Metabolic and behavioral consequences of lidocaine-kindled seizures

Brain Research, 324 (1984) 295-303 Elsevier

295

BRE 10446

Metabolic and Behavioral Consequences of Lidocaine-Kindled Seizures R. M. POST I, C. KENNEDY 2,3, M. SHINOHARA2, K. SQUILLACE 1, M. MIYAOKA2, S. SUDA ~, D. H. INGVAR2and L. SOKOLOF~ 1Biological Psychiatry Branch, and 2Laboratory of Cerebral Metabolism, National Institute of Mental Health, Bethesda, M D 20205; and 3Department of Pediatrics, Georgetown University School of Medicine, Washington, DC 20007 ( U. S. A. ) (Accepted April 17th, 1984) Key words: kindling - - lidocaine - - glucose utilization - - limbic system - - seizures - - aggression

Daily administration of lidocaine results in progressive increases in frequency and duration of convulsions in response to a dose of drug which was previously subconvulsive - - a pharmacological kindling phenomenon. The effects of such lidocaine-kindling on local cerebral glucose utilization were determined by the 2-[14C]deoxyglucosemethod. Lidocaine-treated animals, in the absence of convulsions, exhibited decreased glucose utilization in most brain structures compared to saline-treated animals and showed no increase in aggressive behavior. In animals displaying lidocaine-kindled convulsions there were marked increases in glucose utilization in either the hippocampus and amygdala or in perirhinal cortical areas during the seizure administration; these animals also displayed long-lasting increases in irritable behavior. Seizure duration was positively correlated with the rate of glucose utilization in the hippocampus, amygdala and septum, but inversely correlated in several non-limbic areas. These data suggest that lidocaine-kindled seizures are highly localized to limbic and perirhinal structures and are associated with important behavioral consequences. INTRODUCTION Daily injections of a subconvulsant dose of the local anesthetic, lidocaine, eventually result in convulsive activity of increasing frequency and severity 37,3'~,

hanced convulsive responsivity to lidocaine compared to implanted, sham-stimulated rats 38,39. Acute administration of convulsant doses of lidocaine and related local anesthetic agents has been

a process similar to that induced by electrophysiolog-

shown to activate limbic discharges in studies with depth electrodesg,ll,~2,15,27,43,5o.54,56 and to increase

ical kindling16.~o.41.55. The motor characteristics of

metabolic activity in the hippocampus19,3~,. A pre-

these lidocaine-induced convulsions also resemble those following electrical kindling of the amygdala

dominately limbic seizure pattern has also been reported following intravenous kainic acid2S and intraventricular beta-endorphin18 administration. The

and consist of clonic movements of the head, trunk and forepaws with repeated rearing and falling39. While initial lidocaine-induced seizures last seconds to minutes, following chronic injections their duration usually increases to 30-45 min or longer. Crosssensitization in both directions is observed between electrical kindling of the amygdala and that achieved by lidocaine. That is, lidocaine-seizing rats require

type of seizure, there is no information as to the exact regions of brain which are involved, nor is there knowledge of the magnitude of local changes in neu-

one-third fewer amygdala stimulations to the first major motor seizure (5.2 + 1.2) compared to salinetreated rats (18.3 _+ 2.4) (Post et al., unpublished data). In addition, amygdala-kindled rats show en-

ronal activity. To examine this question we have applied the [14C]deoxyglucose method for the quantitative measurement of local rates of cerebral glucose utilization. This method has been found to be useful,

similarity of the acutely induced lidocaine seizure and that which occurs after a series of daily subconvulsant doses suggests that the kindled variety is also of limbic origin. In the chronic, lidocaine-kindled

Correspondence: R. M. Post, Room 3N212, Building 10, National Institute of Mental Health, 9000 Rockvillc Pike, Bethesda, MD 202(15, U.S.A.

