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EJP 52673

Antagonism of ethanol withdrawal convulsions in Withdrawal Seizure Prone mice by diazepam and abecarnil John C ‘Irabbe Research Sewice, VA Medical Cetrter uttd Deparmmetrrs of Mcdicul Psychology and Pharmacology,

Oregon Health Sciences Uttirersity. Portland,

OR 97201, USA

Received 30 June 1992, accepted 7 July 1992

Abccarnil, a in a number clinical

@-carbolinc

application

abecarnil

acting at benzodiazcpinc

of models. It has rcduccd of diazcpam

with diazepam

scvcrc handling-induced

to prcvcnt

cxperimcnt

or diazepam

Withdrawal

clcvation

to diazcpam. genetically

reduced handling-induced

its effects were shorter-lasting.

of handling-induced

Similar

withdrawal;

1. Introduction Benzodiazepine receptors bind a number of compounds with agonist, antagonist, and inverse agonist properties. The p-carboline derivative, abecarnil (isopropyl-6-benzyloxy-4-methoxymethyl-~-carboline-3carboxylate: ZK 112119), has been shown to have partial agonist effects including high anxiolytic potency with little to no sedative effects (Stephens et al., 1990) and a distinctive anticonvulsant profile in various animal models (Turski et al., 1990). Benzodiazepines remain the drugs of choice for clinical treatment of alcohol withdrawal where withdrawal seizures might be expected to occur. While their sedative effects may be useful in treating the early stages of alcohol withdrawal, their sedative and motor incoordinating effects may be problematic in later stages of treatment. They also have clinical application as antiepileptics and anxiolytics. There is a continuing

Correspondence IO: 3. Crabbe, Research Career Scientist (ISIW). Department of Vctcrans Affairs Medical Center, 3710 SW US Vcterans Hospital Road, Portland, OR 97201, USA. Tel. 1.503.273 5298. fax I SO3.273 535 I.

in naive WSP mice.

Handling-induced (Genetic

convulsion

results were seen in an injection.

Abecarnil

Single doses of abecamil or

convulsion scores suggcstivc of a withdrawal

cffccts; &Carbolines;

to compare

sclcctcd to develop

were exposed to ethanol vapor for 24 h.

had significantly

convulsion scores seen

properties

Given the wide

model was employed

convulsions were assessed after a single high-dose ethanol

scizurc prone mouse (WSPI; Ethanol Anticonvulsant

animal

(WSP) mice,

from chronic ethanol treatment,

also reduced the smaller handling-induced

did not lcad to a rebound

Seizure Prone

at the peak of withdrawal

was slightly more potent than diazcpam. handling-induced

effects in comparison

seizures, a genetic

cffccts. Withdrawal

convulsions after withdrawal

where withdrawal

and diazepam diazcpam

abccamil

has been shown to have anxiolytic and anticonvulsant

and incoordinating

alcohol withdrawal

for its anti-withdrawal

WSP mice given doses of abccarnil scores. While

rcccptors,

musdc relaxant

convulsions; Abecarnil;

reac!ion.

Diazcpam;

animal model)

search for benzodiazepine ligands with more selective anticonvulsant (or anxiolytic) effects versus sedative/ ataxic effects. The handling-induced convulsion score in mice was originally proposed as a useful index of central nervous system hyperactivity during drug withdrawal (Goldstein and Pal, 1971). Ethanol withdrawal handling-induced convulsions were found to be antagonized by most drugs displaying cross-tolerance and cross-dependence with ethanol (Goldstein, 1972), and heritable differences in the severity of ethanol withdrawal convulsions were reported (Crabbe et al., 1983a). We have developed a genetic animal model of sensitivity to ethanol physical dependence by selectively breeding Withdrawal Seizure Prone (WSP) mice to display severe handling-induced convulsions after cessation of chronic ethanol vapor inhalation (Crabbe et al., 1985). The genetic sensitivity of WSP mice has been shown to generalize to withdrawal from barbiturates (Belknap et al., 1988), diazepam (Belknap et al., 1989), and nitrous oxide (Belknap et al., 1987). After many generations of selection, WSP mice are so sensitive that significant elevations in withdrawal handling-induced convulsion scores can be seen several hours after a single injection of several compounds with sedative effects on the

t.WItd WlYOkJSS~SttSll(ClXbht2et al..

IWlil).

