeared to correlate with the loss of augmentation in EP. The sample VERs in Figure 3 for the septal preparation are illustrative of this decremental pattern in LN. Other general changes in LN within and across sessions adhered to earlier findings (Schwartzbaum, DiLorenzo, Mello, & Kreinick, 1972). The VER data also revealed group differences in the late positive (LP) component (Group X Session: F = 4.50, df - 4/64, p < .01) that reflected the more limited development of this component by septal preparations during later test sessions. EXPERIMENT 2 This experiment sought to replicate the pattern of lesion-induced changes in VERs observed in earlier work (Schwartzbaum, DiLorenzo, Mello, & Kreinick, 1972). Since the test conditions of Experiment 1 appeared to generate distinctly higher levels of reactivity to flashes by septal preparations

132

J. S. SCHWARTZBAUM AND C. J. KREINICK DIM BKGND

I/SEC.

SESSION 5 CONTROL

SEPTAL

No. 468

NO. 472

5-6

, A

7-8

L FIGURE 3. Examples of averaged visual evoked responses (VERs) for succesive pairs of flash series in Session 5 to illustrate deoremental pattern of late negative in septal preparations. (Components of the VER that were analyzed are labeled in lower left record; arrow denotes occurrence of flash. Calibration: 50 /*v. and 100 msec. EN = early negative; EP = early positive; LN = late negative; LP = late positive.

and not simply to prolong their reactivity to flashes as in the earlier work, attention was focused on variables that might influence behavioral reactivity. We assumed that conditions of relatively intense "behavioral arousal" as seemed to exist in Experiment 1 might generate one type of VER pattern in septal preparations, while less intense behavioral arousal (expressed primarily by dysfunctions in habituation of response to the stimuli) might be associated with a second type of VER pattern in these braindamaged preparations as seen in the earlier work. In the present experiment, the basic test conditions were retained but the frequency of flashes was reduced to 1 per 2 sec. Method Sixteen Holtzman rats (septal n = 8, control n — 8) were prepared surgically as in Experiment 1. The animals were of equivalent body weights to the earlier groups and were maintained and treated in the same way. Test conditions were altered in two respects. First, the frequency of flashes was reduced to 1 per 2 sec. so that averaged VERs for paks of flash series were now based on 64 sweeps

(32 per series). Second, each test session was extended to include 10 flash series instead of the 8 series formerly administered. This was done to describe more adequately intrasession patterns of change. Following completion of the tests and histological analyses, VER data from one control animal (No. 490) were discarded. This animal showed odd behavioral and electrophysiological patterns (no evidence of theta rhythms) and was found to have extensive bilateral degeneration of the dorsal and ventral hippocampus, particularly the pyramidal fields that were poorly developed and extensively gliosed.

Results •The behavioral data, shown in the middle panel of Figure 1, again revealed augmented behavioral reactivity to flashes by animals with septal lesions, but these preparations now exhibited more distinct habituation of reactivity within each session. Analysis of the data confirmed a significant Group X Baseline Flash interaction (F = 27.72, dj = 1/14, p < .001), which reflected the selectively enhanced activity of the septal group under flash conditions (averaging across sessions and series); data from Rat 490 were included to facilitate statistical analyses with equal ns. Nevertheless, both groups showed decreases in reactivity to flashes within each session (Series: F — 131.52, dj = 4/56, p < .001), and, indeed, the decreases were in some sense more pronounced for the septal group because of the higher initial values (Group X Series: F — 2.70, dj = 4/56, p < .05). The enhanced reactivity of the septal group, thus, was expressed primarily by the sustained reaction to flashes at the outset of each session, i.e., by reduced habituation of response across sessions. The VER data, summarized in Figure 4, revealed a different pattern of lesion effects from that seen in Experiment 1, a pattern that more closely conformed to the one described in earlier work (Schwartzbaum, DiLorenzo, Mello, & Kreinick, 1972). These data were analyzed session by session to identify more clearly the nature of group differences. Septal lesions again produced an increase in EP that did not persist during later sessions although the trend continued. Group differences were reliable in Sessions 1 and 2 (Fs = 4.73 and 6.06; dj = 1/13;