296 not only to map functional pathways in brain, but also to obtain a quantitative index of integrated neuronal activity20,48,s8. The present studies demonstrate increases in metabolic activity in limbic and related structures exclusively in animals experiencing lidocaine-induced convulsions; these animals also display long-lasting increases in irritable-aggressive behavior. METHODS

Male Sprague-Dawley rats. weighing 250-300 g, were pretreated with lidocaine (65 mg/kg, i.p.) or saline once daily, 5 times/week, for an average of 26 rejections. Although lidocaine (65 mg/kg, i.p.) did not produce convulsions on day 1. eventually 11 of 13 animals demonstrated convulsions with an average of 11 days of lidocaine-induced seizures per animal prior to study. Seizures involved salivation, chewing and perioral movements followed by intermittent clonic movements of head. trunk and forepaws: Straub tail phenomenon: and. usually, rearing and failing 37. The relatively long duration of these intermittent seizures (often 30-45 min) makes them particularly suitable for the [laC]deoxyglucose method which measures glucose utilization over a 45-min mterval. The increased seizure responsivity does not appear to be related to altered pharmacokinetics of lidocaine as blood levels measured at 45 min after injection are not increased in chronically treated rats (1.18 + 0.28 #g/ml) compared to those acutely treated (1.36 _+ 0.38#g/ml). Following pretreatment with lidocaine or saline. rats were studied by the 2-[14C]deoxyglucose technique in pairs as previously described 47,48. Briefly, one femoral artery and vein were catheterized under light halothane-nitrous oxide anesthesia: the animals were partially immobilized in a loose-fitting abdominal-pelvic plaster cast and allowed to recover 2 - 4 h from anesthesia. Rats were then injected with lidocaine (65 mg/kg, i.p.) or saline, and 8-10 min later, coincident with the time of onset of lidocaine seizures, were injected with a pulse of 50 keCi of 2-deoxy-D-[1AaC]glucose (spec. act. 50-55/~Ci//tmol) via the femoral venous catheter. Arterial blood gases and pH were determined during the procedure. Blood pressure, taken at frequent intervals, remained within the normal range. In only one instance did one ani-

mal experience a brief period of respiratory arrest associated with transient cyanosis: all other animals maintained adequate ventilation during the study. During the following 45 rain timed arterial blood samples were taken for the measurement of arterial plasma [14C]deoxyglucose and glucose concentrations, At approximately 45 rain following the pulse of [14C]deoxyglucose the animals were decapitated and the brains were removed, frozen m Freon XII. chilled to -50 °C. and sectioned for quantitative autoradiography as previously described 2°.~s-5~ A separate group of rats was treated with saline or lidocaine in order to assess the behavior of animals which develop repeated lidocaine-induced seizures. Animals were rated on the Albert and Richmond scale 2. which has been widely used to assess irritability and aggression following a variety of experimental manipulations that alter these behaviors, including septal lesions. To determine more specifically whether seizure activity itself accounted for the altered behavioral responses, saline controls In = 6) and other control groups that were pretreated with diazepam were included. One group received diazepam (1 mg/kg, i.p.) prior to lidocaine in iection (n = t0) in order to block seizure development and another group received diazepam plus saline (n ~ 6). Animals were rated 5 and 24 h after each lidocaine or saline injection. Local glucose utilization in individual brain regions was determined as previously described ~7.48and analyzed by Bonferroni's t-statistics for multiple group comparisons 31. Behavioral ratings on the Albert and Richmond scale were analyzed by analysis of variance. RESULTS

Lidocaine-treated animals that did not exhibit seizure activity during the [14C]deoxyglucose (DG) procedure showed reductions in glucose utilization in all 40 areas of brain examined, except the substantia nigra (Table IL Reductions averaged 19 -+ 1%. Two overlapping patterns of local increases in glucose utilization were seen in animals studied during lidocaine-induced seizures (Fig. 1 J. In one pattern (Seizure A) there were prominent and statistically significant increases in glucose utilization in hippocampus and amygdala, but statistically significant decreases

