Psychopharmacologia (Berl.) 36, 281--290 (1974) �9 by Springer-Verlag 1974

The Behavioral Pharmacology of Sch 12679. A New Psychoactive Agent*

Allen Barnett**, Rober t I. Taber, and Solomon S. Steiner***

Department of Pharmacology, B.iological Research, Schering Corporation Bloomfield, New Jersey

Received September 10, 1973; Final Version February 7, 1974

Abstract. Sch 12679, N-methyl-Lphenyl-7,8-dimethoxy-2,3,4,5-tetrahydro-3- benzazepine maleate, is active in a broad spectrum of laboratory models of aggres- sive behavior without producing any signs of neurotogic impairment up to lethal doses. Sch 12679 is an effective inhibitor of isolation-induced aggression in mice, murieide and septal lesion-induced aggression in rats and spontaneous aggression in Rhesus monkeys. Sch 12679 also antagonizes methamphetamine aggregate toxi- city in mice and hypothalmic self-stimulation in rats as do major tranquilizers; however, it differs from major tranquilizers in that it does not affect conditioned avoidance response (CAR) performance or produce catalepsy, ptosis or hypothermia. ~%h 12679 does not fit into established profiles for either minor or major tranquili- zers or other existing types of psyehopharmacological agents. Initial clinical studies have confirmed that Sch 12679 reduces aggressive behavior without producing con- comitant sedation.

Key words: Sch 12679 -- Benzazepine -- Aggressive Behavior.

Ini t ial clinical studies have demonstra ted tha t Sch 12 679 significantly reduced aggression in behavioral ly dis turbed adolescents (Itil et al., 1972) and in acute schizophrenics (Park et al., 1972) wi thout producing con- comitant sedation. Another clinical s tudy was performed at much higher doses in chronic schizophrenics wi thout the incidence of significant sedation (Keskiner et al., 1971).

Sch 12679 is a new compound which is no t chemically related to existing classes of psychoact ive drugs (Fig.l) . Sch 12679 specifically reduces aggressive and hyperact ive behaviors in a wide range of labora- t o ry tests in various species, wi thout producing signs of overt CNS depression or neurological impairment . As such, Sch 12679 possess a

* A preliminary report of this work was presented to the American Society for Pharmacology and Experimental Therapeutics in San Francisco, California, July 23--28, 1972.

** Present address: Research Institute on Alcoholism, 1021 Main Street, Buffalo, New York 14203.

*** Present address: Department of Psychology, City College of New York, New "York.

19 Psychopharmacologia (Berl.), u 36

282 A. Barnett et al.

Sch 12679 MALEATE

CH,~O.~ ~ ' . , . . . . / " - " -~

COOH

,CHLORDIAZEPOXIDE HYDROCHLORIDE (LIBRIUM)

NHCH s I f'T.-C\c

C I ~ C = N / H2 �9176 �9 HCl

Fig. 1

PERPHENAZINE DIHYDROCHLORIDE (TRILAFON)

I cs2 CH2 !

cs2

() CH20H

�9 2 H C I

pharmacological profile which is unl ike t h a t of a n y exist ing class of psyehopharmacological agents, e.g., ant idepressants , sedat ive-hypnotics , s t imulants , ma jor t ranqui l izers and minor t ranquil izers .

The following repor t will describe some of the behavioral effects of Sch 12 679 which led to its use in clinical aggressive states.

Methods CF No. 1 male mice (18--22 g), Charles River C-D male rats (180--300 g) and

male Rhesus monkeys (7--10 kg) were used in the present studies except as other- wise noted. All studies were performed with the mealate salt of Sch 12679, the dihydrochloride salt of perphenazine and the hydrochloride salt of chlordiazepoxide. All doses were calculated in mg/kg of free base. All treatments were given as aqueous solutions except for very high doses of Sch 12679 maleate which were administered as suspensions in a 0.5 ~ aqueous carboxymethyleellulose vehicle. Injection volumes of 20 ml/kg (for oral route in mice), 10 ml/kg (for i.p. route in mice), and 1.0 ml/kg (for all routes in other animals) were used. All EDso'S and 95% fiducial limits were calculated by probit analysis (Finney, 1962).

