Behavioral effects and metabolic fate of N,N-dimethyltryptamine in mice pretreated with β-diethylaminoethyl-diphenylpropylacetate (SKF 525-A), iproniazid and chlorpromazine

Pharmacology Biochemistry & Behavior, Vol. 8, pp. 351--356. Printed in the U.S.A.

Behavioral Effects and Metabolic Fate of N,N-Dimethyltryptamine in Mice Pretreated with/3-DiethylaminoethylDiphenylpropylacetate (SKF 525-A), Iproniazid and Chlorpromazine N A N D K U M A R S. SHAH A N D MARTHA P. HEDDEN 2

Ensor Foundation Research Laboratory, William S. Hall Psychiatric Institute, Columbia, SC 29202 (Received 21 June 1977) SHAH, N. S. AND M. P. HEDDEN. Behavioral effects and metabolic fate of N,N,-dimethyltryptamine in mice pretreated with 13-diethylaminoethyl-diphenylpropylacetate (SKF 525-A), iproniazid and chlorpromazine. PHARMAC. BIOCHEM. BEHAV. 8(4) 351-356, 1978. - Behavioral aspects and metabolic fate of N,N-dimethyitryptamine (DMT) were studied in mice pretreated with #-diethylaminoethyl-diphenylpropylacetate (SKF 525-A), iproniazid or chlorpromazine (CPZ). DMT at doses of 2.5, I0.0, and 25.0 mg/kg produced several behavioral changes in a dose-related manner: inhibition of spontaneous locomotor movement, enhanced fright responses to sound stimuli, trembling, head twitching, inco-ordinated movements of hind-legs, flat or extended tail and abnormal posture with the extension of hind-legs. Pretreatment with ipromiazid (153 mg/kg; 4 hr) but not SKF 525-A (50 mg/kg; 1 hr) prolonged the behavioral effects produced by 2.5 mg/kg DMT while CPZ (15 mg/kg; 0.5 hr) completely abolished the responses induced by 25 mg/kg DMT. Earlier behavioral effects generally coincided with the brain concentrations of DMT. Dose-dependent increases with rapid uptake and disappearance in the brain, plasma and hepatic levels of DMT were measured with doses of 10 and 25 mg/kg DMT. Iproniazid but not SKF 525-A markedly enhanced tissue levels of DMT. It is concluded that DMT is metabolized chiefly by monoamine oxidase rather than by drug-metabolizing hepatic microsomal enzymes and that DMT-induced behavioral effects are due to the parent compound rather than its metabolite. DMT

Behavior

Tissuelevels

SKF 525-A

lproniazid

N,N-DIMETHYLTRYPTAMINE (DMT) is a potent indoleamine hallucinogen in man [25,40]. Its psychotomimetic potency is approximately 4 times that of mescaline (described as mescaline unit), a catecholamine hallucinogen [37]. A few clinical studies have indicated the endogenous production of DMT in schizophrenic patients [18,23] and proposed this compound to be a causative factor in the etiology of schizophrenic disorder [9]. Metabolic fate of DMT and related hallucinogen diethyltryptamine (DET) was examined in humans and animals. Studies in man, monkey and rat revealed that DET is chiefly metabolized by liver microsomes resulting in a more active metabolite following 6-hydroxylation [41]. Iproniazid, a mono- and di-amine oxidase inhibitor [36] when administered repeatedly, suppressed the DMT-induced hallucination in human volunteers [24]. In rat, iproniazid pretreatment, on the other hand, prolonged the half-life of DMT in the brain [151. /3-diethylaminoethyl-diphenylpropylacetate (SKF 525-A) is frequently employed in assessing the role of hepatic microsomal enzymes in the metabolism of a variety of

CPZ

psychoactive drugs including barbiturates, diphenylhydantoin, tranquilizers, A l-tetrahydrocannabinol, narcotics and methaqualone [5, 21, 28, 32, 39] ; the inhibition of the drug metabolizing enzymes resulted in potentiation of pharmacologic actions of several of them. Besides its' action on the hepatic microsomal enzymes, SKF-525-A has been shown to alter the tissue distribution of sulfacetamide [16], mescaline [29] and methadone [28]. The major purpose of the present investigation is to examine the influence of iproniazid and SKF 525-A on the behavioral alterations induced by DMT and to see any relationship to tissue concentrations of DMT. The effect of chlorpromazine (CPZ) which antagonizes the actions of several hallucinogens [2, 7, 27] is also examined. METHOD

Drugs DMT was purchased from Aldrich Chemical Co., Inc. (Milwaukee, WI). CPZ hydrochloride, SKF 525-A hydrochloride (Smith, Kline and French Laboratories, Philadel-

Supported in part by the Ensor Research Foundation. 2Present address: Department of Biochemistry, Medical University of South Carolina, Charleston, SC.