En-

stt~ed central nervous system activity (charactcrizcd by hwered seizure thresholds) following acute ethanol treatment was first reported by McQuarrie and Fingl f 195~1. In the current

study. we evaluated

the efficacy of

ct al.. 19S3b). At O7:OO h, mice were injected 2.2 g/kg

ethanol

wire-mesh

(20%

hanging

v/v

cages

in saline)

i.p. with

and placed in

in a chamber

containing

ethanol vapor. At 2 and 6 h after injection, 30 mice wcrc briefly rcmcived from the chamber and a 20 ~1 tail-blood

sample was drawn. At 24 h after injection, all

abecamil as an anticonvulsant against ethanol withdrdwal in WSP mice and compared it with diazcpam,

mice were removed from the chamber, blcs; samples were taken. and the mice were scored for handling-in-

using the handling-induced convulsion score after acute or chronic ethanol exposure.

duced convulsions each h for 15 h, and again at 24 and 25 h. Handling-induced

convulsion scores were deter-

mined using a previously published scale (Crab& 2. Materials

and methods

(score = II to sevcrc, tonic-clonic Adult.

ct al.,

19Yla): non-zero scores range from minimal tonic seizures which must be elicited by spinning by the tail

female WSP mice were bred in our colonies

in Portland. Oregon. USA. Al! animals were naive at the time of testing. Mice were maintained in groups of five in individually ventilated cages (Thorcns) with ad iibitum access to food and water under a 12 : 12 h light : dark cycle at 2h + 1°C.

seizures elicited sim-

ply by removing the cage lid (score = 7). Vapor concentrations were maintained ethanol/l air by adjusting

at approximately 14.5 mg the flow of ethanol onto a

chromatographic paper wick. Blood samples were prepared (Crabbe et al., 1989) and analyzed for ethanol according to gas chromatographic ~i~iii& (Crabbc ei. al., 1982) which have been previously drscribed. Peak withdrawal handling-induced convulsion scores

Ethanol (Midwest Solvents. Muscatinc. IA, USA) was diluted to 20% v/v in saline. Diazcpam was a gift oi Hoffmann LaRochc, Inc., Nutley. NJ, USA. Allecarnil W;IS a gift of Dr. D.N. Stcphcns, Schcring, Berlin. Drugs were initially dissolved in a drop of Tween 80. and saline was added to a final volume of 5 cc.

arc attained

under !hese conditions approximatc!y

h after mice were injected remova?

~EYXII

of abccarnil

(0.5,

4-6

the chambers. At 5 h 3 min, i.p. with vehicle, one of four doses 1.0, 2.0 or 4.0 mg/kg)

or diazepam

(same doses). As most mice had evidently recovered from drug-induced suppression of withdrawal by 8 h, injections wcrc rcpcated

at 7 h 45 min.

In a second study, naive WSP mice were scored for handling-induced convulsions and injected with 4 g/kg All procedures adhere to United States Public Health Service-National Institutes of Health Guidelines for the care and use of laboratory animals and were approved by the two local institutional Animal Care XX! Use Committees. The apparatus and method for inducing ethanol dependence by exposure to ethanol vapor have been dcscribcd previously (Crabbc

O

1

2

3

4

5

6

t

7

8

9101112131415

t TIME (HOURS)

2425

ethanol in saline (20%

v/v).

Handling-induced

convul-

sions were scored at 2, 4, 5 and 6 h, when peak acute withdrawal scores were attained (Crabbe et al., 199la). At

6 h 30 min

after

ethanol

injection,

mice

were

injected i.p. with vehicle, abecarnil (0.1, 0.2 or 0.5 mg/kgl, or diazepam (0.2 or 0.5 mg/kg). Handling-induccd convulsions wire again scored, at 10 min intcr-

0

1

2

3

4

5

6 t

7

B

9 101112131415

2425

t TIME (HOURS)

Fig.. I. hleai; !aar:Ging-indocd ca)bdsion scores in groups of WSP rnicc withdrawing irum 24 h chronic rnhalatbi~ of ethimcil vapor. lnjcctions ot vehicle or ihe mdicated doses of ahecarnil (A) or diazepam (B) were given at the timczsindicated by arrow%. Vehicle group (N = IX) is shown in both panels. N = ‘#./drug dose. S.E.s arc omitted for clarity. and range from 0.19 (smaller than symhol size) to 0.07. Open circles, vehicle. Filled circles. 0.5 mg/kg. Filled triangles. 1.0 mg/kg. Filled squnrcs . . 2.0mg/kg. Filled dlamcrilds. 4.0 mg/kg.

x7

vals starting to II h.