----1

Fig. l, Transforms of autoradiographs of coronal sections of rat brain into color-coded images indicating the distribution of local rates of glucose utilization. The color key at the right indicates the range of rates of glucose utilization that corresponds to a given color in the image. The 3 panels of 4 sections each are taken from the anterior, middle and posterior regions of the brain. The sections in each panet are representative of: (1) the controls (upper left); (2) rats given lidocaine but which did not develop seizures (upper right); (3) animals whose seizures resuited in high metabolic rates in hippocampus and amygdala designated ~seizure A'; and (4) animals whose seizures resulted in high rates in entorhinal and cingulate cortices designated 'seizure B'. The mean rates of glucose utilization for various brain structures for each of these 4 groups of animals arc listed in Table [ under the headings: Control, No fit, Hippocampal and Cortical, respectively.

298

TABLEI R e g i o n a l glucose utilization rumol/lO0 g/min) f o l l o w i n g chronic lidocaine or saline a d m i m s t r a t i o n V a l u e s are m e a n s + S . E . M . G l u c o s e utilization w a s l o w e r in all a r e a s in l i d o c a i n e - i n j e c t e d rats that did nol h a v e a s e i z u r e t h a n in saline c o n t r o l ( * P < 0.05: **P < 0.01). I n t h e h i p p o c a m p a l s e i z u r e t y p e v a l u e s w e r e significantly e l e v a t e d in the h i p p o c a m p u s , d e n t a t e . a m y g d a l a a n d a c c u m b e n s , but d e c r e a s e d in t h e c a u d a t e c o m p a r e d to n o n - s e i z i n g l i d o e a i n e - t r e a t e d a n i m a l s

Visual c o r t e x - A Entorhinal cortex Auditory cortex - A

Saline

Lidocaine

Control ~n = SJ

N o fit tn = 4)

Mixed ~n = 3~

Cortical ~n = 3~

89 ± 6

72 _~ t~ 42 -,~ 3 86 -± ~

58 ~_ 3 45 z 0.3 68 ± 4

73 _~ 2 50 1- a 81 ~__7

63 ~z 4 67 * 4 74 z a 711 ~_ a

72 59 63 62

II 8 ± 9

Insular Parietal c o r t e x - A Cingulate - B Sensory-motor cortex

81 _+ 4 88 _+ 8 93 z 10

Olfactory cortex Frontal cortex T h a l a m u s - dl Thalamus - vm Thalamus habenula Mediat geniculate Lateral geniculate Hypothalamus Hypothalamus mam. body Hippocampus - A Hippocampus - B dentate Amygdala Septal n u c l e u s Caudate nucleus A c c u m b e n s nucleus Prefrontalcort. Globus-pallidus Subthalamic nucleus Substantia nigra R e d nucleus Vestibular nucleus Cochlear nucleus S u p e r i o r olives

8l 74 85 80 77 101 73 53 88 66 61 43 44 89 61 103 46 77 52 69 [0(I 86 104

_+ 7 ~ ± 5 _+ 5 ± 5 + 3 _+ 6 ~ _+ 5 ± 3 ± 5 ± 4 _+ 3 *~ +_ 3 _+ 3 ± 7 ± 4 ± 7 _+ 3 ± 5 _+ 3 +_ 4 _+ 5** +_ 6 ~ + 6~

57 _~ 2 q4 -x 3 72 z .J. 63 r 3 63 _t 2 7~, ~_ a 62 ! 2 44 z 2 71-; ~_ t~ 611 ~ . " 4¢~ :,_ 2 3¢~ ± 2 38 ~ I 82 ~ ~" 55 z I 87 z I 37 :_- I 62 ,_ _" 52 _ma 56 ~-_ 1 7~ z 3 ho ~ h 67 z t~

Lateral lemniscus I n f e r i o r colliculus Midline nuclei S u p e r i o r collic. ( s u p ) S u p e r i o r collic. ( d e e p ) Pont±he g r a y Spinal g r a y

85 + 4" ~ 149 +_ 6 ~

53 ± a 96 7_ ~

.