Antagonism o/Isolation-Induced Fighting in Mice. A modification of the method of Yen et al. (1959) was used. Isolated mice were tested for aggression by placing one isolated mouse into the home cage of another 30 min after saline or drug adminis- tration. The presence or absence of aggression was measured (on a blind basis) over a 3 min period. All pairs of mice used for drug studies fought when tested on the

Behavioral Pharmacology - - Sch 12679 283

previous day. As a measurement of neurological impairment , isolated mice were placed wi th all four paws on the f ront of their cage, and those mice falling off were considered to be neurologically impaired. Mice were tes ted for impairment imme- diately before being tested for aggression. The data for bo th anti-aggressive act ivi ty and neurologie impairment were expressed quantally.

Antagonism o[ Muricide Behavior in Rats. Male hooded Long-Evans ra ts weighing between 250 and 300 g were preselected for their abili ty to kill mice within 2 min af ter exposure on 3 consecutive days. Ra ts were tested for muricidal behavior 30 min prior to drug t rea tment and a t 30 and 60 rain after i.p. injection of tes t drug or saline. As an index of neurological impairment, ra ts were tested for their abil i ty to s tay on an inclined screen (45 ~ angle) wi thout sliding or falling, immediately prior to being tested for antimuricide activity. The data used for calculating the EDs0's were obtained 60 min post-drug.

Antagonism of Aggression in Septal-Lesloned Rats. Male hooded Long-Evans rats, weighing 250--300 g were used in this study. Bilateral electrolytic lesions were placed in the septal area of the brain according to the method of Stark and Hender- son (1966). Animals were tested for aggressiveness 1 week post-surgery by grading the reaction to presentat ion of two inanimate objects, a pencil and a glove, to the tail-restrained rats. Reactions were graded as follows: 0 = indifference to ei ther object ; 1 = nibbling of one or bo th objects; 2 ----- vigorous a t tack of ei ther object ; and 3 = vigorous a t tack of bo th objects (Malick et al., 1969; Sofia, 1969). Only those animals which received a score of 3 (maximum score) were used for the drug studies. Animals were tested 30 rain prior to s tudy and 60 rain after i.p. adminis t ra t ion of tes t drug or saline. Animals which showed a 0 or 1 score were considered to show a block of aggression. All measurements of aggression were performed in a bl ind manner. Ra ts were tested for their abili ty to stay on an inclined screen for 60 rain post-drug, immediately prior to being tested for aggression.

Taming Action in Aggressive Monkeys. Monkeys were pre-selected for aggressive- ness and stabi l i ty of response in two control sessions after subcutaneous saIine administrat ion. The aggressive behavior of male Rhesus monkeys was quantified using a modification of the rat ing system of Heise and Bog (1961). The aggressive level of each monkey was assessed on a blind basis. Percent reduction in aggression was calculated by the formula:

Control score -- drug score x 100.

Control score

Antagonism o] Methamphetamine Aggregate Toxicity in Mice. Test drugs were given to groups of 10 mice housed in covered plastic cages (30 • 15 • 13 era) 30 rain prior to an i.p. challenge of methamphetamine 10 mg/kg. The number of deaths in each group was counted 18 h later. Percent protection was calculated as follows:

No. of deaths in saline control group -- :No. of deaths in drug t reated group • 100] No. of deaths in saline control group

Antagonism o] Hypothalamiv SelJ-Stimulation in Rats. The hypothalamic self- s t imulat ion procedure used was t h a t previously described by Steiner and Stekely (1973). Each ra t was allowed to self-stimulate at intensities of 0.2, 0.4, 0.6, 0.8, and 1.6 mA w i t h a period of 10 rain allowed at each intensity. For bo th control and drug studies, da ta from only the last 5 rain a t each intensi ty were used. The ra te of st imu- lat ion was recorded before and 30 min after i.p. t r ea tment wi th the tes t drug. Two rats were used for each dose of tes t drug. At least 1 week was allowed between drug t reatments . The minimal effective dose was the lowest dose which reduced the self- s t imulat ion r a t e of bo th rats by more than 500/0 a t twice the threshold stimulus

19"

284 A. Barnett et al.

intensity (threshold is defined as the minimal intensity producing a response rate of greater than 50 responses/min).

