131

Epilepsy Res., 11(1992) 131-139 Elsevier EPIRES 00464

Characteristics

of dorsal and ventral striatal kindling in rats

Deborah M. Saucier and Michael E. Corcoran Department of Psychology, Universiq of Victoria, Victoria, BC V8W3P5

(Canada)

(Received 21 August 1991; revision received 7 January 1992; accepted 12 January 1992) Key words: Kindling; Ventral striatum; Dorsal striatum; Nucleus accumbens; Caudate/putamen

We examined the characteristics of kindling of seizures with stimulation of the dorsal or ventral striatum in rats. Different groups of rats carried electrodes directed towards the nucleus accumbens or the head, middle, or tail of the caudate. Thresholds for afterdischarge (AD) were high at all sites, and stimulation often produced forced motor responses (motor responses that occurred during the stimulation and were not a consequence of kindling). Kindling at sites in the accumbens proceeded more slowly than at the sites in the caudate, which did not differ among themselves. The duration of accumbens seizures increased dramatically over the course of kindling, whereas the duration of caudate seizures remained relatively short and invariant. Although the kindled seizures resembled seizures kindled from limbic sites, they also contained aspects of seizures triggered from stimulation of the anterior neocortex. We conclude that striatal kindling comprises elements of both limbic and neocortical kindling.

to dampen seizure susceptibility. Data from other studies suggest, however, that the dorsal striatum may facilitate seizure activity. For example, actiIn the rat, the caudate and the putamen are ofvation of the caudate has been found to potentiate ten referred to as the dorsal striatum, and the seizures induced by convulsant drugs or metal more ventral nucleus accumbens and lateral structures are referred to as the ventral striatum13. Maions27’v*30 and lesions of the caudate reduced the nipulations of the dorsal striatum can have multiseizures produced by these agents*. Perhaps the ple effects on experimentally induced seizures. The most provocative evidence for a proconvulsant results of some studies have indicated that activarole of the dorsal striatum has come from studies in tion of the caudate can suppress seizures7~8~11~15~16~20which seizures were kindled by electrical stimulaand lesions of the caudate can facilitate seizures tion of the caudate’0*22~23~31. provoked by various treatments14.17 or can themAlthough it is generally recognized that two maselves induce seizures24. These results have typijor types of kindling occur in rats, limbic and neocally been taken to suggest that neuronal circuits cortica14*25326*2v, the few studies of kindling with in the neostriatum and related structures may act striatal stimulation have been unclear as to the pattern of kindling that is produced. Furthermore, the results of these studies are inconclusive because the experiments typically examined kindling Correspondence to: M.E. Corcoran, Department of Psy from a limited number of sites in the head of the chology, University of Victoria, P.O. Box 3050, Victoria? BC V8W 3P5, Canada. caudateiO~**.We therefore attempted to provide a INTRODUCTION

0920-1211/92/$05.00 0 1992 Elsevier Science Publishers B.V. All rights reserved

132

more extensive examination of the striatum’s susceptibility to kindling than has previously been reported. In addition to replicating kindling with stimulation at sites in the head of the caudate, we examined kindling at 2 additional sites in the caudate: the tail of the caudate, where kindling has not been studied previously; and the middle caudate. The latter site was chosen because it is an area in which infusions of the convulsants bicuculline and NMDA reportedly produce anticonvulsant effects7.*. We also examined kindling in the nucleus accumbens, because, as far as we are aware, kindling in this part of the ventral striatum has not been described except as an incidental observation in a previous experiment18. METHODS Twenty-six male Long Evans hooded rats (Charles River Canada) weighing 350-450 g were individually housed in stainless steel cages under a constant 12-h light-dark schedule. Food and water were available ad libitum. The rats were anesthetized with sodium pentobarbital (60 mg/kg, i.p.). Bipolar stimulating/recording electrodes made of twisted nichrome wire (127 ,um diameter), insulated except at the cut ends, were implanted bilaterally into homotopic sites in the 2 hemispheres. A surgical screw in the frontal bone served as ground reference for EEG recording. Electrodes were tested for current leak prior to implantation. Seizures were kindled with l-s trains of constantcurrent biphasic square wave pulses, with a pulse duration of 1.0 ms. Ten days after surgery, thresholds for afterdischarge (AD) were determined with an ascending series of intensities”, to a maximum current of 2500 PA. Threshold was arbitrarily defined as the lowest intensity of stimulation that elicited AD, and kindling stimulation was subsequently administered once daily at threshold intensity for the rest of the experiment. Once behavioral seizures occurred, they were classified according to the system described by Racine26. We