74 73 56 51

+ 4 _+ 4 _+ 3 ~_ 3

59 61 52 40

,_ 2 1- "3 ± t~ z 3

Cerebellar hemisphere C e r e b e l l a r nuclei Corpus callosum Corpus callosum genu Internal capsule

49 88 33 24 28

± 3 ± 4* _~ 1 ~ ~ z 2 _ 1~

41 o~ 25 20 23

x 3 ± 3 _~ 1 -- 2 1-- 1

45 73 24 19 23

Cerebellar white

31 z 1

pocampal the

CA2-3

vated.

regions

increases area

Prominent

in i n d i v i d u a l claustrum

or

of brain. were

and

dentate

increases

in most

gyrus

were

endopyriform

were

also noted

nuclei of the amygdala

the hip-

areas, less

but acti-

(Fig.

l)

as well as in the

n u c l e u s 23. A c c o m p a n y -

ing the

.

.

were

33 .2 a

89 52 60 56

51 q7 "2 61 70 54 51

_~ a ± ± 5 ~_ ~ ~- - ± 3 = n

a7 + h 76 _~ 14 ~5 m 9 rio _+ 6 (~3 n - ~ 44 z 4 46 _~ 2

54 z 6 74 ~_ a 25 ~_ 2 21 _~ 2 23 _~ 0.3 28__ . "~ .

49 +_ a 70 ~- ~, 26 _+_2 18 +_ 1 23 ± 0.3 "~6+ 1

glucose

utilization

reductions

glucose

even

were

in the lidocaine-treated,

25 s t r u c t u r e s .

A second

in these

in c e r e b r a l

and brainstem

utilization

5 3 _'3

52 _~ "61 x 2

tures, the diencephalon,

found

z z z &

t~l~ z 2 ~7 ± a 57 ~- 4 61 ~ 6 56 _~ a 52 _+. 2 71 ~_ 10 94 ~- 11 "~ 6~; ± 2 ~ " ¢,a ± 8 ~ 50 x 5 71 ~_ 1 ,62 -~ l* 71 z 5 54 ± 9 67 _* a 65 _+ 58 ~_~q 7¢~ z 5 q9 T 7 ~4 .z ~J

.

increased

structures

z z x z

.... 76 z 15 67 ± -

52 z811 _+ 1 l ha z 62 ~ " 78 + ~ 72 _~ 3 61 -_ a 40 ± 2 83 +_ 61 . -- a . 51 m 2 37 .z 38 _~: i 85 z 3 55 m 3 87 _+ 5 48 +_ 5 72 z 5 62 ~_ 12 ~6 ~_ 8 79 _~ 3 ha + 7 (~8 ! 5

z 3 + 9 ± 2 ± 3 + ~ ± 4 _+ 6

_+ 6 ± 4 _+ 4 2 2 _+ 3 23 + . ~

24 z 2

In this pattern

striking

t22 69 85 7-i

42 -z 9 61 z 3 64 ~ 4 65 _~ ~; 51 z 3 08 z 3 54 ! 2 44 z 2 77 ~ . 61 -~ 5. 50 ± 5 37 ± 2 39 -_- 2 811 z .~ 59 m ,1 8t) z t~ 42 z t, 64 ± 4 52 _~ 60 _~ ¢~ 7t z 3 (~4 ~ a 63 7z 5 48 91 62 54 S9 47 36

in most other

~_ 8 ± ~ _~. 2 ~ •

Hzppocampal ¢n = 3)