10 min after injection,

and hourly !-cm 7

In a third study, the effect of abecarnil on handlinginduced convulsions was tested in naive WSP mice. After

scoring basclinc

handling-induced

convulsions,

placebo, 0,02,0.2 or 2.0 mg/kg doses of abecarnil were administered, and handling-induced convulsions were scored at 10 min intervals for I h, and again 2, 3 and 4 h after injectlon. In a fourth

study, the possibility that single doses of

abccarnil or diazepam might themselves provoke acute withdrawal responses was evaluated. Handling-induced convulsions were scored, and vehicle, doses of each

drug

were

z

4 PRE : : 2: : 4

I

1.0 or 2.0 mg/kg

administered

to scparatc

groups of mice. Handling-induced convulsions were scored hourly for 8 h as described, beginning 1 h after injection.

Fig. 2. Mean

TIM&OURS)

handling-induced

mice aculely withdrawing arrow).

Injections

ahecarr,il

(indicated

or diazepam

Handling-induced

convulsion scores in groups of WSP

from 4 g/kg

ethanol (given at hour 0: large

by smail arrow) of vehicle or doses of

were

given at h h 30 min after

thus, the 30 min score occurred 7 h post-ethanol. (0.1 mg/kg

For most analysts, was employed, Newman-Keuls,

single- or two-factor

ANOVA

and post-hoc tests used the method of employing

the

studentized

range

mg/kg

abecarnil

upward

triangles.

It.9 mg/kg

Results of the first experiment vapor exposure induced

are shown in fig. 1. stable blood alcohol

levels. At 6 h after exposure. mean ) S.E. blood alcohol concentrations were 1.97 + 0.1 I mg/ml, and trcatmcnt groups did not differ significantly (F(8. 21) = 0.5, P > 0.10). Mice had blood ethanol concentrations averaging 2.09 + 0.11 mg/ml at the time of withdrawal, and no significant diffcrcnccs among groups wcrc seen (F(8, 81) = 1.3 P > 0. IO). Handling-induced convulsion scores, which typically average 2 in naive WSP mice (Crabbc ct al., lY9lbL wcrc rcduccd by ethanol during the first hour of withdrawal. Between 1 and 3 h of withdrawal, as the animals eliminated blood ethanol, they

began

0.2 mg/kg

ahecarnil.

Filled

ahecarnil. squares,

diamonds. ti.S mg/kg

Results

Ethanol

for

to display

characteristically

cxaccrbatcd

handling-induced convulsions, which pcakcd at 4-S h after removal. Abecarnil (fig. IA) and diazepam (fig. IB), administered IS min bcforc the 6 h scoring, inhibitcd withdrawal handling-induced convulsions dose dcpcndently. The change in handling-induced convulsion scores bctwccn 5 and 6 h diffcrcd significantly among groups (F(X, 81) = 5.7. P < 0.0001). Post-hoc tests versus the vehicle-treated group revealed that abecarnil was signilicantiy cffcctivc at the 2 and 4 mg/kg doses, while diazcpam had significant effects only at the 4 mg/kg dose (P < 0.01). This suggests that abecarnil

N = IX (vehicle).

IO

groups) or 16 (both 0.2

ciarity, and range from I) to

0.61. Open circles. vehicle. Filled circles. 0.1 mg/kg

statistic. qF.

3.

group. hoth 0.5 mg/kg

S.E.s iire 0.10). It seems likely that the dose-related effects apparent in fig. 1 (A,B) did not reach significance due to the rclativcly small group sizes and corresponding magnitude of within-group error. Analyses of responses to the second injection revcalcd a similar pattern of outcomes. The suppression of h;lliC!!ing-i!K!tJCCC! convulsions by di:tzepam appeared to have been of longer duration, at least at the highest dose, for ahccarnil-trcatcd mice had rccovcrcd to control levels of handling-induced convulsion scores by 3 h after the second injection. This is not surprising, since abccarnil has a shorter half-life

than diazcpam

in mice

(Dr. D.N. Stcphcns, personal communication). The withdrawal response following a single acute ethanol dose was also supprcsscd by diazcpam and abecarnil; fig. 2 shows the results of the second study. Ethanol

initially

reduced handling-induced

convulsion

this possibility. we reanJyzed the data in a way that would facilitate direct comparison. The vehicle group

>,corcs in ali groups (compare scores at 2 and 4 h with those (PRE) just before injection). By 6 h. handling-induced convulsion scores had rebounded to levels abo;e

was cxcludcd,

prc-ethanol

may have been rnorc potent tharr diazcpam.