REACTIVITY MECHANISMS FOLLOWING SEPTAL LESIONS

133

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p < .05), and approached significance in Session 3 (F = 4.01, df = 1/13, p = .06). Of particular interest, the lesions now tended to augment LN. Group differences in elaboration of LN were significant in Session 1 (F = 13.93, df = 1/13, p < .01) and interacted significantly with series in Sessions 3 and 4 (Fa = 4.10 and 2.56; df - 4/52; p < .05); the latter reflected heightened LN in septal preparations at the outset of these sessions. An opposing pattern of group differences from that of Experiment 1 also emerged with respect to LP. This component became progressively larger in septal preparations during later test sessions. The differences between groups approached significance in Sessions 3 and 4 (Fs = 4.04 and 4.21; df = 1/13; p < .10) and were reliable in Session 5 (F = 8.01, df = 1/13, p < .05). Thus, in contrast to the results of Experiment 1, test conditions of this experiment tended to generate larger LP and LN components of the VER in animals with septal lesions. Group differences in EN were not reliable, but nevertheless the trend conformed to earlier findings (Schwartzbaum, DiLorenzo, Mello, & Kreinick, 1972).

EXPERIMENT 3 We next attempted to extend the findings of Experiment 1 by increasing the behavioral arousal produced by I/sec flashes through elimination of background illumination. This was based on earlier observations (Schwartzbaum, Kreinick, & Levine, 1972). It was also hoped that these conditions might add to the information on normal patterns of VERs associated with varying degrees of behavioral arousal to provide a context for assessing lesion-induced changes. Analyses are included of comparative results obtained in this and the earlier experiments. Method Sixteen additional Holtzman rats (septal n = 8, control n = 8) were prepared surgically as in the earlier experiments. All maintenance and test conditions (10 flash series per session) were unchanged except that flashes were presented at I/sec frequency against a dark background.

Results As seen in the lower panel of Figure 1, septal lesions affected behavioral activity in

134

J. S. SCHWARTZBAUM AND C. J. KREINICK

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the same way as in Experiment 1 (upper panel). The lesions produced sustained increases in reactivity to the flashes with minimal intrasession decrements. Overall group differences were reliable (F = 14.49, df = 1/14, p < .01) as was the Group X Baseline Flash interaction (F = 15.57, df = 1/14, p < .01). Both groups did display some decrements in reactivity within sessions (F = 46.46, df = 4/56, p < .001). The VER data (Figure 5) also showed the same patterns seen in Experiment 1 with respect to LN, i.e., lesion-induced decrements in LN with repeated flash series within the later test sessions. This effect was reflected in Group X Series (F = 14.94, df = 4/56, p < .001), Group x Session (F = 3.31, df = 4/56, p < .05), and Group X Session X Series interactions (F = 2.63, df = 16/224, p < .01). In percentages, the decrements exceeded those of Experiment 1 because the initial values for the septal preparations also tended to be smaller. Control animals, by contrast, showed no appreciable evidence of such decremental patterns. A lesion-induced augmentation of EP was again evident as a function of both session and series (F = 2.07, df — 16/224,

p = .01). The analysis also indicated that the initially enhanced EN of septal preparations was significant (Group X Sessions: F = 2.59, df = 4/56, p < .05). Comparisons Across Test Conditions In order to compare VERs and activity patterns under the 3 test conditions, analyses were made on averaged values for Sessions 4 and 5 when the patterns stabilized. These data are presented in Table 1. Values are only shown for the first 4 pairs of series because the fifth pair was omitted in Experiment 1. Analysis of baseline activity failed to reveal reliable differences across conditions or groups. Such effects were obtained with respect to flashes. The overall Group X Condition interaction approached significance (F = 3.16, df = 2/42, p < .10), and there was evidence of a triple-order interaction between groups, condition, and series (F = 2.24, df = 6/126, p < .05). In effect, septal preparations showed more enhanced reactivity to flashes in Experiments 1 and 3 and more evidence of within-session decrements in reactivity to flashes in Experiment 2. These differences in activity patterns be-

REACTIVITY MECHANISMS FOLLOWING SEPTAL LESIONS

135

TABLE 1 MEAN VALUES FOE ACTIVITY AND VISUAL EVOKED RESPONSES FOR SUCCESSIVE PAIBS OF SERIES AVERAGED ACKOSS SESSIONS 4 AND 5

