Comparison of stimulants and hallucinogens on shuttle avoidance in rats

Gen. Pharmac. Voi. 18, No. 2, pp. 123-128, 1987 Printed in Great Britain. All rights reserved

0306-3623/87 $3.00+0.00 Copyright © 1987 PergamonJournals Ltd

COMPARISON OF STIMULANTS A N D HALLUCINOGENS ON SHUTTLE AVOIDANCE IN RATS W. M. DAVIS and H. T. HATOUM* Department of Pharmacology, School of Pharmacy University of Mississippi, University, MS 38677, U.S.A. [Tel: (601) 232-7330] (Received 11 July 1986)

Rats were trained to a high level of performance of a conditioned avoidance response in a shuttlebox to test effects of several classical stimulants in comparison to a variety of hallucinogens. 2. A previously-reported biphasic pattern of effects of mescaline on shuttle avoidance was replicated and extended to 12 other hallucinogens of both phenylethylamine and indolealkylamine classes. 3. Response patterns of hallucinogens could be differentiated from 3 stimulants and from a methoxyamphetamine compound that lacks hallucinogenic activity. Abstract--l.

INTRODUCTION Early psychopharmacological studies of mescaline showed that it impaired the performance of a shuttlebox conditioned avoidance response (CAR) by welltrained rats (Courvoiser, 1956; Chorover, 1961). Later it was noted by Smythies and Sykes (1964) that mescaline actually had a dual action on the CAR that often was manifested in a biphasic response over time. Thus, early in a 2 hr C A R test session, the response latency rose above the control level, as did also the number of shocks received, whereas later in the session the rats regained a normal avoidance rate and showed below-normal response latency. However, inter-individual variability was marked as some animals showed increase or decrease in response time. Specifically, 5 were hiphasic, 2 mainly increased and 2 mainly decreased response time. Variability was even greater for a 12.5mg/kg dose. In a second experiment, the authors reported data separately for subjects showing higher and lower responses to 25 mg/kg of mescaline. That the same close of mescaline could act both to disrupt and to facilitate C A R performance was further demonstrated by Gorelick and Bridger (1977), who found disruption of the C A R in good performers and facilitation of the C A R in poorperforming rats. Whereas many researchers have tended to emphasize the behavioral inhibition produced by hallucinogens, Bridger (1973) has suggested a greater significance for the excitatory component of the action of mescaline, as analogous to its psychotomimetic effects clinically. A noteworthy finding of Gorelick and Bridger (1977), confirming earlier data of Smythies and Sykes (1966), was the absence of a dual action for the chemically-related but nonhallucinogenic homolog of mescaline, 2,4-dimethoxyphenylethylamine (DMPEA), which produced disruption but not facilitation of shuttle avoidance *Present address: Department of Pharmacy Practice, College of Pharmacy, University of Illinois at Chicago, 833 S. Wood Street, Chicago, IL 60612, U.S.A.

in rats. In order to extend works such as those of Smythies and Sykes (1964), Gorelick and Bridger (1977), and others, we have tested several stimulant and hallucinogenic compounds for mescaline-like properties relative to shuttle avoidance performance in rats. This is particularly of interest as the validity of the frequently used discriminated Sidman avoidance procedure and Bovet-Gatti profiles for distinguishing hallucinogenic and stimulant activities has been questioned (Calil, 1978). MATERIALS AND METHODS