pattern

lower

cortical where than

non-seizing (Seizure

the

limbic strucrates of levels

animals

in

BI was char-

299 acterized by increased glucose utilization in the perirhinal and cingulate cortices and not in the amygdala and hippocampus. The elevation in the perirhinal area was heterogeneous with a higher rate seen in layer IV and layer I. This area appears to be roughly equivalent to the insular cortex in the primate. The region of increased metabolism in the cingulate gyrus was seen through its full anteroposterior extent. No differences in behavior or seizure patterns were observed which correlated with these two diverse patterns of changes in metabolic activity. In the whole group of 13 animals studied with lidocaine-kindled seizures, the duration of the seizure was positively correlated with the rate of glucose utilization in the hippocampus (r = 0.66), dentate gyrus (r = (I.57), amygdala (r = 0.63) and septum (r = {I.75), and negatively correlated with metabolic activity in the lateral thalamus (r = -0.61), lateral lemniscus (r = -0.61) and medial geniculate (r = -0.58): these correlations were all statistically significant, P < O.05. An additional group of 3 lidocaine-kindled animals that consistently developed seizures when challenged with lidocaine were studied with 2-deoxyglucose following administration of saline instead of the lidocaine-challenge. This was done to establish whether the earlier repeated lidocaine seizures had altered the basal pattern of brain glucose utilization. These animals showed a pattern of glucose utilization similar to that observed following chronic saline administration, however, and no clear change that might be related to the 'kindled substrate' or altered vulnerability to lidocaine seizures was evident in these few animals studied. DISCUSSION These studies extend the observations made with neurophysiological methodstl,a3,50 and confirm the inw~lvement of limbic structures in lidocaine-induced seizures. They describe regional increases in metabolic activity in amygdala and hippocampus or perirhina[ cortical areas during seizure activity 'kindled" by repeated lidocaine administration37,>. The regional increases are clearly related to the seizure activity itself inasmuch as the same challenging dose of lidocaine which failed to produce convulsions depresses metabolic activity in most brain areas corn-

pared to the values in saline controls (Table I and Fig. 1). Moreover, seizure durations were positively correlated with glucose utilization in limbic system areas, including hippocampus, amygdala and septurn. Partial restraint of the animals precluded detailed observation of their behavior during the deoxyglucose procedure. However, in animals separately prepared, repeated lidocaine administration led to the development of irritable, aggressive behavior only in those animals that experienced seizures (Fig. 2). Increases in aggression were not wominent during or immediately following the ictus, bul were observed at 5 and 24 h after seizures and persisted for days to weeks in the interictal period following termination of chronic injections. The aggressive behavior was characterized by biting and extreme resistance-tocapture on the Albert and Richmond rating scale es and developed only following lidocaine injections that resulted in seizures (n - Ill (Fig. 3). No changes in aggressive behavior occurred in the lidocaine-non-seizing animals (n = 8). Aggressive behavior was also not increased in the other control groups: saline-injected rats (n = ~) or lidocaine-injected rats in which seizures were blocked by diazepam (1 mg/kg, i.p.) pretreatment. Thus, once animals developed lidocaine-induced seizures, they developed not only long-lasting increased susceptibility to further seizures, but displayed sustained irritable and aggressive behavior in the interictal period. In other studies, and particularly when animals were housed alone, the degree of aggression could, at times, be extreme with rats .jumping out of their cages in apparent directed attacks at laboratory personnel; when cornered on the floor of the laboratory, these animals might also viciously attack and bite shoes or gloved hands of laboratory personnel. Similar degrees of aggressive behavioral changes were not observed following chronic seizures of other types, including pentylenetetrazol or electroconvulsive seizures (Fig. 4). We have also not seen these types of aggressive behavior following repeated seizures electrically kindled from the amygdala 3~ (data not shown). These data are in accord with the observations of Bawden and Racine ~ and Mclntyre >, but not those of Pinel and associates 34. who reported increases in resistance to capture following electrical kindling of amygdala and hippocampus but not cau-

300 LIDOCAINE INDUCED AGGRESSION DEVELOPS ONLY FOLLOWING SEIZURES 0.8

the two patterns of changes in glucose utilization that were observed (Fig. 1), it is possible that they reflect the relative p r e d o m i n a n c e of either the convulswe or

Aggression Rating 5 Hours Post Injection

internal quiescent components o~ the intermittent seizure which, in turn. could relale to the predomi-

0.6

nance of excitatory or inhibitory mechanisms during the seizure process. For example, Engel has reported

E0.4 d3

differences in glucose utilization following electroconvulsive shock apparently depending on whether ictal or post-ictal components arc more prominent L.~ Engel ~-~ and A c k e r m a n et al. ~ l~ave also reported