Measure

Activity

Early negative

Series

Late negative

a

Experiment 3: I/sec dark

Septal

Control

Septal

Control

Septal

6-10" 2-6 2-8

8-13 4-6

10-22

1-5

2-7

3-17 2-11 2-12

10-14 4-10

4

10-28 4-28 4-26 2-21

7-22

2 3 1 2

62.1 64.0 62.9 63.8

57.0 56.8 57.0 57.6

58.6 61.4 59.4 56.7

39.1 36.7 38.0 37.5

43.8 38.3 38.3 38.3

2 3 4

36.2 39.7 38.2 38.4

1 2 3 4

47.7 49.8 45.2 45.9

1

1 2 3 4

Late positive

Experiment 2: 1/2-sec dim

Control

3 4

Early positive

Experiment 1: I/sec dim

1

3-10 2-7

6-22 4-20 2-20

63.6 63.5 61.5 60.3

58.0 60.1 59.9 59.3

58.3 61.1 58.4 57.7

32.6 26.0 28.4 25.9

40.9 35.9 35.1 32.5

33.6 33.4 31.8 34.8

39.7 35.2 36.2 35.9

32.3 32.7 31.2 30.9

36.2 36.3 37.7 34.9

44.5 48.6 51.7 47.6

30.5 31.6 29.6 29.1

34.1 31.7 31.9 29.4

45.0 42.6 41.6 35.7

47.1 57.7 55.2 54.7

56.0 57.1 55.3 52.6

29.6 30.5 30.7 30.1

33.6 30.1 22.7 21.3

3-6

First value refers to baseline activity and second value to flash-related activity.

tween the experimental conditions are understated because of the gating operations of the recording equipment required to prevent spurious counts from flash activation of the photocells. Activity counts were gated out for 100 msec, about each flash. This represented 10% of the total period with I/sec flashes and only 5% of the total period with 1 per 2-sec. flashes. Analyses of VERs revealed no significant variation with respect to conditions and groups in the EN and EP components during Sessions 4 and 5, although there were suggestive group and Group X Series effects in EP (F = 3.30, df - 1/42; F = 2.61, df = 3/126, respectively), reflecting the somewhat higher values for septal preparations. In general, the stabilized values of these components (as opposed to earlier values of EP) appeared relatively insensitive to the various treatments. The LN component, on the other hand, showed highly reliable differ-

ences for both groups across test conditions (F = 29.71, df = 2/42, p < .001), which reflected the reduced values with dark background (Experiment 3). Group differences in serial patterning of LN, i.e., decremental trends (Group X Series: F — 9.75, df = 3/126, p < .001) did not reliably interact with test conditions, since there was also some indication of this pattern in Experiment 2. The LP component also varied reliably for both groups across test conditions (F = 5.75, df = 2/42, p < .01) and showed a Group X Condition interaction (F = 4.99, df = 2/42, p < .05). On an overall basis, this component was smallest with dark background. Septal lesions increased its amplitude over control values under the least behaviorally arousing condition (Experiment 2) and reduced its amplitude below control values or resulted in nondifferentiated group values under the more behav-

136

J. S. SCHWARTZBAUM AND C. J. KREINICK

iorally arousing conditions. The changes in late components (LP and LN) for control animals across test conditions, although not associated with reliable variation in their behavioral reactivity to flashes, agreed in directionality with the behavioral and electrophysiological pattern of results for septal preparations.

ment 2. The question, therefore, arose as to what extent alterations in cholinergic activity might account for the divergent lesion-induced changes seen in Experiments 1 and 3. Other observations with amphetamine (Schwartzbaum et al., 1974) suggested closer links between these patterns of changes and dysfunction in catecholamine systems. Accordingly, an effort was made to EXPERIMENT 4A characterize pharmacologically the patterns of changes seen in the 2 experiments by In earlier work (Mello & Schwartzbaum, utilizing conditions of Experiment 1 with 1973; Schwartzbaum et al., 1974) the different groups of animals that received anticholinergic agent, scopolamine, was varying dosages of either scopolamine or shown to reproduce essential features of the amphetamine. lesion-induced electrophysiological and behavioral patterns observed in other studies Method (Schwartzbaum, DiLorenzo, Mello, & KreiThirty-six previously untested Holtzman rats nick, 1972) and replicated here in Experi- were used that weighed 250-300 gm. They were preSCOPOLAMINE FLASHES

35

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\'VVVV° I SESSION FIGUBE 6. Mean activity counts for successive pairs of flash series (upper panel) and corresponding baseline periods (lower panel) within each session as a function of drug treatment. (Dosages are indicated in the Method section.)

REACTIVITY MECHANISMS FOLLOWING SEPTAL LESIONS pared surgically in the same way as controls in earlier experiments, and they were maintained and tested (with one exception) in exactly the same way as animals of Experiment 1, i.e., I/sec flashes with dim background illumination. Ten series of flashes instead of 8 were administered in each session. All animals were randomly assigned for drug treatment and each received the same treatment throughout the tests. The drugs were administered intraperitoneally 25 min. before the start of each test. The control group (n = 7) received isotonic saline (1.0 ml/kg) of equivalent volume to the drugs. Three experimental groups received injections of scopolamine hydrobromide: "low" dose .5 mg/kg (n = 5); "mid" dose 1.0 mg/kg (n = 3); and "high" dose 2.0 mg/kg (n = 3). Dilution procedures were employed to maintain equivalent volume (milliliters/kilogram) of injection. In view of earlier findings (Mello & Schwartzbaum, 1973; Sehwartzbaum et al., 1974), no control treatment was included for peripheral actions of the scopolamine. Three other groups received injections of d-amphetamine sulfate of equivalent volume: low dose 1.0 mg/kg (n — 6); mid dose 2.0 mg/kg (n = 6); and high dose 4.0 mg/kg (n — 6).