E/leers of Drugs on Conditioned Avoidance in Rats. Groups of 10 rats were trained to avoid a 10 see, 0.8 mA footshoek by crossing a hurdle during a 10 sec warning period, indicated by a loud buzzer. Drug-induced avoidance errors were calculated as a percent of the saline control group according to the following formula:

saline group correct response -- drug group correct responses saline group correct responses

X 100.

Escape errors were calculated as percent of the total number of trials. All drug or saline treatments were administered i.p.

Results

Antagonism o/ Isolation-Induced Fighting in Mice. This f o r m of aggression results after prolonged periods of social isolation. Sch 12679 antagonized this behavior at doses which did not cause neurological impairment (Table 1). Perphenazine and chlordiazepoxide antagonized aggression at doses not significantly different from those producing neurologic impairment.

Antagonism o/ Muricide and Septal Lesion-Induced Aggression in Rats. Sch 12679 antagonized both muricide and sePtal lesion-induced aggres- sion in rats at doses which did not produce neurological impairment (Table 2). The antimuricide and septal lesion EDs0's for chlordiazepoxide did not differ from those producing ataxia. In contrast, perphenazine was a selective inhibitor of murieide but only inhibited septal ra t aggres- sion at ataxic doses. Sch 12679 and perphenazine were more potent antagonists of murieide t han scptal lesion-induced aggression whereas ehlordiazepoxide was equipotent vs the two behaviors (Table 2).

Antagonism of Aggression in Rhesus Monkeys. Selected Rhesus mon- keys display aggressive behavior when approached by an investigator. The da ta in Fig.2 indicate tha t Sch12679 (1.25--10.0 mg/kg, s.c.) reduced this aggression in a dose-related manner. The degree of neuro- logical impairment of these monkeys was assessed by carefully observing them for any gait impairment or other motor abnormalities during the t ime they were being tested for aggression. Sch 12679 produced a marked taming effect in these monkeys without any evidence of neurological impairment. The only abnormal effect of any kind in these monkeys was an increase in salivation, which seemed to parallel the taming effect both in potency and duration. In contrast, perphenazine, at a threshold dose (0.25 mg]kg, s.c.) for an antiaggressive effect, caused marked catalepsy and thus, its antiaggressive effect was not considered to be selective. Chlordiazepoxide did not reduce aggression significantly in the dose range tested, 2.5--10 mg/kg s.c. (Fig. 2). Chlordiazepoxide also failed to inhibit aggression in Rhesus monkeys by the i.p. route (Gluckman, 1965). The

Behavioral Pharmacology -- Sch 12679

Table 1. Anti-aggressive effects of Sch 12679 in isolated mice

285

lea EDso vs. isol.-induced Ataxia EDso fighting in mice (950/0 F.L.) (950/0 F.L.) in isolates (mg/kg, i.p.) (mg/kg, i.p.)

Sch 12679 20 14.6 (9.0--22.7) > 60 b Chlordiazepoxide 25 23.8 (18.0--37.7) 32.5 (21.4--49.4) :Perphenazine 30 1.0 (0.5--1.9) 3.0 (1.9--4.7)

a Number of pairs of mice receiving each drug. b Only 1 of 10 mice receiving 60 mg/kg, i.p. was unable to stay on the inclined

screen.

Table 2 Antagonism of muricide and septal lesion-induced aggression in rats by Sch 12679

N a EDs0 (950/0 F.L.) Ataxia EDso vs murieide behavior (950/0 F.L.) in rats murieidal rats

Sch 12679 40 5.6 (3.2--15.2) > 25 Chlordiazepoxide 40 18.7 (13.0--31.2) 17.2 (11.8--25) Perphenazine 25 0.9 (0.4--1.8) :> 10

~ a EDso (950/0 F.L.) Ataxia EDso vs septal-lesion (950/0 F.L.) induced aggression in septal rats

Sch 12679 31 22.2 (13.1--36.9) ~ 40 Chlordiazepoxide 23 14.1 (6.7--28.2) 8.2 (5.5--12.2) Perphenazine 23 4.5 (2.1--9.0) 7.0 (4.5--12.2)

a Number of animals used.

previously reported taming effects of chlordiazepoxide in monkeys (Randall et al., 1960) occurred after oral administrat ion.