0.2

marked uncoupling of glucose utilization and blood flow during limbic seizures, rinsing the possibility

0 _z 0.8 I-< Z O

that anoxic damage and n e u r o n a l loss could occur during these seizures. Collins and Caston 7. studying

Aggression Rating 24 Hours Post Injection

£12

glucose utilization in focal penicillin and bicuculline

0.6

q3 tad or"

seizures, concluded that the behavioral symptoms were not the expression of the locus but of its circuits. Kliot and Poletti 21 suggest "that hippocampal at-

l

L9

< 0.4

terdischarges spread along the same efferent pathways used by less intense physiological activity' In the case of lidocaine seizures the pathways would ap-

0.2 N

{6~

tl]l 13~{10H10) I

0 DAY TREATMEN I

5 10 15 20

5 10 15 20

SALINE SALINE

SALINE LIDOCAINE

II

pear to involve not only discrete regions of the hippocampus and amygdala, but also the claustrum and en-

5 10 15 20

5 10 15 20

5 1E 15 20

SALINE I It)uCAtNE

DIAZEPAM IDOCAINE

DIAZEPAM SALINE

b[.IZURE

dopyriform nuclei as well as perirhinal and cingulate cortices. These areas have been previously linked to amygdala and hippocampus pathways bv a variety of

Fig. 2. Selective development of aggression in animal displaying lidocaine-induced seizures. Animals displaying seizures following lidocaine (65 mg/kg, i.p.) administration showed more irritability and aggression (particularly in the resistance-to-capture measure2) than all other non-semng groups including animals whose seizures were blocked by diazepam (1 mg/kg, i.p.) pretreatment. This interietal behavioral change was evident at both 5 and 24 h following seizures, but not immediately post-ictally. Number of animals rated in each group is in parentheses.

R E L A T I O N S H I P OF A G G R E S S I O N 1 0 O N S E T OF L I D O C A I N E SE{ZURES

24 H{3Uf/b PC1"] tNJEL;T'~jN •

• 3E ZFRS • NC;N SE~Z[-~{q

J

date nucleus. O u r observations, therefore, suggest that seizures induced by lidocaine, but not those induced by pentylenetetrazol, electroconvulsive shocks, or amygdala kindling, are associated with aggression in the interictat period. Further studies are warranted to characterize the ethological type of aggression that follows the lidocaine seizures. The lidocaine-kindled seizures are characterized by oscillations between clonic c o m p o n e n t s involving head, trunk and forepaws with rearing and falling and periods of quiescent immobility. Although we have not observed different behavioral correlates of

A

8

1

,

•

4

3

2

DAY~ PRIOR TO SEIZURE

--

"

2

,£1ZURE DA Y

Fig. 3. Relationship of behavioral change to the emergence of lidocaine-induced seizures. In animals chronically injected with lidocaine, notable increases in aggression were noted 24 h following the second lidocaine-induced seizure, but there was little evidence of behavior change in these lidocaine-injected rats in the days prior to their first seizure (open circles, n = 11/. Similarly, no changes in aggressive behavior occurred in a parallel group of lidocaine-treated animals (n = 8) that did not display smzures: 'seizure day' for these control animals was designated by matching animals in the two groups for number of injections.

301 SELECTIVE INCREASE IN AGGRESSION FOLLOWING LIDOCAINE, BUT NOT ELECTROCONVULSIVE OR PENTYLENETETRAZOL SEIZURES i

5 HOURS POST SEIZURE

SEIZURE TyPE

! 3200 ~

•

~,Doc~,~

[]

PENT'tLEN~ TETRAZOI

8 cc 8

0 .