C o p y r i g h t © 1978 A N K H O

I n t e r n a t i o n a l Inc.--0091-3057/78/0804-0351500.75

352

SHAH AND HEDDEN

16

Ai~

• Saline Control DMT (2.5 rng/kg) ® DMT (25 mg/kg) • CPZ +DMT (25 mg/kg)

//A~

.c

E

12-

Plexiglas cage (39 cm long, 25.5 cm wide and 15.5 cm high) and the l o c o m o t o r activity was m o n i t o r e d using an A n i m e x activity m e t e r type O (Farad Electronics, S t o c k h o l m , Sweden). The instrument was kept in a quiet r o o m at 23.5 -+ 1.0°C. The settings of tuning 40 u A and of sensitivity 40 uA were used throughout. The activity of animals (body m o v e m e n t and l o c o m o t i o n ) was recorded in 15 min periods for 2 hr and in some instances for additional 45 min (Fig. 1). Statistics

x v--

Results are expressed as mean -+ SD. The statistical significance of difference b e t w e e n mean values is determined with a Student's t test and p values o f 0.05 or less are considered significant. RESULTS

Time in 15-Min Blocks

FIG. I. Effect of saline (A), 2.5 mg/kg DMT (~), 25 mg/kg DMT (o) or a combination of CPZ and 25 mg/kg DMT ( e ) on spontaneous locomotor activity. Saline or CPZ (15 mg/kg) was given 0.5 hr before DMT. Control animals received saline followed by saline containing 0.1 N HC1 (vehicle). Ordinate: counts/15 min on the Animex. Abscissa: time in 15 rain sessions. Arrows indicate the time of administration of saline, CPZ, or DMT. phia, PA) and iproniazid phosphate ( H o f f m a n LaRoche, Inc., Nutley, NJ) were received as gifts. Animals Several e x p e r i m e n t a l l y naive Swiss-Webster albino mice of either sex, born and raised in our animal quarters and weighing 2 8 - 3 2 g were used. They were housed in wire cages in groups o f 6 with ad lib food and water. T e m p e r a t u r e in animal quarters was maintained at 23°C with relative h u m i d i t y at 55%. Pharmacological Procedure DMT was prepared in 0.1 N HC1 and diluted with physiological saline to a desired v o l u m e ; o t h e r drugs were made in saline. All drugs were freshly prepared and injected IP in a v o l u m e of 0.3 ml; doses are r e p o r t e d as their salts. Where indicated, the following drugs were given prior to DMT: iproniazid (153 mg/kg, 4 hr); SKF 525-A (50 mg/kg, 1 hr); saline or CPZ (15 mg/kg, 0.5 hr). The doses o f DMT were 2.5, 10, or 25 mg/kg. In some animals, saline, iproniazid, CPZ or SKF 525-A in doses reported above was injected and after appropriate time intervals, a dose of saline instead of D M T was given; brain, liver and plasma from these animals were e x a m i n e d for any interference of these drugs with the f l u o r o m e t r i c assay procedure for DMT. Mice were sacrificed by decapitation 0.25, 0.5, 1 and 2 hr after DMT injection. Blood was collected for the separation of plasma; w h o l e brain and liver were p r o m p t l y removed and frozen on dry ice. DMT was isolated from tissue h o m o g e n a t e s prepared in 1 N HC1, by toluene e x t r a c t i o n [ 4 ] ; the native fluorescence of DMT was read in an A m i n c o - B o w m a n S p e c t r o p h o t o f l u o r o m e t e r at 280 n m (excitation) and 360 nm (emission). Gross Behavior and L o c o m o t o r Activity T w o mice of identical body weights were placed in a