Seh 12679 has been shown to be a selective antagonis t of all four models of aggressive behavior whereas neither perphenazine nor ehlor- diazepoxide exhibited this overall profile of selectivity. The next phase of investigation was devoted to characterizing the effects of Sch 12679 on behaviors other t han aggression.

Antagonism o/Methamphetamine Aggregate Toxicity. Major tranquili- zers are potent antagonists of methamphe tamine aggregate toxici ty (Janssen et al., 1965) whereas minor tranquilizers are ineffective (Gar- docki et al., 1966). Seh 12679 antagonized methamphe tamine aggregate toxic i ty at doses causing no overt depression or impairment (Table 3).

286 A. Barnett et aL

~ 3

6O

tlr

4C

" 7

o g 2c

n . - .

0 1.25 2.5 5.0 10,0

DOSE (mg/kg, S.C.)

~Fig.2. Effect of~qch 12679 (= . . . . e} and chlordiazepoxide ( a - - = ) on aggressive behavior in Rhesus monkeys, Each point represents the mean • S.N.M. and the

number of animals used per dose is parenthesis

Table 3. Antagonism of metham hp e~amine aggregate toxicity in mice and hype- thalamie self-stimulation in rats by Sob 12679

Treatment Antagonism of methamphetamine aggregate t~xicity in mice-minimal protective dose (MPD~0) a-mg/kg, p.o,

Antagonism of hypothalamie self-stimulation in r~ts-minimal effective dose (MED) b-mg/kg, i.p.

~r 12679 20.0 1.25 Perphena~ine 0.6 0,25 Chlordiazepoxide > 30 > 10

a Minimal dose (using 0.25 log nni~ increments) producing 50Q/0 or greater protection against metham]~het~mine group lethality. The dose of methamphet- amine used was 10 mg/kg, i.p.

b Doses administered were ~qeh 12679, 0.625, 1.25, 2.5 and 5.0mg/kg, i.p.; perphenazine, 0.125, 0.25, 0.5 and 1.0 mg/kg, i.p. ; and chlordiazepoxide, 10 mg/kg, i.p. Two rats were used for each dose of drug. The minimal effective dose was the lowest dose which reduced the self-stimulation rate of both rats by more than 500/o, measured at a current intensity which is twice threshold for each animal Threshold current intensity for each ray is defined as the minimal intensity producing a self- stimulation rate of greater than 50 bar presses per minute.

I n ag reemen t wi th ear l ier findings, pe rphenaz ine was a p o t e n t an t agon i s t o f th is effect whereas eh lord iazepoxide was ineffect ive (Table 3).

Hypothalamic Sell-Stimulation in Rats. Major t ranqui l izers are p o t e n t an t agon i s t s o f h y p o t h a l a m i e se l f -s t imula t ion whereas minor Sranquil izers

Behavioral Pharmacology -- Sch 12679 287

Table 4. Comparative effects of Sch 12679 and perphenazine on conditioned avoidance behavior in rats

Treatment Dose h r Percent Percent (mg/kg, i.p.) avoidance errorsa escape errors b

8ch 12679 2.5 4 2.5 0 10 4 12.5 0 30 6 9.6 0

Perphenazine 0.5 6 77,6 2.5 Perphenazine 2.0 6 100.0 55.0

a Drug-induced errors for ten trials given at the rate of one trial every 30 mln were calculated by the formula:

Saline group correct response -- Drug group correct response • 100 Saline group correct responses

b Percent failure to escape by jumping over the hurdle during the 10-sec foot- shock period (expressed as a percent of the number of trials).

are relatively ineffective in doses which do not produce ataxia or neuro- logical impairment (Dresse, 1966; Stark et al., 1969). Sch 12679 was a potent antagonist of hypothalamic self-stimulation as was perphenazine; chlordiazepoxide was ineffective (Table 3).