found it necessary to modify Racine’s scheme, however, by including an extra category, stage 4+, to characterize generalized seizures that involved a sustained loss of balance rather than rearing and falling (described in detail in the Results). After 3 consecutive stage 5 seizures had been triggered, stimulation was suspended. To assess the persistence of the kindled state, stimulation resumed (rekindling) 1 week after the last stage 5 seizure. Rekindling proceeded until 3 consecutive stage 5 seizures had been triggered. Electrode placements were examined histologically on coronal sections 80 ym thick that were stained with thionine. Rats were assigned to 1 of 4 groups on the basis of the histological examination. Rats with electrodes in the nucleus accumbens were grouped together (accumbens group, n = 7). Rats with electrodes in the caudate-putamen were divided into 3 groups on the basis of the placement of the electrode on the anterior-posterior axis. The head of the caudate group consisted of rats whose electrodes were found to be in the caudate-putamen between 1.2 mm and 0.7 mm anterior to bregma (n = 4). The middle caudate group consisted of rats whose electrodes were found to be between 0.2 mm anterior and 0.3 mm posterior to bregma (n = 6). The tail of the caudate group consisted of rats whose electrodes were found to be between 1.8 mm and 2.3 mm posterior to bregma (n = 9). Data were analyzed with multivariate analysis of variance, followed, when justified, by the Neumann-Keuls test for post-hoc comparisons. For nonparametric data, we used the Kruskal-Wallis l-way ANOVA. RESULTS Electrode placements

The placement of the tips of the electrodes, as determined histologically, is shown in Fig. 1. Electrodes in the accumbens group were clustered in the dorsomedial aspects of the accumbens. Electrodes in the head of the caudate group were scat-

Fig. 1. Reconstruction of the placement of individual electrode tips (0) on sections taken from the atlas of Paxinos and Watso#. (A) Accumbens group (n = 7); (B) head of the caudate group (n = 4); (C) middle caudate group (n = 6); (D) tail of the caudate group (II = 9). Numbers indicate the position anterior or posterior to bregma. CPU, caudate-putamen; Acb, nucleus accumbens.

133

134 TABLE I Means (+ SEM) of measures of seizure development and AD threshold by group AD

Number of ADs

Number of ADs

ADS to

Consecutive

Total

Total number

threshold

to first

to first

completion

omissions”

number

of ADs between

behavioral

stage 5 seizure

of kindling

of omissions

the first behavioral

(PA)

seizure ___.

Accumbens group (n=7) Head of the caudate group (n=4) Middle caudate group (n=6) Tail of the caudate group (n=9)