Animals Subjects were Sprague-Dawley derived male rats weighing about 160g at the beginning of the training period. Food and water were available ad libitum except during experimental sessions. Drugs Agents used in the present study were: ( + )-amphetamine sulfate (AMP; SK&F); methylphenidate (MPD; CibaGeigy); ( - )-2-amino- l-(2,5-dimethoxy-4-methylphenyl) butane (BL-3912A; Bristol Labs); mescaline HCI (MES; Sigma Chemical Co.); cocaine HCI (COC); ( _+)-4-methoxyamphetamine HCI (PMA); (+)-3,4-methylenedioxyamphetamine HC1 (MDA); (_)-2,5-dimethoxyamphetamine HCI (DMA); (+_)-2,5-dimethoxy-4-methylamphetamine HCI (DOM); (_)-2,4,5-trimethoxyamphetamine HCI (TMA-2); ( +_)-4-bromo-2,5-dimethoxyamphetamine HBr (DOB); ( __.)-2-methoxy-4,5-methylenedioxyamphetamine HCI (MMDA-2); (+)-lysergic acid diethylamide tartrate (LSD); dimethyltryptamine fumarate (DMT); diethyltryptamine HCI (DET); 5-methoxydimethyltryptamine (5MDMT); and psilocybin (PSI). All but the first two agents were provided by the Division of Research, National Institute on Drug Abuse. Solutions were prepared in isotonic saline and injected intraperitoneally (i.p.) in a volume of 1.0 ml/kg body wt. Doses expressed in terms of the salts were: 1.25 and 2.5mg/kg of AMP; 2.5 and 10mg/kg of MPD; 10mg/kg of COC; 5 and 10mg/kg of BL-3912A; 12.5, 25 and 50 mg/kg of MES; 5 mg/kg of both PMA and MDA; 0.625 and 5 mg/kg of DOM; 5 and 10 mg/kg of TMA-2; 0.62, 2.5, 5 and 10 mg/kg of DOB; 5 mg/kg of MMDA-2; 0.62, 0.125, 0.8 and I mg/kg of LSD; 5 and 10 mg/kg of DMT; 10 mg/kg of DET; 0.62 and 2.5 mg/kg of 123

W. M. DAVIS and H. T. HATOUM

124

5 M - D M T ; and 5 and I0 mg/kg of PSI. Selection of these doses was based primarily on our prior behavioral testing of these agents, i.e. for effects of various doses on m o t o r activity of rats (unpublished data), plus n u m e r o u s literature references on behavioral doses o f the agents tested.

Apparatus and test procedures The chamber used in this escape-avoidance procedure was BRS/LVE No. 146-04 floor-toggle shuttlebox (dimensions in cm: 45.5 long, 20 wide, 19.5 high). The unconditioned stimulus (US) was a 1.0 m A a.c. constant current scrambled shock delivered through the grid flooring. The 2.5 K H z auditory stimulus (CS) used as the warning signal was delivered by a 112-01 Sonalert positioned in the ceiling directly above the center of the chamber, which was used without a barrier between the halves. A procedure modified from that reported by Smythies and Sykes (1964) was used. O n the first day of training, each rat was placed in the shuttlebox for 10 rain. Subsequent to this adaptation period, a 2.5 hr training period was initiated. Such training periods were run 5 days per week. Each session was divided into five blocks of 20 trials each, separated by a 5 min time-out period. The trials were presented on a variable time one minute (VT 1") schedule. A trial consisted of a 5 sec CS presentation followed by a 15 sec US presentation during which time the CS continued. The animal could avoid shock by crossing to the other half of the shuttlebox during the 5 sec warning signal. W h e n this response was not made during the 5 sec signal, shock was delivered through the grid floor. The animal could then escape the shock by crossing the center line. W h e n neither an avoidance nor an escape response was made, both US and CS were terminated automatically 20 sec following onset of the CS. Rats were trained in the shuttlebox until they achieved a high O.e. >~80% avoidance on two 100-trial sessions) and stable (~<10% difference between the two days) baseline avoidance performance on two consecutive days. Although the n u m b e r o f sessions to reach this criterion varied, a 10-day period was normally adequate. U p o n satisfaction of the stated criterion, a two-day drug test was implemented. On the first treatment day, each rat was placed in the chamber as usual and one block o f trials was run. After being removed from the shuttlebox and injected i.p. with 0.9% saline, the rat was then returned to the chamber, and the usual 2 . 5 h r session was begun, This procedure was repeated on the next day, but with a selected dosage of a test drug substituted for the saline injection. During each block of trials, the following parameters were recorded: the number o f shocks received, the n u m b e r ofintertrial responses (i.e. crossing when neither CS nor US was present), the n u m b e r of avoidance responses and the latency o f response (i.e. time from CS onset to crossing to the uncharged half o f the box). Statistical analyses on avoidance responses and l a t e n c i e s were carried out between drug-treated and saline control groups using the Wilcoxon matched-pairs signed-ranks test (Wilcoxon and Wilcox, 1964). The number o f intertrial responses observed following treatment was compared to the corresponding control values using Student's t-test. a