and the diffcrcncc

To pursue:

bctwccn the 5 h (last

basclinc, indicating a state of ~CLI~Cethanol

witbdr~wal similar to that previously reported (Crabhe et ai.. I99is). Since groups did not differ significantly

interaction (F(32.440) = 2.X. P < 0.0001). A separate one-way ANOVA of the scores I h post-injection was

(P > tl. it)) at 6 h. a similar degree of acute dependence cm ethanol in alI groups may be inferred. injections of abevarnii or diazcpam :,I h ,h 30 min after ethanol

yses showed that the 2 mg/kg

reduced

inje&,‘tion

handling-induced

convulsion

scores

significant (F(4, 55) = 4.7, P < 0.01) and post-hoc analdose groups of either

drug, and the I mg/kg dose group treated with diazepam, had significantly reduced handling-induced

dose dependently. ANOVA for the three initial postdrug scores revealed only a significant effect of treat-

convulsion scores versus the placebo group (P < 0.01).

ment group. Post-hoc tests revealed that the groups treated with 05 mg/kg doses of abecarnil or diazepam

lowered handling-induced

had significantly attcnuatcd

withdrawal

scores (P < 0.01

and t.OS. respectively). Although groups treated iower doses appeared to have somewhat lower

By 2 h, only the diazcpam-trcatcd This suggests. once longer-lasting effect.

mice still showed

convulsion scores (P < O.OI).

again,

that

diazepam

had

the

with han-

dling-induced coavuision scores than vehicle-trcatcd mice (see fig. 2). these differences were not significant. Abecamii also effectively reduced handling-induced convulsion scores in naive mice. Mean ( + S.E.) baseline handling-induced convulsion scores for the 29 mice tested in Esperiment 3 were 3.2 + 0. I. and handling-induced conkruision scores 40 min after ir?jcction were 1-S + 0.1. 0.4 + 0 3. :ir.d !I i il. f01 the groups given 0_(12, 0.2. and 2 mg/kg ahccarnii. respectively. The latter two groups were significantly rcduccd from bascline means (P < O.Oi). By I80 min after injection, the respective handling-induced convulsion scores were 2.3 f 0.2. 2.4 -+ 0.2. and 2.7 + 0.4. These did not differ significantly from each other. or from baseline scores. Figure 3 again shows that abecarnii or diazepam effectively reduced handling-induced convulsion scores in naive mice. No treatments employed showed signs of provoking an acute withdrawal response. since no groups significantly excccdcd baseline scores during the S h test. Analysrb indicated a significant effect of treatment group (F(4. 55) = 35. P < O.Oi ) and time (RX 440) =4-S. P < O.oUOi), as wcli as a significant

4. Discussion The finding withdrawal

that diazepam

handling-induced

could suppress ethanol convulsions

in mice was

;lot surprising. Goldstein (1972) reported such antagonism in genetically heterogeneous mice, but she used a lonpcr ncriod of dure

that

c!had

included

r;xyosurc (72 h), and a proccadjunct

treatment

with

pyrazole

hydrochloride. an alcohol dehydrogenase inhibitor. Howcvcr. she found a SO mg/kg dose of diazepam (but not 5 or 20 mg/kg) that 20-100 mg/kg

to be significantly effective, and chloridazepoxide was also effec-

tive. In the current studies, a 4 mg/kg dose of diazepam inhihited withdrawal. Greater sensitivity to diazepam was seen in the current experiments:

this could

bc due to our USC of WSP mice. rather than the generic Swiss-Webster used by Qr. Goldstein, or to the greater degree of dependence instilled by use of 72 h inhalation coupled tion.

with

pyrazole-induced

metabolic

inhibi-

Abecarnil clearly inhibited handling-induced convulsions seen after withdrawal from 24 h chronic ethanol intoxication. it appeared to have been more potent than diazepam. although the difference was not marked. it seems likely that its cffcct was of somewhat shorter duration. Both drugs also an!agnnized wi!hdrawal in the single-injection acute withdrawal model, at cvcn lower doses (0.5 mg/kg). In the abscncc of information

about brain or plasma levels for the two

drugs. firm conclusions regarding relative potency cannot bc drawn from thcsc data. ::nd await further studies. Abecarnil

is a potent anticonvulsant

in several ani-

mal models of cxpcrimcntal seizures (Turski et al., IYYO; Fischer et al., 1991). We have previously re-

4

;

4

:

Ii

7

I

ported enhancement of handling-induced convulsions in naive WSP mice with the bcnzodiazcpinc inverse

8

nME(HOLJRS) Fig. 3. Mran + S.E. handling-inducedccmvulsion WSP (open Open

agonist, Ro IS-45 1.3, at doses from 0.1 to 10.0 mg/kg SCW~S in gmqx

of

mice

(each N = I?). Injections (indic:!rcd hy arrow) of vchiclc rquart?i) llr cimr% +.Tfabcrarnil or di;lzcplm wcrc given i.n. circles.

arepam.