Results The activity patterns generated by scopolamine are summarized in Figure 6. Each dosage was compared separately with control values under baseline and flash conditions through analysis of variance of the repeated measures; the scatter of values for the drug groups would make the results of a more general analysis difficult to interpret. As seen in the lower panel (Figure 6), all dosages of scopolamine reliably increased baseline activity (^s = 5.05, 64.98, and 22.47 for ascending dosages; d/s = 1/10, 1/8, and 1/8). Nevertheless, reliable decrements occurred within each session (p at least .05) and, in general, the drug-induced increments in baseline activity were not large. Flash-related activity was differentially enhanced by scopolamine. Significant group differences were indicated in each of the drug comparisons with control values (Fs = 19.17, 317.40, and 25.20; djs = 1/10, 1/8, and 1/8). The specific pattern of effects across sessions and series varied with dosage. With the mid and high dosages, Group X Session interactions were indicated (Fs = 5.27 and 10.54; dfs = 4/32 and 4/32), which reflected the apparent elevation and attenuation, respectively, in flash-related activity

137

TABLE 2 MKAN DIFFERENCE BETWEEN FLASH AND BASELINE ACTIVITY AVEHAGKD ACROSS SERIES AND SESSIONS Drug

Saline Scopolamine (mg/kg) .5 1.0 2.0 Amphetamine (mg/kg) 1.0 2.0 4.0

Mean difference 4.6

12.4 11.8

8.2 2.3 .9 -.4

during later test sessions. The repetition of tests appeared to generate more variable and generally heightened activity after the third session. Nevertheless, all dosages generated larger differences between flash and baseline activity, averaging across series and sessions (Table 2), than did the control treatment (only one drug animal overlapped the control distribution). The associated VER data, summarized in Figure 7, revealed, first, an enhancement of EP by scopolamine throughout the tests. This effect, which was relatively ordered with respect to dosage, was reflected in an overall analysis of the data by a significant groups component (F = 5.45, df — 3/14, p < .01). The drug treatment did not interact with other changes in EP across series and sessions. No effects of scopolamine were evident in EN and, with the exception of the initial phase of Session 1, in LP (see Mello & Schwartzbaum, 1973). Of primary interest, scopolamine failed to reduce the amplitude of LN or generate a serial decremental pattern in LN under these test conditions —quite unlike the lesion effects. Indeed, in spite of the enhanced behavioral reactivity to the flashes, the LN component of the VERs for the drug groups could not be differentiated from control values, and there was even some suggestion of enhancement in Session 1 with the high dosage. In effect, scopolamine reproduced major features of the lesion pattern seen in Experiment 2 and earlier work (Mello & Schwartzbaum, 1973;

138

J. S. SCHWARTZBAUM AND C. J. KREINICK

SCOPOLAMINE

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f

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SESSION FIGURE 8. Mean activity counts for successive pairs of flash series (upper panel) and corresponding baseline periods (lower panel) within each session as a function of drug treatment. (Dosages are indicated in the Method section.)

But, interestingly, this dosage appeared to generate a decremental pattern in LN within each of the last 3 sessions, which averaged about 20% per session. Examples of this pattern and that produced by septal lesions are shown together in Figure 10 along with a comparative scopolamine series. These effects of amphetamine on LN were not associated with any reliable changes in EN. The drug tended to attenuate LP as a function of sessions and series (F = 1.39, df = 48/ 336, p < .05). It also altered EP, but primarily by blocking the progressive decrease in this component across sessions seen in control animals. This effect was evident in a Group X Session interaction (F = 3.13, df = 12/84, p < .001). Cross comparison of results obtained with scopolamine and amphetamine, derived by pooling the data for all dosages of a given

drug, confirmed marked differences in the selectivity of their effects upon behavioral activity (Table 2). There was only one overlap among all scopolamine- and amphetamine-treated animals, and values for the latter provided no indication of reactivity to the flashes. Differences in drug-induced changes in EP and LN were also highly reliable. The amplitude of EP with scopolamine treatment was higher (averaging across sessions and series) than with amphetamine (F = 16.88, df ~ 1/27, p < .01). This pattern also held for LN (F = 21.31, df = 1/27, p < .01) for which there was also a significant Scopolamine-Amphetamine X Series interaction (F - 7.81, df - 4/108, p < .01). EXPERIMENT 4B This experiment was designed to check on the decremental pattern in the LN compo-