RESULTS I n this s t u d y , a t t e n t i o n h a s b e e n g i v e n to t h e responses under drug treatment of individual subjects, f o l l o w i n g t h e e x a m p l e o f S m y t h i e s a n d S y k e s (1964) f o r m e s c a l i n e in C A R r e s e a r c h . T h e s e a u t h o r s classified s u b j e c t s b y t h e i r r e s p o n s e i n t o either o f t w o g r o u p s , b u t we h a v e e x p a n d e d o n this to e m p l o y f o u r g r o u p i n g s b y r e s p o n s e p a t t e r n . Similarly, in evaluating various psychotropic drugs including h a l l u c i n o g e n s in t h e d i s c r i m i n a t e d S i d m a n a v o i d a n c e

p r o c e d u r e , Calil (1978) f o u n d it e x p e d i e n t to segregate individuals into three typical classes by response profiles, p l u s a g r o u p o f s u b j e c t s s h o w i n g " n o n typical" responses. The value of individual-animal a n a l y s i s in b e h a v i o r a l p h a r m a c o l o g y h a s also b e e n r e c o g n i z e d b y Will a n d C h e c c h i n a t o (1973) c o n cerning stimulant drug action on operant behavior. I n d i v i d u a l v a r i a t i o n s in e m o t i o n a l i t y a r e k n o w n to i n f l u e n c e b e h a v i o r a l r e s p o n s e s to p s y c h o t r o p i c d r u g s ( V a h e l l i a n d B e r n a s c o n i , 1971). T h u s , o u r 4 - w a y c l a s s i f i c a t i o n w a s as follows:

Type A: b i p h a s i c p a t t e r n , initial i n c r e a s e in response latency followed by a decrease, with tendency f o r a c o r r e s p o n d i n g d e c r e a s e a n d i n c r e a s e in a v o i d ance proficiency; Type B: n o n - b i p h a s i c w i t h i n c r e a s e in r e s p o n s e l a t e n c y a n d r e d u c t i o n in a v o i d a n c e ; Type C: " i n v e r t e d b i p h a s i c " p a t t e r n , initial d e c r e a s e in r e s p o n s e l a t e n c y f o l l o w e d b y a h i n c r e a s e , w i t h t e n d e n c y f o r c o r r e s p o n d i n g i n c r e a s e a n d dec r e a s e in a v o i d a n c e ; Type D: n o n - b i p h a s i c w i t h d e c r e a s e in r e s p o n s e l a t e n c y a n d t e n d e n c y to i n c r e a s e a v o i d a n c e . Use of this classification process permits examination of the results for a predominance of one or another type of response under treatment with each d o s e o f e a c h d r u g tested. S u c h a n a n a l y s i s is p r e s e n t e d in T a b l e 1.

l. Number of rats showing each of four response patterns in 200-trial shuttlebox a v o i d a n c e s e s s i o n after drug treatment Difference

Table

in

Drug (mg/kg

dose)

AMP (1.25) (2.5) MPD (2.5) (10) COC (10) MES (I 2.5) (25) (50) PMA (5) MDA (5) DMA (5) (10) TMA (5) (10) DOM (0.62) (5) DOB (0.62) (2.5) (5)

MMDA-2 (5) LSD (0.062) (0.125) (0.8)

(I) DMT (5) (10) 5-M-DMT(0.62) (2.5) DET (10) PSI (5) (10)

No. of rats per response type A% B C D --6 2 ---8 1 -3 4 --4 6 1 -6 1 2 2 5 -1 -7 -8 ---8 . . . . 8 . . . . 3 -5 -7 -2 -2 4 -2 7 1 --1 -5 -8 ---7 --I 4 4 ---

intertrial responses treatedcontrol 73 366* 72 335* 83* 5 34 33 7 9 3 -22 - 22 95 31 14 48 35

2

6

--

--

-6

4 -2

4 4 5

-4 1

1 ---

4

4

--

--

6 5 4 7 4 8 7

2 3 4 1 2

3 --1 --

2

l ---2 . --

7

--

- 2 - 2 -8 Il 10 --- 16 5 -14 - 85 - 16

I

.