Gross Behavior and L o co m o t o r Activity The l o c o m o t o r activity of mice injected twice with saline and saline containing 0.1 N HC1 (vehicle) declined s o m e w h a t over a period of 2 hr (Fig. 1). In contrast, a rapid decline in spontaneous l o c o m o t o r activity was displayed during the first 30 min following 2.5 mg/kg DMT with a gradual return approaching to normal activity in the next 30 min. During the first 30 min period, animals laid quietly in a corner of the cage assuming a flattened posture. The tail r e m a i n e d relaxed on the floor with occasional wiggling. There were no signs of Straub tail or fine tremors. Fright responses were evoked in the animals by ordinary sound or could be elicited by merely touching the cage or by snapping the fingers. A dose of 10 mg/kg DMT p r o m p t l y declined the spontaneous m o t o r activity (not shown in Fig. 1) which paralleled 2.5 mg/kg dose; the activity decreasing effects lasted for 60 min. Animals exhibited jerkiness of the m o v e m e n t , rigidity, head twitching, trembling and occasional extension of the tail. Head twitches were counted after the DMT injection and compared with saline treated controls; during first 15 rain test period, no noticeable changes were measured b e t w e e n 2 groups; whereas the c o m b i n e d score for the next 30 rain test period averaged 7 (n = 8) for control group and 20 (n = 6) for the DMT (10 mg/kg) group. N u m b e r of head twitches exhibited by mice receiving 2.5 mg/kg DMT was not different from controls for the 45 min observation period. A dose of 25 mg/kg of DMT p r o d u c e d marked behavioral changes; the spontaneous m o t o r activity was markedly decreased (Fig. 1) within 5 to 10 rain followed by incoordinated m o v e m e n t s of hind-legs and an abnormal posture with the extension of hind-legs lasting for 90 to 105 min before they regained normal behavioral activity. During this period, alternate extension of the tail in an upward direction f o l l o w e d by flattening on the floor was frequently seen. N u m b e r of head twitches averaged 23 (n = 4) during 15 to 45 rain time interval following the drug injection. Occasional trembling but no signs of aggressiveness or convulsions were observed. Scratching responses which are typical of mescaline effects in mice [33] were not displayed with any dose of DMT. When injected alone, SKF 525-A or iproniazid did not disrupt the normal behavioral pattern or l o c o m o t o r movements. Behavioral effects induced by 2.5 mg/kg DMT were neither intensified nor prevented by prior administration of S K F 525-A (not shown in Fig. 1). Animals pretreated with iproniazid followed 4 hr later by DMT (2.5 mg/kg) displayed several similar behavioral

353

BEHAVIORAL EFFECTS AND METABOLIC FATE OF DMT TABLE 1 THE LEVELS OF DMT IN THE PLASMA

ug/ml Dose

Time of Sacrifice (min)

Treatment

mg/kg

15

30

60

Saline + DMT

10

2.3 ± 0.4 (3)

0.7 ± 0.1 (3)

ND (3)

Saline + DMT

25

4.7 ± 0.8 (5)

2.3 ± 0.3 (4)

0.6 ± 0.04 (3)

SKF 525-A + DMT

50 + 25

5.6 ± 1.1 (4)I

1.9 • 0.5 (4)t"

1.3 ± 0.0l

(4)*

-

Iproniazid + DMT

153 + 25

-

2.6 ± 0.3

(6)*

-

CPZ + DMT

15 + 25

-

0.9 ± 0.2

(7)*

5.4 ± 0.9 (7)I"

120

ND (3)