J. S. SCHWARTZBAUM AND C. J. KREINICK

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AMPHETAMINE

75 100 LoJ 100 O 75 50

25 I < 0 25

0--0 Q....Q • X—X

LOW DOSE MID DOSE HIGH DOSE CONTROL

50 h^^^S,^

SESSION FIGURE 9. Mean amplitude of each component of averaged visual evoked responses for each flash series in Session 1 and for pairs of flash series in succeeding sessions as a function of drug treatment. (Inset summarizes results of Experiment 4s in terms of mean amplitude of late negative during each of the first 4 flash series and average across the last 12 flash series as a function of drug treatment. The interval between administration of d-amphetamine [4.0 nag/kg] and start of the flash series was varied. EN = early negative; EP = early positive; LN = late negative; LP = late positive.) nent of VERs that seemed to occur with the high dosage (4.0 mg/kg) of amphetamine and to determine to what extent it could be attributed to temporal factors in the action of the drug. Method Five Holtzman rats were used that had been implanted for recording of cortical VERs. All had prior experience with the photic-reactivity tests. They were tested daily with varying drug treatment over a 7-day period. The test conditions were identical to those of the preceding experiment except that 16 series of flashes were administered each session. In Sessions 1 and 2, isotonic saline (1.0 ml/kg) was administered ip 25 min. before the start of the session. In Sessions 3, 4, and 6, 4.0 mg/kg ^-amphetamine was administered ip 25 min. before the start of the session. In Session 5, the same

dosage of d-amphetamine was administered 40 min. before the start of the session so that the onset of the tests coincided with the time at which maximal decrements in LN were observed with the 25-min. presession administration of the drug. Finally in Session 7, saline was readministered 25 min. before the start of the session. Saline data from Sessions 2 and 7 were pooled as were the 25-min. presession drug data of Sessions 3, 4, and 6 to yield serial measures for 3 test conditions. Results The results on serial patterning of LN obtained with the 3 test conditions are shown in the inset of Figure 9. Since the drug-induced decrements in LN stablized after the fourth pair of flash series, mean values are shown for the last 4 pairs of series. Analysis of all 8 pairs of series revealed overall differences in

REACTIVITY MECHANISMS FOLLOWING SEPTAL LESIONS SEPTAL

AMPHETAMINE

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SCOPOLAMINE

Na473

FIGURE 10. Examples of averaged visual evoked responses for successive pairs of flash series in Session 5 to illustrate decremental pattern of late negative (LN) produced by septal lesions and administration of amphetamine (4.0 nig/kg). (Included for comparative purposes is a scopolamine series [2.0 mg/kg] for the animal showing the most pronounced intrasession decrements in LN with that drug.)

LN among drug treatments (F = 17.65, df = 2/8, p < .01) and serial declines in this component (F - 2.53, df - 7/28, p < .05). The declines, however, related exclusively to the amphetamine treatments and averaged about 30%. No differences were evident between amphetamine treatments. In effect, these data confirm the observations that high dosages of amphetamine lead to decremental patterns in LN, and they demonstrate that the phenomenon is not due to temporal factors in the action of the drug. Behavioral effects of the amphetamine treatments also paralleled earlier observations with the high dosage, i.e., moderate increments in activity under baseline and flash conditions.

paradoxical in terms of the associated augmentation in behavioral reactivity to the flashes, but it reflects basically a dissociation between electrophysiological and behavioral patterns. This contrast is most evident in the late negative (LN) wave of the VER. Normally, the amplitude of LN bears an inverse relationship to the associated behavioral activity of the animal (Schwartzbaum & Kreinick, 1973). Its amplitude is relatively small during active ambulatory behavior and is relatively large during relaxed stationary behavior, e.g., dozing as evident by cortical slow-wave activity, or when the animal engages in species-specific types of behavior such as lapping fluid. It has been suggested in the context of interrelationships between VERs and hippocampal electroenDISCUSSION cephalographic (EEG) rhythms (Pond & The present data provide evidence of 2 Schwartzbaum, 1972; Schwartzbaum & distinct electrophysiological patterns of re- Kreinick, 1973) that movement patterns activity to photic stimuli following large are intimately related to the operation of septal lesions in rats, and they suggest some electrophysiological arousal mechanisms, of the behavioral and pharmacological fea- which, in turn, exert major influences upon tures of each of these patterns. transmission and cortical elaboration of senOne electrophysiological pattern of reac- sory evoked responses (Steriade, 1970). tivity displayed by septal preparations may These inferences are borne out in more rebe characterized as a hypoarous&l pattern cent observations (J. S. Schwartzbaum, (Experiment 2). This description may seem manuscript in preparation) on multiunit