I

mg/kg

dia7epam.

Filled lrianplrs.

I mg/kg

Open

triangles,

ahecarnil.Filled

ahecarnil.

2 mg/kg

Ji-

circles. 2 mg/kg

(Crabbe et al., 199lb). In addition, many other drugs including psychostimulants, direct and indirect GABA antagonists. the calcium channel agonist BAY K 8644, corticosteronc, and excitatory amino acid receptor agonists, clcvatc

handling-induced

convulsions

in WSP

XY

mice (Crabbe et a!., 1991b; Roberts et a!., 1991; Crabbe and Kosobud, 1990; Phillips and Crabbe, 1991). Abecarni! clearly antagonized handling-induced convulsions, both in ethanol-withdrawing and naive mice, thus resembling drugs with central nervous system depressant effects (Crabbe et a!., 199la; Kosobud and Crabbe, 19861, and several other anticonvulsants (Crabbe and Kosobud, 1990; Phillips and Crabbe, 1991). In Experiment 4, we saw no signs that withdrawal from a single dose of abecarni! or diazepam led to a rebound exacerbation of handling-induced convulsions. This agrees with unpublished data with diazepam in our laboratory. WSP mice are extremely sensitive to such acute withdrawal effects, which are easily seen after ethanol (Crabbe et a!., 1991a; Kosobud and Crabbe, 1986), t-butano!, pentobarbita!, and acetaldehydc (Kosobud and Crabbe, 1986). Earlier studies had reported that cessation of thrice daily administration of 5 mg/kg abecarni! to rats led to no marked signs of spontaneous withdrawal during several days after trcatment Uscher et a!., 1991). and 6 weeks of daily administration of 4 mg/kg to dogs produced no spontaneous withdrawal reaction even when f!umazeni!-prccipitated Escher et a!., 1990). Thus, existing data suggest that the risk of physical dependence on this compound is relatively low. Comparison of the results seen in Experiments l-3 with published literature suggests that the effects of abecarnil against alcohol withdrawal may be dissociable from its genera! anticonvulsant effects. while the same would apparently not be true of diazepam. The cffectivc dose for producing sedative effects in mice clearly depends upon the specific test employed, and probably on the strain of mice. Nonetheless, when the hanging wire and rotarod tests of ataxia were employed in NMRI strain mice (Stephens et a!., 19901, the ED+ for abecarni! were 38 and > 100 mg/kg, respectively; for diazepam, the comparable values were 0.99 and 14 mg/kg, respectively. Our studies showed efficacy of both of these compounds against alcohol withdrawal at doses no higher than 4 mg/kg. In conclusion, abecarni! or diazepam, given to genetically WSP mice at the peak zf chronic ethanol withdrawal, significantly reduced handling-induced convuision scores. While abecarni! was somewhat more potent than diazepam, its effects were shorter-lasting. Similar results were seen in an cxpcrimcnt where withdrawal was assessed after a single high-dose ethanol injection. Abecarni! and diazepam also inhibited the lower handling-induced convulsion scores seen in naive mice, indicating that this convulsive sign in mice is sensitive to anticonvulsants. Single administrations of diazcpam or a!?ccarni! did not lcad to spontaneous withdrawal-induced increases of handling-inducetl CcJI1vu!sion severity. Doses of abecarni! effective in reducing withdrawal handling-induced convulsion scores

were lower than published values for tests of ataxia, suggesting that it might be possible to dissociate the antiwithdrawal and ataxic effects of abecarni!.

Acknowledgments These studies were supported ment of Veterans AAOXb2I.

Affairs.

DAtii22X).

I thank Catherine

by a grant from the US Depart-

by grants from

and USPHS-NIDA

Merrill

the USP!IS

Contract

(AAO624.3.

No. 271-90-7405.

for her expert help with these experiments.

and Drs. David N. Stephens and Graham Jones (Schering-Berlin)

for

their comments on the manuscript.

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Antagonism of ethanol withdrawal convulsions in Withdrawal Seizure Prone mice by diazepam and abecarnil.

Abecarnil, a beta-carboline acting at benzodiazepine receptors, has been shown to have anxiolytic and anticonvulsant properties in a number of models...
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