E//ects on Conditioned Avoidance Behavior in Rats. ~ a j o r tranquilizers are also potent antagonists of conditioned avoidance responses (CAR) (Janssen et al., 1965), and the effect of Sch 12679 was assessed on a simple hurdle-cross experiment in previously trained rats. Sch 12679 had little or no effect on CAI~ at a dose (30 mg/kg, i.p., Table 4) which is 24 times higher than tha t affecting hypothalamic self-stimulation (1.25 mg/kg, i.p., Table 3). In comparison, pcrphenazine almost completely disrupted avoidance behavior at a dose (0.5 mg/kg, i.p.) which is only twice the effective dose for antagonizing self-stimulation (Tables 3 and 4). This dose of perphenazine (0.5 mg/kg, i.p.) is also lower than the dose which antagonized both types of aggression in rats (muricide and septal lesion- induced aggression).

D i s c u s s i o n

Sch 12 679 is a novel chemical ent i ty with an interesting pharmaco- logical profile. The most striking effect of Sch 12 679 was the antagonism of four different models of aggressive behavior without evidence of neuro- logical impairment. Neither perphenazine nor chlordiazepoxide speci- ficaUy antagonized all of the four models of aggression. The selectivity of the antiaggressive effects of Sch 12679 compared to perphenazine and chlordiazcpoxide can be seen in Fig. 3, which summarizes their effects on aggression, neurological impairment and CAR in rats. Moreover, when

288 A. Barnett et al.

LOG DOSEOF Sch 12679 (mg/kg.' i=p.)

e~

N O ] I ~ I I IInJ I I r l ln , t z'lO0

+g [ A It ==~ o / r T , , . Ill +'DO[ !~ SEPTAL RATS ond MURICIDAL RATS'

. 101 <- v ~ r ICI r tlllll f l

LOG DOSE OF" PERPHENAZlNE ( rag/rag, i.p.]

0 1111[ t T I I I I r l [ I I I r t

10o[ SE~PTAL RATS

50 / &MURICIDAL RA'rs

10 ~ A ~ A N C E ERRORS

AVOIDANCE 51[• l i r ,=~--r ' -~"- - - '~_ , I~,,ll I IHII ] I

I0 1C0 0.5 I 10

r

il 1

Fig. 3. A summary of the effect of Seh 12679 (.

LOG DOSE OF CHLORDIAZEPOXIDE ( mg/kg, i.p.)

11~11111J

~ r ~ t t H t

O/RAT~ ~ SEPTAL /

/ / MURIClD.~L (=1 / RATS

/ I ,01~/ RA?' ' , 111l' IO 100

I I 50 .). perphenazine (, ,) and

chlordiazepoxide (= .) on muricide (first horizontal column), septal aggression (second horizontaI column), ataxia (third horizontal column) and CAR (fourth

horizontal column) in rats

gross observational techniques (Irwin, 1964) and body temperature measurements were used to s tudy Sch 12679 in normal (non-aggressive) mice and rats, Sch 12679 did not produce catalepsy, ptosis or hypo- thermia (unpublished data), as major tranquilizers are known to do (Janssen et al., 1965). Sch 12 679 actually had little effect on gross behavior in mice or rats and only produced ataxia at lethal doses (unpublished data).

The four models of aggression used in these studies have no obvious similarities. Four weeks of isolation are required to produce fighting in mice, and this occurs only in male albino mice (Valzelli, 1967). Muricide occurs spontaneously, in both male and females, and requires no special preconditioning (Karli, 1956). Both types of aggression are long-lasting and stable behaviors when established. Septal lesion aggression in rats involves a generalized state of hyperirritability produced by a brain lesion, occurs in both sexes, but the aggression only lasts for a short time (Brady and Nauta, 1955). Aggression in Rhesus monkeys, as we are using it, involves an aggressive response to a human and not all Rhesus

Behavioral Pharmacology -- Sch 12679 289

monkeys are aggressive unde r l a b o r a t o r y condi t ions. I n aggressive mon- keys , th i s behav io r is ve ry s table over t ime i f these monke ys are no t h a n d l e d too of ten b y the inves t iga tor . This behav ior requires no precon- d i t ion ing and involves obvious hyper i r r i t ab i l i t y . Thus, the re are m a n y differences among these four models of aggression and a selective an tago- n i s t o f all four t ypes of aggression raises the poss ib i l i ty t h a t there is a f inal common p a t h w a y b y which the m a n y forms of cl inical aggression can be reduced.