Mice were pretreated with saline (0.5 hr), SKF 525-A (1 hr), iproniazid (4 hr) or CPZ (0.5 hr) prior to DMT. Values are expressed as mean + SD with number of separate experiments in parentheses. ND = not detectable *Significantly different from control (saline + DMT 25 mg/kg), p<0.001 to 0.01 -~Not significantly different from control (saline + DMT 25 mg/kg), p>0.2 to 0.5 signs elicited b y 25 m g / k g DMT alone. U n d e r o u r experimental conditions, iproniazid extended the behavioral effects i n d u c e d b y 2.5 m g / k g D M T for a p e r i o d o f 90 min. S h o r t l y a f t e r DMT, t h e animals lost l o c o m o t o r activity ( n o t s h o w n in Fig. 1) and f r e q u e n t l y e x h i b i t e d t r e m b l i n g a n d head t w i t c h i n g . Sniffing was more p r o m i n e n t d u r i n g t h e first 30 min. N u m b e r of h e a d t w i t c h e s b e t w e e n 15 a n d 45 m i n a f t e r DMT i n j e c t i o n averaged 19 (n = 5). A n i m a l s regained n o r m a l activity a b o u t 90 m i n f r o m t h e t i m e o f DMT injection. In o n e s t u d y , i p r o n i a z i d ( 1 5 3 m g / k g ) and DMT (2.5 m g / k g ) were a d m i n i s t e r e d s i m u l t a n e o u s l y instead o f 4 hr a p a r t to see w h e t h e r t h e p o t e n t i a t i n g effect o f i p r o n i a z i d is related t o m o n o a m i n e oxidase ( M A O ) inhibition. U n d e r this e x p e r i m e n t a l s i t u a t i o n t h e b e h a v i o r a l effects i n d u c e d by 2.5 m g / k g DMT were n o t i n t e n s i f i e d b y i p r o n i a z i d . Since i p r o n i a z i d is a slow acting irreversible MAO i n h i b i t o r [ 3 8 ] , it is a s s u m e d t h a t MAO was n o t i n h i b i t e d , h e n c e n o p o t e n t i a t i o n of b e h a v i o r a l effects following s i m u l t a n e o u s a d m i n i s t r a t i o n o f b o t h drugs. As e x p e c t e d , a d m i n i s t r a t i o n o f CPZ (15 m g / k g ) prod u c e d i n h i b i t i o n o f s p o n t a n e o u s l o c o m o t o r activity (Fig. 1); a n i m a l s b e c a m e q u i e t a n d d r o w s y w i t h i n 10 m i n a f t e r t h e injection. A d m i n i s t r a t i o n of DMT (25 m g / k g ) 30 m i n a f t e r CPZ s h o w e d n o signs o f DMT effects such as a b n o r m a l p o s t u r e with the e x t e n s i o n o f h i n d legs, a l t e r n a t e e x t e n s i o n and r e l a x a t i o n o f the tail, fine t r e m o r s , fright r e s p o n s e s to s o u n d , rigidity or j e r k i n e s s o f t h e m o v e m e n t . While lying flat in a c o r n e r o f the cage, a n i m a l s w o u l d raise o n e h i n d leg p e r s i s t e n t l y t o u c h i n g the wall o f t h e cage w i t h t h a t leg. Given alone, CPZ did n o t p r o d u c e this l a t t e r effect. N u m b e r o f head t w i t c h e s d u r i n g 15 a n d 45 m i n interval a f t e r DMT i n j e c t i o n averaged 2 (n = 4) c o m p a r e d to 23 for saline + DMT (25 m g / k g ) g r o u p . D M T Tissue Levels

S p e c t r o f l u o r o m e t r i c analysis of tissue samples f r o m animals receiving various p r e t r e a t m e n t s b u t w i t h o u t DMT revealed n o evidence of i n t e r f e r e n c e with the DMT assays by i p r o n i a z i d , S K F 5 2 5 - A or CPZ. Tissue e x t r a c t s f r o m