.

. ---

"}'See text for description of response patterns A-D. *Significant difference (P <0.05) between treated and control groups.

Hallucinogenson avoidance Table 2. Summaryof shuttlebox responses to known stimulants and hallucinogens and comparison to a non-hallucinogenichomolog No. (and %) of rats per responsetype Treatment A B C D (A) Stimulants 2 (5) -19(45) 21 (50) (B) Hallucinogens 120(55) 55(25) 32(15) 10(5) (C) BL-3912A 2(13) -13(81) I (6)

The Type A biphasic response pattern ( = Class I of Smythies and Sykes, 1964) was the only response at 5 out of the 26 doses of all drugs tested and was the predominant response in 8 further ones for a total of 13/26. For 4 other doses, the majority response was Type C, the "inverted biphasic" pattern. For 3 doses the Type B response (only increased latency) was in the majority. In no case was there a major proportion of animals in the Type D response, only a decreased response latency, which corresponds best to the Class II response of Smythies and Sykes with a lower dose (12.5 mg/kg) of mescaline. However, a small number of rats showed the Type D response in 6/26 possible doses. For the 3 stimulants tested at 5 doses, the inverted biphasic (Type C) pattern was the predominant one for 2 doses, while in the remaining 3 it was the Type D pattern. However, there were 2 subjects, 1 each for methylphenidate and cocaine, that showed the "mescaline-like" biphasic Type A pattern. Type B responses were lacking for the stimulant drugs. Table 2 compares the total number of subjects for all stimulants and all hallucinogens tested showing each of the 4 response patterns. The rats treated with stimulants gave Type C or D responses in 87% of subjects, whereas rats receiving hallucinogens showed Type A and B responses 80% of the time. Also included for comparison are the data for compound BL-3912A, a non-hallucinogenic methoxyamphetamine, which clearly match the data for the stimulants much more than those for the hallucinogens. A presentation of intertrial response data for the drug treatments, as different from the saline control value, is included in Table 1. Significant increases in intertrial responses occurred consistently only among the stimulant group. Some suggestions of an increased intertrial activity were seen for the hallucinogens, but most such cases were not statistically significant, often having quite high variance when the mean difference from saline values was high. Representative group data to supplement that which appeared in a prior preliminary presentation (Davis et al., 1976) are shown in Fig. 1, based on only subjects having the same (predominant) response type. DISCUSSION Most of our subjects receiving a low dose (1.25 mg/ kg) of ( + )-amphetamine exhibited responses characterized by an initial excitatory phase, which lasted for almost two hours, followed by an inhibition, seen in the response latency. A biphasic effect of this sort by amphetamine on the CAR has rarely been reported, probably because most studies do not include a sufficiently long post-treatment interval, or because the procedure of dividing the experimental session

125

into several blocks has not been commonly used. In fact,ifthe present amphetamine data were combined over blocks, the biphasic effect would be obscured because of the magnitude of the initialfacilitation. Bovct and Oliverio (1967) reported that during long avoidance sessions (2500 trials)after treatment with amphetamine, a performance decrement appeared after the first500 trialsin both naive and previouslytrained mice, although theirescape response remained at 100%. Increasing the dose of amphetamine to 2.5 mg/kg caused a uniform improvement of performance shown by a significant decrease in response latencies below saline values at all intervals, which was not, however, accompanied by an increase in number of avoidances. The significant increase in exploratory activity between trials on treatment day over saline day is indicative of the general excitatory effect of amphetamine. It is interesting that with increasing doses of amphetamine the pattern of response shifted from the "inverted biphasic" pattern to only a facilitation of responding. The single dose of cocaine tested gave predominantly the "inverted biphasic" response pattern as did the lower dose of amphetamine. In another study (Torrelio and Izquierdo, 1976), the same dose of cocaine produced only an increase in percent avoidances and decrease in latency of response over a 2 hr test session. In contrast to amphetamine, increasing doses of mescaline shifted the pattern in a completely opposite fashion; it progressively altered the behavioral pattern from predominant facilitation in low to moderate doses to the biphasic "hallucinogenic pattern" of disruption-facilitation seen with higher doses. Our results indicate, in accord with those of Smythies and Sykes (1964), that a lower dose (12.5mg/kg) produced a greater excitatory effect; however, the dose that produced the biphasic pattern in our study is twice as high as the one reported in their study, but similar to one used by Bridger and Mandel (1971). Such a discrepancy could well result from a strain difference in sensitivity. The biphasic temporal pattern we found with mescaline at the highest dosage was quRe consistent with that of Smythies and Sykes (1964). Our results indicate that PMA, MDA and DOM at 5mg/kg as well as TMA-2 and DMA at l0 mg/kg each exerted a behavioral effect closely resembling the biphasic pattern of mescaline. Lower doses of DOM and DMA produced predominantly Type C, a response pattern shared by lower doses of ( + )-amphetamine and mescaline. In this respect, our results for DOM are in accord with its characterization as a euphoriant in humans at low doses and a hallucinogen at high doses (Snyder et al., 1967), properties also indicated by the Bovet-Gatti profiles for discriminated Sidman Avoidance in rats (Beaton et al., 1969). The doses of DOM found to show the hallucinogenic pattern in the present study and in that of Beaton et aL (1969) were similar, but for the amphetamine-like response our dose of DOM was one-half that of the prior report. The present findings on DMA are compatible with its characterization in humans (Shulgin et al., 1969) as having hallucinogenic activity and pharmacological effects similar to those produced by LSD in