_____._..

985.71 (291.49) 1212.50 (490.24) 883.33 (282.15) 608.89 (162.65)

~~~~ _ 19.29’ (2.14) 13.25 (2.10)

12.79d (2.07) 2.0

(0.0)

16.14c (2.38) 11.25 (2.95)

2.33 (0.84) 5.22 (1.24)

6.17 (2.12) 11.11 (1.70)

6.5 (2.14) 16.56

11.57b (2.14) 1.0

seizure and the first stage 5 seizure

(2.90)

(0.7)

12.57d (2.48) 4.50 (1.55)

(1.04) 11.25 (2.95)

4.29

2.67 (0.84) 4.11 (1.33)

2.67 (1.02) 7.67 (1.92)

3.83 (1.68) 8.11 (2.16)

.______-. . a Consecutive omissions’ refers to the highest number of consecutive ADS that did not result in a behavioral seizure. b The accumbens group differed significantly from the other groups (P < 0.05), which did not differ among themselves. ’ The accumbens groups differed significantly from the middle caudate group (P < 0.05); no other differences were significant. d The accumbens group differed significantly from the head of the caudate group and the middle caudate group (each P < 0.05); no other differences were significant.

tered throughout the head of the caudate. Electrodes in the middle caudate group were clustered in the ventral half of the middle caudate, and electrodes in the tail of the caudate group were scattered throughout the tail of the caudate. Motor responses during stimulation

A number of motor responses were observed during the l-s trains of stimulation, typically including contralateral turning of the head and torso, shaking of the head from side to side, and ipsilateral forelimb clonus. Certain rats occasionally exhibited more violent behaviors, such as rearing, falling, and rolling around the longitudinal axis of the body. These behaviors were then followed by AD and behavioral seizures occurring during AD, which we considered to be ictal behaviors. Every rat in the middle caudate group displayed motor responses during stimulation in almost every testing session, whereas motor responses occurred only intermittently in a minority of rats in each of the other 3 groups. AD threshold

As compared

to limbic sites, AD thresholds

were quite high, ranging from a mean of 609 ,uA in the tail of the caudate group to 1212,~A in the head of the caudate group (Table I). The differences between the groups in AD threshold failed to reach significance (fl3,22] = 0.83, P > 0.05), however, presumably because of the large variability in all groups. Rate and pattern of kindling

As shown in Table I, the groups differed significantly in the number of ADS required to trigger the first behavioral seizure (1;13,22] = 11.43, P < 0.001). Post-hoc comparisons indicated that the accumbens group was significantly slower than each of the caudate groups, which did not differ among themselves. There was no significant difference among the groups in the severity of the first behavioral seizure (Kruskal-Wallis l-way ANOVA (adjusted 2) = 5.19, P > 0.05). The groups also differed significantly in the number of ADS required for the development of the first stage 5 seizure (fl3,22] = 3.45, P < 0.05). Posthoc comparisons indicated that the accumbens group was significantly slower than the middle caudate group, with no other differences reaching

135 significance. As shown in Table I, there were no significant differences among the groups in the number of ADS that occurred between the first behavioral seizure and the first stage 5 seizure (I;13,22] = 2.45, P > 0.05). Thus the rate of kindling of generalized seizures was slowest in the rats in the accumbens group because they required more ADS for nonconvulsive seizures to develop into convulsive seizures. The groups differed in the number of ADS required to reach the criterion of 3 consecutive stage 5 seizures (measured from the first seizure; q3,22] = 3.93, P c 0.05). Post-hoc comparisons indicated that the middle caudate group required significantly fewer ADS to meet the criterion than the accumbens group, with no other differences reaching significance (Table I). This difference between the groups may have been due to the instability in evoked seizures we observed in the accumbens group. To quantify ictal instability, we computed 2 measures: consecutive omissions, the largest number of consecutive ADS unaccompanied by a behavioral seizure that each rat displayed; and total omissions, the total number of ADS unaccompanied by a behavioral seizure for each rat. The groups differed significantly in the number of consecutive (1;13,22] = 8.12, P < 0.001) and total (1;13,22] = 4.47, P < 0.05) omissions. As shown in Table I, post-hoc comparisons indicated that the accumbens group showed significantly more consecutive and total omissions than the head of the caudate group and the middle caudate group. In summary, the accumbens group displayed significantly slower kindling and significantly more omissions than the other groups. The groups with placements in the caudate did not differ significantly from each other, although the middle caudate group consistently displayed the fastest kindling and fewest omissions of all groups tested.