saline t r e a t e d a n i m a l s p r o d u c e d a l m o s t negligible readings. Plasma, b r a i n and h e p a t i c levels o f DMT a f t e r IP i n j e c t i o n s of 10 a n d 25 mg]kg doses are s h o w n in Tables 1, 2, a n d 3. In s a l i n e - p r e t r e a t e d c o n t r o l s , t h e tissue levels o f DMT increased in a dose-related m a n n e r . At b o t h dose levels, t h e p e a k c o n c e n t r a t i o n s o c c u r e d at 15 m i n ; the t i s s u e : p l a s m a c o n c e n t r a t i o n ratios for t h e b r a i n and the liver were 4.2 a n d 7.0 respectively a f t e r 10 m g / k g a n d 3.9 a n d 8.0 a f t e r 25 mg/kg. At b o t h t h e doses, DMT c o n c e n t r a t i o n s declined rapidly. The 60 m i n levels in mice receiving 10 m g / k g were 0.06 + 0 . 0 0 8 ug/g in t h e brain, 1.1 ± 0.3 ug/g in t h e liver a n d negligible in t h e plasma. At a dose o f 25 mg/kg, small a m o u n t s o f DMT in t h e b r a i n a n d liver were d e t e c t a b l e at 120 min. The tissue levels of DMT in mice p r e t r e a t e d with various drugs f o l l o w e d by 25 m g / k g DMT were investigated (Tables 1, 2 a n d 3). The DMT c o n t e n t s in the plasma, brain a n d liver o f mice p r e t r e a t e d w i t h SKF 5 2 5 - A were n o t significantly d i f f e r e n t ( p > 0 . 0 2 to 0.5) at various time intervals, t h e e x c e p t i o n being t h e p l a s m a c o n t e n t at 60 m i n ( p < 0 . 0 0 1 ) . I p r o n i a z i d , o n t h e o t h e r h a n d , m a r k e d l y elevated b r a i n ( p < 0 . 0 0 1 ) , liver ( p < 0 . 0 0 1 ) and plasma ( p < 0 . 0 0 1 ) levels o f D M T ( o n l y 1 h r levels r e p o r t e d ) . In CPZ p r e t r e a t e d mice, brain, plasma a n d h e p a t i c c o n c e n t r a t i o n s o f DMT 15 m i n a f t e r 25 m g / k g dose were n o t significantly d i f f e r e n t from t h o s e n o t given CPZ ( p > 0 . 2 to 0.4). CPZ pretreatm e n t , h o w e v e r , p r o d u c e d small b u t significant increases in b r a i n ( p < 0 . 0 0 1 ) , plasma ( p < 0 . 0 5 ) and h e p a t i c ( p < 0 . 0 0 5 ) levels at 1 hr a f t e r DMT. D ISCUSSION A p r o m p t o n s e t of b e h a v i o r a l effects w o u l d suggest t h a t DMT p e n e t r a t e s t h e b l o o d - b r a i n b a r r i e r with great ease. In c o n t r a s t , studies with mescaline in mice, rats a n d r a b b i t s have s h o w n t h a t this m e t h y l a t e d c a t e c h o l a m i n e hallucinogen p e n e t r a t e s p o o r l y in the CNS [30, 31, 3 5 ] . F u r t h e r m o r e , c o m p a r e d to mescaline, DMT appears to be t a k e n up in the b r a i n by an active t r a n s p o r t m e c h a n i s m as e v i d e n c e d by the b r a i n : plasma DMT c o n c e n t r a t i o n ratio o f 4 as

354

SHAH A N D H E D D E N

TABLE 2 THE LEVELS OF DMT IN THE BRAIN

ug/g Dose

Time of Sacrifice (min)

Treatment

mg/kg

15

30

60

120

Saline + DMT

10

9.6 ± 2.1 (3)

3.1 ± 0.7 (3)

0.06 ± 0.008 (3)

-

Saline + DMT

25

18.2 ± 2.9 (5)

7.4 ± 1.1 (4)

1.3

± 0.3

(3)

SKF 525-A + DMT

50 + 25

19.6 ± 3.7 (4):~

6.5 ± 1.I (4)$

1.1

+- 0.07

(4)$

Iproniazid + DMT

153 + 25

-

6.8

± 0.8

(7)*

-

CPZ + DMT

15 + 25

-

2.7

± 0.3

(8)~

-

20.0 ± 3.3 (7)$

0.1 ± 0.04 (3)

Mice were pretreated with saline (0.5 hr), SKF 525-A (1 hr), iproniazid (4 hr) or CPZ (0.5 hr) prior to DMT. Values are expressed as mean ± SD with number of separate experiments in parentheses. *Significantly different from control (saline + 25 mg/kg DMT), p<0.001 tSignificantly different from control (saline + 25 mg/kg DMT), p<0.05 ~Not significantly different from control (saline + 25 mg/kg DMT), p>0.2 to 0.5 TABLE 3 THE LEVELS OF DMT IN THE LIVER

ug/g Dose

Time of Sacrifice (min)

Treatment

mg/kg

15

30

60

120

Saline + DMT

10

16.1 ± 3.4 (3)

10.5 ± 2.9 (3)

1.1 -+ 0.3 (3)

-

Saline + DMT

25

37.9 ± 6.8 (5)

13.5 _+ 3.9 (4)

3.1 ± 1.0 (3)

0.8 -+ 0.09 (3)