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activity of the midbrain reticular formation duced changes in EP relates more to the (RF) and dorsal lateral geniculate (LG) pharmacological "tag" that it provides. This hypoarousal electrophysiological nucleus of the freely moving rat. The RF activity, which reflects some facets of pattern after septal lesions has basic choarousal processes, relates closely to move- linergic determinants. Both the augmentament patterns and also to the elaboration of tion in EP and electrophysiological-behavcortical VERs. Low RF activity is a neces- ioral dissociation expressed in LN can be sary condition for a well-articulated LN simulated with anticholinergic agents as wave (and any subsequent afterdischarge scopolamine (see also Mello & Schwartzcomponents). This relationship can, in turn, baum, 1973; Schwartzbaum et al., 1974); be partially understood in terms of phasic peripherally active forms of the drug, e.g., interrelationships observed between RF ac- methyl scopolamine, that do not readily pass tivity and flash-evoked postburst suppres- the blood brain barrier, are ineffective sion of multiunit activity in LG, which (Schwartzbaum et al., 1974). Under some contributes to the development of the corti- conditions, such drugs also facilitate develcal LN wave. In the case of septal lesions, opment of late components of the VER in there is under certain test conditions a more terms of afterdischarge responses (Fleming, rapid elaboration of LN which then either Rhodes, Wilson, & Shearer, 1972). It is, of exceeds or equals control values despite the course, significant that these drugs also reexaggerated accompanying behavior activity produce the augmented behavioral patterns (see also Schwartzbaum, DiLorenzo, Mello, of reactivity to the flashes seen with the le& Kreinick, 1972). For this reason, the elec- sion, a point to which we shall return. The trophysiological pattern is described as hy- hypoarousal pattern of septal preparapoarousal. It would also seem to be associ- tions, thus, represents basically a pattern ated with enlargement of the late positive similar to scopolamine. This is consistent (LP) component as detected in some of the with the well-known action of anticholinerearlier work (Schwartzbaum, Kreinick, & gic agents in blocking major electrocortical Levine, 1972), but the time course of this manifestations of reticular activation proceffect in relation to the changes in LN is not esses (Longo, 1966). However, it is not to suggest that the lesion and drug are identical clearly understood. A second feature of the hypoarousal pat- in their mode of action. They are not. As suggested in earlier work (Schwartztern produced by the lesion, namely, an augmentation in the "early positive" component baum, Kreinick, & Levine, 1972), the lesionof the VER with respect to control values, induced hypoarousal may reflect impairment must be treated more cautiously. Although in the operation of an ascending cholinergic the augmentation in EP has distinctive phar- system of fibers to the neocortex that has macological attributes that are consistent been implicated in electrophysiological with pharmacologically induced hypoarousal arousal functions (Shute & Lewis, 1967). patterns expressed in LN, the EP component However, the precise nature of the involveof normal VERs shows no simple relation- ment of this system is not clear. A ventral ship to behavioral parameters. The ampli- tegmental component of the system, which tude of EP is normally large at the outset of runs in the medial forebrain bundle (MFB), flash series when behavioral and electro- arches around the genu of the corpus callophysiological arousal activity are high, and sum to distribute fibers to medial and dorsal then becomes progressively smaller as be- regions of the cortex, including visual cortex. havioral and arousal reactions habituate to It is possible that the ventral and/or rostral the stimuli. However, EP may decrease even encroachment of septal lesions upon these further if behavioral reactivity to the flashes ascending MFB projections is responsible is reactivated through introduction of ap- for the hypoarousal pattern. In the cat, petitive contingencies (Schwartzbaum & many of the ascending cholinergic fibers to Kreinick, 1973). Because of these com- the cortex appear to originate within the plexities, the significance of the lesion-in septal nuclei (Krnjevic & Silver, 1965,