ten did not recover from for the rest of the seizure. During these episodes the rats typically remained supine and displayed bilateral forelimb clonus, unilateral or bilateral hindlimb tonic extension, and opisthotonos. Furthermore, the stage 5 seizures that eventually developed displayed some unusual features, including weak tonic extension of the hindlimbs, either unilaterally or bilaterally, accompanied by tonic retraction of the forelimbs and hypersensitivity to auditory stimulation. The durations of the first behavioral seizure differed among the groups (fl21,54] = 3.83, P < O.OS), with post-hoc comparisons indicating that the accumbens group’s seizures were significantly longer than those of each of the caudate groups, which did not differ among themselves (Fig. 2). Similarly, the durations of the first stage 5 seizures differed among the groups (1;121,54] = 9.12, P < O.OOl), with post-hoc comparisons indicating that the accumbens group’s seizures were significantly longer than those of each of the caudate groups, which did not differ among themselves. As might be expected, the absolute difference in the durations of the first behavioral seizure and first stage 5 seizure also varied significantly among the groups, with the accumbens group showing a significantly larger increase than each of the caudate groups, which did not differ among themselves. Fig. 2 demonstrates that the caudate groups had relatively brief seizures that did not change in duration during kindling whereas the accumbens group dis-

Morphology of kindled seizures

The first 4 stages of striatal seizures were similar to those triggered by limbic stimulation25. However, striatal kindling involved an additional stage, which we designated stage 4+, consisting of a generalized seizure wherein an immediate loss of balance occurred during stimulation, which the rat of-

First

Behavioral

Seizure

First

Stage

5 Seizure

Fig. 2. Comparison of the durations of the first behavioral seizure and first stage 5 seizure for each group. Asterisk indicates a significant difference from the other groups, P < 0.05.

136 0 accumbens 0 head * middle A tall

caudate

caudate

of the

first or second AD triggered; the other 9 rats lost their electrode pedestals before completing this phase of the experiment.

In=71

of the

(n=4)

In=61

caudate

(n=9)

/

DISCUSSION

I

middle

I

last

AD Fig. 3. Mean duration of the first, middle, and last AD for the 4 groups.

played initially brief seizures that dramatically increased in duration during kindling. Morphology of AD

The maximal frequency, amplitude, and duration of AD were quantified for each rat. In order to assess changes in AD over kindling and to make comparisons among rats that received different numbers of stimulations due to their different rates of kindling, we quantified each rat’s first, middle, and last AD. Although there was significant variation over the course of kindling (Pillais test, q6,86] = 6.82, P < 0.0001) on each of the three measures of AD, the groups effect and interaction were not significant. ANOVAs indicated that AD had grown significantly on each measure by the time generalized seizures had been kindled (frequency: fl2,44] = 11.53; amplitude: fl2,44] = 14.69; duration: 1;12,44] = 32.23; each P < O.OOOl),and post-hoc comparisons indicated that the differences between the first and last AD were significant, with no other differences reaching significance. Fig. 3 shows the changes in duration observed in each of the groups in the 3 ADS. There were similar changes in the amplitude and frequency of AD during kindling (data not shown). Persistence of kindled seizures

After a holiday of 7 days, 16 of 17 rats had the first of 3 consecutive stage 5 seizures during the

The results of the present experiment suggest that striatal kindling is genuine kindling, in that the following criteria were met: at most sites evoked AD initially failed to induce seizures, which appeared only after multiple ADS had been triggered; the intensity of the behavioral seizures and the AD increased with repeated stimulations; and the increased susceptibility to seizures persisted over a rest period without stimulation. The rate and pattern of striatal kindling were influenced by the location of the electrodes within the striatum, seizures developing significantly more slowly with stimulation of the nucleus accumbens than with stimulation of sites in the caudate nucleus. There were no significant differences in rate and pattern of kindling produced by stimulation at different sites in the caudate itself, although the middle caudate group tended to develop generalized seizures more rapidly than the other caudate groups. The pattern of kindling at most sites in the dorsal striatum is not readily characterized as being either limbic or neocortical, but rather resembles a blending of these two prototypical forms of kindling. Stimulation of sites in the caudate caused forced motor movements followed by AD, and AD could be evoked in the caudate only at high intensities of stimulation, both features that are similar to the responses to neocortical stimulation4,*‘. In addition, the head of the caudate group displayed behavioral seizures in response to the first AD, and first-trial behavioral seizures are a cardinal characteristic of anterior neocortical kindling. Furthermore, the 3 caudate groups showed only small increases in the duration of the behavioral seizures during kindling; and neocortical kindling is also characterized by the triggering of brief seizures that increase only slightly in duration. In contrast, the middle caudate and tail of the caudate groups did not display behavioral seizures during the first evoked AD, but instead required means of 2.7 and 4.1 ADS, respectively, before the