Sch 12679 is a b road spec t rum t ranqui l i z ing or an t iaggress ive agen t wi th min ima l sedat ive , au tonomic or neuro tox ie effects and should be a c l in ical ly useful p sycho the rapen t i c agent . The publ i shed cl inical repor ts on Sch 12679 (Kcskiner et al., 1971; I t i l et al., 1972; P a r k et al., 1972) have es tab l i shed t h a t i t is effective in two different popula t ions of aggressive pa t i en t s in doses t h a t are c lear ly no t sedat ive. Signif icant an t i -p sycho t i c or e x t r a p y r a m i d a l effects were no t seen in these cl inical s tudies .

Acknowledgements. The authors are especially grateful to Dr. Lewis A. Walter and Mr. Wei Chang for their excellent chemical support in the development of this compound. The authors gratefully acknowledge the assistance of Jeffrey Malick and Miklos Latranyi for some of the aggressive behavior studies and the technical assistance of Miss Joyee Dempscy, Mrs. Eleanor Doren, Mrs. Diane Keller, and Mrs. Jill Rendell. The editorial assistance of Mr. Paul Gittelson was greatly appre- ciated. The authors are grateful to Roche Laboratories for supplying the chlor- diazepoxide used in these studies.

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Finney, D. J. : Probit Analysis, 2nd Edition, Cambridge University Press 1962 Gardocki, J .F . , Schuler, M.E., Goldstein, L.: Reconsideration of the central

nervous system pharmacology of amphetamine 11. Influence of pharmacological agents on cumulative and total lethality in grouped and isolate mice. Toxicol. appl. Pharmacol. 9, 536--554 (1966)

Gluckman, M. I. : Pharmacology of oxazepam (serax), a new antianxiety agent. Curr. ther. Res. 7, 72i (1965)

Heise, G. A., Boff, E. : Taming action of chlordiazepoxide. Fed. Prec. 20, 393 (1961) Irwin, S.: Drug screening and evaluation of new compounds. In: Animal and

clinical pharmacologic techniques in drug evaluation, J. H. I~odine and P. E. Siegler, Eds., pp. 36--54. Chicago: Yearbook Medical Publi. 1964

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Janssen, P. A.J . , Niemegeers, C. J .E . , Schellckens, K. H. L. : Is it possible to predict the clinical effects of ncuroleptic drugs (major tranquilizers) from animal

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data ? Part 1: "Neuroleptic activity spectra" for rats. Arzneimittel-Forsch. 15, 104--117 (1965)

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i~Ialick, J. B., Sofia, R. D., Goldberg, M. E. : A comparative study of the effects of selected psychoactive agents upon three lesion-induced models of aggression in the rat. Arch. int. Pharmacodyn. 181, 459--465 (1969)

Park, S., Gershon, S., Floyd, A.: A clinical trial of a benzazepine (Sch 12679) in acute schizophrenic patients. Curr. thor. Res. 14, 298--302 (1972)

Randall, L.O., Schalleck, W., Heise, G.A., Keith, E .F . , Bagdon, R .E . : The psychosedative properties of methaminodiazepoxide. J. Pharmacol. exp. ther. 129, 163--171 (1960)

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Stark, P., Henderson, J. K.: Differentiation of classes of neurosedatives using rats with septal lesions. Int. J. Neuropharmacol. 5, 385--389 (1966)

Stark, P., Jurk, J. A., Redman, C. E., Henderson, J. K. : Sensitivity and specificity of positive reinforcing areas to neurosedatives, antidepressants and stimulants. J. Pharmacol. exp. Ther. 166, 163--169 (1969)

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Dr. Allen Barnett Research Institute of Alcoholism 1021 Main Street Buffalo, New York 14203 U.S.A.