REACTIVITY MECHANISMS FOLLOWING SBPTAL LESIONS

1966), but we are not aware of comparable data in the rat. The alternate possibility of a septohippocampal substrate for the lesioninduced hypoarousal, though less attractive on behavioral and neurochemical grounds (Green, Beatty, & Schwartzbaum, 1967; Pepeu, 1972), cannot be ruled out. Recent findings (Grantyn, Margnelli, Mancia, & Grantyn, 1973) point to an excitatory influence of hippocampal outflow on units in the brain stem reticular formation. Moreover, the hippocampal modulation of thalamic activity may not simply be antagonistic to that of brain stem arousal mechanisms (see Parmeggiani & Rapisarda, 1969; Redding, 1967). The evidence for a disruption in cholinergically mediated arousal processes is supported by electrophysiological findings in cats of cortical deactivation, notably positive dc shifts and EEG slow-wave activity, immediately after septal lesions (McGeer, Wada, Terao, & Jung, 1969; Parmegiani & Rabini, 1964). More impressive are the neurochemical findings (Nistri, Bartolini, Deffenu, & Pepeu, 1972; Pepeu, 1972) that have demonstrated a substantial depletion of acetylcholine (ACh) in the neocortex of rats and cats following septal lesions (see also Sorenson & Harvey, 1971). Significantly, the same pattern of depletion was not obtained with hippocampal lesions in rats, arguing somewhat against septohippocampal substrates. Nor could the effect be attributed to some antecedent overdriving of the system in view of the rapidity with which the depletion developed postoperatively. These findings complement the present electrophysiological data in pointing to a basic hypoarousal electrocortical condition following septal lesions, ignoring for a moment the behavioral consequences. The present data also provided evidence of a lesion-induced hyperarousal electrophysiological pattern of reactivity to the photic stimulation (Experiments 1 and 3) characterized primarily by an attenuation in late components of the VER, particularly LN. This pattern seemed to depend upon repeated exposure to certain conditions of stimulation, and it appeared to represent a transformation of a hypoarousal pattern of

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reaction. With each flash condition, scopolamine like changes in the VERs of septal preparations were evident in Session 1: EP was augmented relative to control values, and LN could not be distinguished from control values in spite of enhanced behavioral activity. The only indication of an emergent hyperarousal reaction in Session 1 was the absence of a more rapid elaboration of LN. With repeated tests under these flash conditions, the septal preparations began to show a differential attenuation in LN that became progressively more pronounced with repeated flash series within the session as if there were some progressive build-up in electrophysiological reaction to the stimuli. The LP component also tended to shrink below control values (depending upon the level of control values—compare Experiments 1 and 3). Finally, it was shown that pharmacological agents such as d-amphetamine, which stimulate catecholaminergic behavioral arousal mechanisms (Taylor & Snyder, 1971), and, indirectly, cholinergic electrophysiological arousal mechanisms (e.g., Nistri et al., 1972) simulate the attenuation in the LN wave of the VER (see also Schwartzbaum et al., 1974). The drug does not, however, act antagonistically to scopolamine in reducing EP. It may in fact augment EP above control values with repeated administration, possibly reflecting a depletion of ACh with the recurrent arousal (Domino & Olds, 1972). Of particular interest, higher dosages of d-amphetamine reproduced the intrasession decremental pattern in LN seen with the lesion, and again the effect was shown to depend upon repeated exposure to the stimuli. The decremental pattern also seemed to be facilitated by repeated administration of the drug. In effect, septal lesions may induce either hypoarousal or hyperarousal patterns as reflected in cortical VERs. The hyperarousal, which conforms to earlier electrophysiological observations of these brain-damaged animals during appetitive behavior (Schwartzbaum & Kreinick, 1974), would appear to be compatible with deficiencies in ascending cholinergic processes either through residual cholinergic mechanisms and/or through parallel contributions of other widely distribu-

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ted biogenic amine systems that originate within the brain stem (Phillis, 1970). Septal lesions, for example, may block the cortical release of ACh produced by administration of amphetamine but not the electrocortical arousal reactions evoked by the drug (Nistri etal.,1972). Both the lesion-induced hypo- and hyperarousal patterns are associated with augmented behavioral reactivity to the flashes, but they appear to differ in the degree of accompanying behavioral arousal. The hypoarousal pattern would seem to relate to test conditions that are not excessively .arousing behaviorally (Experiment 2). Septal preparations showed marked habituation of behavioral reactivity within sessions under these conditions. The hyperarousal pattern, on the other hand, would seem to develop with conditions inducing high behavioral arousal (Experiments 1 and 3) as evidenced by the more sustained reactivity to the flashes within sessions. In a more general sense, it may be suggested that septal lesions induce an electrophysiological hypoarousal pattern when relatively weak reinforcing stimuli are operative, and a hyperarousal pattern when stronger reinforcing contingencies operate such as food or aversive stimuli. The higher frequency of flashes may fall in the latter category (Schwartzbaum, Kreinick, & Levine, 1972). We recognize that flash parameters and ambient illumination affect sensory evoked response even in the deeply anesthetized preparation (e.g., Peck & Lindsley, 1973), but these processes cannot account for the observed behavioral and pharmacological relationships of VERs. The diametrically opposed electrophysi'ological patterns in septal preparations probably relate to the divergent behavioral alterations produced by the lesion. Thus, under some conditions, septal preparations are hypoactive behaviorally, while under other conditions, they are hyperactive (Fried, 1972). Similarly, one can rationalize on the basis of the scopolaminelike hypoarousal pattern the effectiveness of anticholinergic drugs in simulating various behavioral effects of the lesion (Fried, 1972) and the ability of cholinomimetic agents to coun-