24 HOURS POST SEIZURE

I

co 3200 ~

co

i

< 2200p 1200

2o0.>'. lOO~ 0

'

~ 1

~

2

3

~

4

SEIZURE DAY

Fig. 4. Albert and Richmond scale ratings of aggression were markedly increased compared with controls following repeated once-daily seizures induced by lidocaine (65 mg/kg, i.p.), but not by pentylenetctrazol (80 mg/kg, i.p.), or by electroconvulsive shock (120-140 V for 1 s administered by ear clip electrodes versus sham controls). These increases were observed both 5 and 24 h following lidocaine, but not the other seizure types.

techniques2~ 25.sL again suggesting that the lidocaine seizures are activating either the amygdala and hippocampus directly or their synaptically-related projection areas, including claustrum, endopyriform nuclei and perirhinal and cingulate cortices. The mechanisms of lidocaine's limbic convulsant effects are poorly understood. At low doses local anesthetics are anticonvulsant 4,22,52, and membrane effects, especially mediated through calciumZ6,~4-4~, or sodiumS, are implicated in the local anesthetic effect. Lidocaine does not block catecholamine reuptake as does cocaine 57 and accordingly tends to produce behavioral sedation37, 4'~ rather than the psychomotor stimulant effects of cocaine ~-~. Lidocaine does not alter whole-brain levels of norepinephrine, dopamine or serotonin 22 or those levels in discrete brain structures, including hippocampus, amygdala and caudate

nucleus (Jacobowitz, personal communication) although Ciarlone and Smudski ~' reported decreased serotonin and dopamine in the mesodiencephalon. The pattern of increasing glucose utilization in limbic system structures and associated pathways produced by lidocaine seizures is clearly different from that produced by other seizures~e and convulsant agents, such as pentylenetetrazol (Kennedy, unpublished data, 198(t), amygdala kindling~a or electroconvulsive seizures 5, all of which are also not associated with the same increases in aggression. Although lidocaine seizures behaviorally resemble those seen following electrical amygdala kindling, they persist for longer periods of time. and the patterns of glucose utilization differ: in contrast to the lidocaine seizures, generalized amygdala-kindled seizures show increased glucose utilization bilaterally in the substantia nigra, globus pallidus, thalamus, and large areas of neocortex M. Thus, the increases in aggression following lidocaine seizures might relate to the long-term consequences of the predominantly limbic system activation produced by the seizures. A limbic pattern of changes in glucose utilization similar to that folk)wing lidocaine seizures has been reported following intraventricular beta-endorphinSS and intravenous kainic acid administration'S, but the long-term behavioral consequences of these seizure types were not reported. In recent studies of kainic acid seizures in cats, Tanaka et al. ~-~ did report increases in aggression and irritability when seizures involved hippocampus and amygdala, and Mellanby et al. 30 reported aggression on handling following tetanus toxin-induced hippocampal seizures in the rat. The clearly interictal and relatively long-lasting behavioral consequences of lidocaine-induced seizures are of interest in relation to the continuing clinical controversies regarding the possible association of complex partial seizures and aggression in manl°,33,4E Much clinical investigative work has focused around the more limited question of whether aggressive acts in man occur during the complex partial seizure. Our data would suggest the utility of examining the broader question of whether the experience of some types of seizures, but not others, might not lead to long-term consequences on behavior. In our experimental model, the emergence o| irritable and aggressive behavior was dependent on the occurrence of the lidocaine-induced seizures, but an-

302 peared to be a downstream

consequence

of seizure

k i n d l e d s e i z u r e s a r e a s s o c i a t e d w i t h i n c r e a s e s in irrt-

occurrence. The aggressive behaviors did not occur

table-aggressive

d u r i n g t h e fetal p r o c e s s i t s e l f a n d p e r s i s t e d d u r i n g t h e

u t i l i z a t i o n in t h e a m y g d a l a a n d h i p p o c a m p u s

interictal period.

lated perirhinal and cingulate cortex and may pr~-

The repeated

administration

o f initially n o n - c o n -

behavior

vide a useful paradigm

a n d i n c r e a s e s in g l u c o s e or re-

f o r t h e stttd~ o f t h e m e c h a -

vulsive doses of lidocaine eventually evokes seizures

msms

of increasing severity and duration. These chemically

with limbic system setzures.

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