126

W . M . DAVIS and H. T. HATOUM

• AMP(1.25mg/kg)

• AMP(2.Smg/kg)

• Saline

• Saline

3.75-

I

• ., .

2.5-

J

~

/,,m

m

"'..,,, .............• ............ m.'

t~ Z 1.25-

i

i

i

!

i

/

I ®

® F .....

1 • DOM (0.625 rng/kg) • Saline 3,75-

• DOM (5 mg/kg) • Saline

m

• ,.......,_~,

2.5-

,~.............. ..............,....

; ~

~ 1.25-

!

0 =.

20

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15 L

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. . . . 2

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3

4

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5

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3

4

• BL-3912A(5mg/kg) • Saline

• ~L-3912A(lOmg/kg) • Saline

........... ~,~....,

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3.75-

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~ 2.5Z

1.25=

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l BLOCKS

BLOCKS

Fig. 1. Representative time-effect curves as both response latency and number of avoidances over the five blocks of a 200-trial shuttle avoidance session. Values plotted as mean ( _+ SEM) of all 8 subjects tested when only a single response type occurred, or all subjects showing a predominant response type (N = 5-7). Asterisks indicate significant deviations of treated from control values. The upper 4 blocks present ( + )-amphetamine, 1.25 mg/kg (Type C) and 2.5 mg/kg (Type D). The middle 4 blocks present DOM, 0.625 mg/kg (Type C) and 5 mg/kg (Type A). The lower 4 blocks present BL-3912A, 5 and l0 mg/kg (Type C responses).