I37 first behavioral seizure appeared. Stimulation at limbic sites is also typically associated with the gradual emergence of behavioral seizures out of the early stages of nonconvulsive responses. Thus the head of the caudate supports a form of neocortical-type kindling, whereas the other sites in the caudate support a form of kindling that seems to combine elements of limbic and neocortical kindling. It may be significant that in previous studies of caudate kindling, stimulation was restricted to the head of the caudate and a neocortical pattern of kindling was observed, at least in response to the early ADS”**‘. Kindling with stimulation of the ventral striatum also showed features of limbic kindling and, to a lesser extent, neocortical kindling. Stimulation of the accumbens produced motor behavior that was present during the stimulation intermittently, and the threshold for AD was much higher than at limbit sites, features that are reminiscent of the responses to both neocortica14’29 and caudate stimulation The accumbens group required a mean of 12.7 ADS before the first behavioral seizure was evoked, however, and each measure of the rate of kindling was significantly slower than in the caudate groups. This slow progression of nonconvulsive seizures into convulsive seizures is reminiscent of kindling at limbic sites. Throughout kindling, the accumbens group also displayed significantly more omissions, ADS unaccompanied by behavioral seizure, than did the caudate groups. Omissions of this type are characteristic of both anterior neocortical kindling29 and kindling at some limbic sites ‘* . Finally, the duration of the behavioral seizures in the accumbens group increased dramatically during the course of kindling, a change that is similar to what occurs with kindling at most limbic site?. We note parenthetically that our accumbens electrodes were clustered in the dorsomedial aspect of the nucleus accumbens. Whether a similar pattern of kindling would be produced by stimulation of other aspects of the nucleus accumbens remains to be determined. The mo~hology of the seizures kindled by stimulation of the dorsal and the ventral striatum also displayed features of both limbic and neocortical seizures. Seizures through stages 4 or 5 closely re-

sembled limbic-type seizures, but differences from limbic seizures became apparent in stage 4+. In the latter, the rats typically lost their balance at the outset of AD, remained supine during the seizures, and displayed opisthotonos, tonic extension of the hindlimbs, and retraction of the forelimbs. Collectively the characteristics of dorsal and ventral striatal kindling suggest that they cannot be easily assigned to either of the two prototypical categories of kindling, limbic and neocortical. Striatal kindling instead seems to exhibit a unique mixture of features of both types of kindling. We note that the striatum is thus one of several sites supporting atypical patterns of kindling, sites such as the brainstem reticular formation’, sensory relay nuclei in the thalamusj, and posterior neocortex6. Anatomical studies have revealed that the dorsal and ventral striatum are divided into two partly interposed compartments, the patch and the matrix, which have different distributions in striatal tissue and different connections with various cortical and subcortical regions (see White34 for a recent review). The matrix and the dorsolateral striatum are strongly interconnected with neocortex, and the patches and the ventral striatum are strongly interconnected with limbic structures and allocortex. The results of functional studies have also indicated that different regions of the striatum play different roles in behavior. The patches and the ventral striatum seem to be involved in reward-related functions, and the matrix and the dorsal striatum seem to be involved in acquisition of S-R memory~,34. Lesions of the medial and lateral caudate nucleus also have somewhat different effects on behavior4, suggesting that these areas differ in function. The differences between dorsal and ventral striatum in patterns of kindling observed in the present experiment are in general agreement with the anatomical and ~nctional distinction outlined above. Unexpectedly, however, we failed to observe any striking differences in patterns of kindling produced by stimulation of different sites in the caudate nucleus, contrary to what might be expected from the anatomical34 and behaviora13,27V33 studies. The one difference that did emerge was the rapid kindling observed with stimulation

138 of the middle caudate, an area that has been identified as exerting anticonvulsant effects on amygdaloid-kindled seizures”‘. The differences in parameters of kindling at different sites in the caudate did not reach statistical significance, however, possibly suggesting that the anatomical and functional compartmentalization of the dorsal striatum is irrelevant to its participation in seizures. In agreement with this hypothesis, other recent data1,32,33suggest that various regions of the caudate participate in a uniform fashion in epileptiform activity. Another possible explanation for our results is that the relatively large electrodes we

used, and the high intensities of stimulation required for striatal kindling, produced fields of current” that were greater than the size of some of the striatal compartments, thereby obscuring any local differences in function. This idea could perhaps be evaluated in future studies by using smaller electrodes for striatal kindling.

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