teract some of the behavioral alterations (Stark & Henderson, 1972). The same rationale may be applied in terms of hyperarousal pattern to explain the amphetaminelike behavioral disturbances produced by the lesion and the heightened sensitivity of septal preparations to amphetamine (Carey & Salim, 1970); such increased sensitivity undoubtedly holds for anticholinergic agents. The two divergent electrophysiological patterns of response produced by septal lesions must in some ways reflect upon basic dimensions of the behavioral dysfunctions produced by the lesions (see e.g., Schwartzbaum & Kreinick, 1974). However, the way in which these lesioninduced electrophysiological alterations may relate to the etiology of the behavioral overreactivity to photic stimulation is not entirely clear. The results would suggest some form of cholinergically mediated dysfunction because (a) the most general electrophysiological correlate of the hyperreactivity to flashes was a scopolamine-like hypoarousal and not a hyperarousal pattern, and (b) scopolamine as opposed to damphetamine was able to reproduce the effect of the lesion in differentially augmenting reactivity to the flashes. Cholinergic mechanisms have been implicated in the inhibitory control of behavior, including habituation of behavioral reaction to sensory stimuli (Carlton, 1963, 1969). Key roles in these processes have been assigned to the hippocampus and frontal cortex, primarily in terms of inhibitory feedback influences on diencephalic and brain stem mechanisms underlying behavioral arousal or movement patterns (Carlton, 1969; Lynch, Ballantine, & Campbell, 1969). The septal involvement in hippocampal functions is well-recognized (Fried, 1972), and a corresponding effect of the lesion on frontal functions is not unlikely, e.g., through disruption, of ascending cholinergic fibers to frontal cortex and consequent reduction of suppressive cortical influences acting subcortically. In these terms, the cholinergically mediated hypoarousal reflected in visual processes, i.e., VERs, would simply be symptomatic of dysfunctions in other nonvisual systems presumed to be crucial for the behavioral alterations.

REACTIVITY MECHANISMS FOLLOWING SEPTAL LESIONS

However, consideration should also be given to the consequences of reduced arousal activity impinging on the specific sensory systems. We believe that behavioral hyperreactivity to sensory stimuli may well involve a hypoarousal condition of the corresponding sensory system. This may lead to impaired modulation of sensory input and/ or closely related effector processes linked to the behavioral reaction to the stimuli. Deficiencies in corticofugal control associated with hypoarousal may be especially critical, judging from disinhibitory phenomena observed during slow-wave sleep (Evarts, 1967; Jouvet, 1967). Indeed, a similar argument may be offered for other gross manifestations of septal hyperreactivity (Fried, 1972). Analyses of the neural substrates of the hyperreactivity would not rule out involvement of cholinergic arousal processes (see, e.g., Carey, 1972; Thomas & Van Atta, 1972), and cholinomimetic agents may in fact counteract the hyperreactivity pattern (Stark & Henderson, 1972). Other observations of sensory hyperreactivity with lesions or pharmacological depression of brain-stem reticular mechanisms are also consistent with this view (Capps & Stockwell, 1968; Nakajima, 1964). If the hypoarousal hypothesis of sensory hyperreactivity is valid, then one might raise the additional question whether the electrophysiological hyporarousal pattern displayed by septal preparations served any compensatory functions. Various conceptualizations, particularly in psychiatric contexts (Silverman, 1972), have stressed the role of arousal mechanisms in "gating" more intense sensory input. Whether this modulation is achieved through occlusive processes (Gijsbers & Melzack, 1972) or by other more complex interactions, the hyperarousal and associated behavioral activity might be viewed as an adaptive reaction. It would presumably involve catecholaminergic mechanisms in view of the similar hyperarousal pattern produced by amphetamine. However, at this stage, the more critical issue concerns the hypoarousal and involvement of the specific sensory systems in controlling behavioral reactivity to sensory stimuli.

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