127

Hallucinogens on avoidance animals (Vaupel et al., 1977), but conflict with one report (Bradley and Johnston, 1970), that it produced only an amphetamine-like profile, and with another on its lack of effect (Smythies et al., 1969). We found not only a stimulant-like effect in low doses, but also a high-dose mescaline-like response in higher dosage. Our findings with PMA concur with its characterization as a true hallucinogen (Smythies et al., 1967a). Reports that TMA-2 and M D A possess hallucinogenic activity in humans (Shulgin et al., 1969) and analogous properties in animals (Smythies et al., 1967a) are supported by the present finding of a close similarity between effects of these agents and of mescaline. The ~-methyl analog of DOM, BL-3912A, is classified as a partial agonist at serotonergic receptors (Dyer, 1976) and is reported to improve performance while lacking hallucinogenic activity in humans (Standridge et al., 1976). Our data for it give a favorable correlation because BL-3912A lacked the mescaline-like response seen after the other methoxysubstituted amphetamine derivatives tested. In this respect our results are in accord with the finding of Rusterhoiz et al. (1977), that BL-3912A failed to alter significantly the behavior of cats, whereas DOM, DOB and D M A had effects like those seen with classical hallucinogens. Earlier reports showed differences between amphetamine and BL-3912A on avoidance behavior of rats with low baseline performance (Tilson et al., 1977) or when the acquisition of conditioned avoidance behavior in rats was tested (Standridge et al., 1976), but the present study did not differentiate the behavioral response to BL-3912A from that to a lower dose of (+)-amphetamine. Higher doses of BL-3912A were not tried because Tilson et al., (1977) indicated that no reliable data resulted when such doses were tested. D M T and its 5-methoxyl analog have been compared by Stoff et al., (1978) to mescaline for their effects on shuttlebox avoidance of rats. They reported a difference for these agents from mescaline in their lack of the facilitative component of the latter. However, our data show no difference between the two DMT's and the responses to mescaline. This is more in accord with the earlier study of Smythies et al. (1967b) that found both 5-M-DMT and DMT to show a biphasic mescaline-like effect on shuttle avoidance of rats. All the recognized hallucinogenic agents we tested showed a temporally biphasic pattern of effects at some dose level on shuttle avoidance in trained rats. This lends some support to the inference of Smythies and Sykes (1964) that this behavioral pattern is characteristic of hallucinogenic agents. However, our data fail to support an absolute differentiation in that some rats also showed the biphasic response when treated with classical stimulants or with a non-hallucinogenic methoxyamphetamine derivative. Furthermore, some doses of hallucinogens caused significant numbers of rats to respond with "stimulant-type" responses. These deviations may reflect appropriately an overlap in certain properties of the two pharmacologic classes. Whereas psychomotor stimulants may have only excitatory properties acutely, there are well-known occurrences of hallucinatory psychotic responses to repeated doses of G.P. Ig/2--B

amphetamine (Angrist and Gershon, 1970; Gritfith et al., 1972; Bell, 1973) and cocaine (Post, 1975), plus limited reporting of hallucinations or bizzare feelings after methylphenidate (Danielson et al., 1981). Human observations are supported by animal experimental findings in the case of chronic amphetamine (e.g. Nielson et al., 1980; Ellison et al., 1981). The present study was to evaluate the selectivity of shuttle avoidance behavior in discriminating between the psychomotor stimulants and mescaline and other hallucinogens. It was not extended to detecting possible similarities in CAR effects of these agents with tranquilizers, analgesics, or hypnotics in their behavioral effects as Calil (1978) did. Other such agents might have shown some similarities in effects on CAR to those reported here for stimulants and hallucinogens. We do not have evidence at this point to contend for an absolute utility of shuttle avoidance as a selective method for discriminating hallucinogenictype properties. Yet, as part of a battery of testing approaches, it seems that it would have significant value. Thus, our conclusion in this respect may be rather similar to that of Calil (1978) regarding the standing of the discriminated Sidman avoidance test.

SUMMARY

(1) Rats trained to a high proficiency in a shuttle avoidance procedure were tested for the comparative effects of three psychomotor stimulants and 12 agents recognized as hallucinogens in man. These 12 drugs included mescaline and 7 methoxyamphetamine derivatives plus LSD and 4 other indolealkylamine derivatives. Additionally, one non-hallucinogenic methoxyamphetamine compound was tested. (2) Behavioral responses were analyzed by individual subjects as to concordance with four response types or patterns of change in C A R latency. Two such types included 87% of all rats receiving stimulants. The other two types were those including 80% of all rats treated with hallucinogens. Thus, there tended to be two behavioral patterns associated with stimulants and two other behavioral patterns associated with hallucinogens. (3) The non-hallucinogenic methoxyamphetamine showed a response pattern matching that of the stimulants rather than the hallucinogens. However, a minority (5%) of rats receiving stimulants showed the one response pattern most associated with hallucinogens, and 20% of rats treated with hallucinogens showed the two behavioral responses most associated with psychomotor stimulants. (4) Therefore, absolute specificity of discrimination between the two classes was not achieved through this behavioral test. The results may reflect an overlap of properties between the members of the two classes. Nevertheless, there appears to be significant usefulness to this behavioral testing procedure.

Acknowledgements--This research was supported by NIDA contract ADM-45-74-107, and in part by the Research Institute of Pharmaceutical Sciences, the University of Mississippi. We are grateful to Judy Richey and Edith Pritchard for secretarial assistance.

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