SKF 525-A + DMT

50 + 25

32.6 ± 7.9 (3)t

12.3 -+ 3.3 (4)t

4.0 ± 1.4 (4) t

-

lproniazid + DMT

153 + 25

13.9 ± 3.6 (7)*

-

CPZ + DMT

15 + 25

5.4 ± 0.8 (8)*

-

41.1 ± 5.5 (7)i

-

Mice were pretreated with saline (0.5 hr), SKF 525-A (1 hr), iproniazid (4 hr) or CPZ (0.5 hr) prior to DMT. Values are expressed as mean ± SD with number of experiments in parentheses. *Significantly different from control (saline + DMT 25 mg/kg), p<0.001 to 0.005 1"Not significantly different from control (saline + DMT 25 mg/kg), p>0.2 to 0.5 o p p o s e d to mescaline ratio o f 1 [31] u n d e r identical c o n d i t i o n s . S h o r t d u r a t i o n o f a c t i o n o f DMT w o u l d indicate t h a t the drug is rapidly m e t a b o l i z e d in the brain. D M T - i n d u c e d behavioral e f f e c t s generally c o i n c i d e d with its c o n c e n t r a t i o n in the brain m o r e so during t h e earlier phases. This could be d e m o n s t r a t e d b y the dose-related p r o l o n g a t i o n o f the a b n o r m a l behavior. F o r e x a m p l e , the behavioral e f f e c t s elicited by 2.5 m g / k g DMT lasted f o r a s h o r t d u r a t i o n while t h e s e e f f e c t s were m a r k e d l y i n t e n s i f i e d and p r o l o n g e d by elevating brain DMT c o n c e n t r a t i o n e i t h e r b y increasing the doses o f DMT or by b l o c k a d e o f its m e t a b o l i s m . In t h e rat, the level o f DMT in the brain necessary for a b n o r m a l b e h a v i o r was a p p r o x i m a t e l y 1.3 ~g/g o f brain [ 4 ] . By e n h a n c i n g brain levels o f DMT

following 25 m g / k g dose, we o b s e r v e d c o n t i n u e d d e p r e s s i o n o f l o c o m o t o r m o v e m e n t s (Fig. 1) as well as o t h e r behavioral changes for 60 min at which time the levels o f DMT in the brain w e r e 1.3 ug/g (Table 2), sufficient e n o u g h to m a i n t a i n the a b n o r m a l behavior. These data t h e r e f o r e would establish a c o r r e l a t i o n b e t w e e n t h e brain DMT levels and the a b n o r m a l behavior. It was p r o p o s e d t h a t 6 - h y d r o x ylated m e t a b o l i t e o f DMT or DET f o r m e d in the liver by m i c r o s o m a l e n z y m e s could be responsible for a b n o r m a l behavioral e f f e c t s o f these i n d o l e a m i n e hallucinogens [41 ]. In view o f these findings, we e x a m i n e d the e f f e c t s o f 2 agents o n the DMT-induced changed b e h a v i o r and its m e t a b o l i s m : SKF 525-A, a k n o w n i n h i b i t o r o f a wide variety o f h e p a t i c m i c r o s o m a l d r u g - m e t a b o l i z i n g e n z y m e s

BEHAVIORAL EFFECTS AND METABOLIC FATE OF DMT [3,19] a n d i p r o n i a z i d , a n i n h i b i t o r o f m i t o c h o n d r i a l a n d c y t o p l a s m i c M A O [ 3 6 , 4 4 ] . T h e findings o f t h e s e studies p r o v i d e d e v i d e n c e in s u p p o r t o f i n v o l v e m e n t o f M A O r a t h e r t h a n h e p a t i c m i c r o s o m a l drug m e t a b o l i z i n g e n z y m e s in t h e d e g r a d a t i o n o f DMT. F u r t h e r m o r e , t h e findings t h a t MAOi n h i b i t o r p r o l o n g s the D M T - i n d u c e d a b n o r m a l b e h a v i o r suggests t h e i n v o l v e m e n t o f t h e p a r e n t c o m p o u n d r a t h e r t h a n 6 - h y d r o x y m e t a b o l i t e as an active principle in DMTi n d u c e d b e h a v i o r a l effects. S u p p o r t in favor o f this argum e n t is derived f r o m the w o r k o f o t h e r investigators [4, 22, 4 2 ] w h o r e p o r t e d 6 - h y d r o x y DMT to be significantly less p o t e n t t h a n DMT in various b e h a v i o r a l responses. T h e p r o l o n g a t i o n o f the D M T - i n d u c e d h y p e r t h e r m i a a n d m y d r i asis in t h e r a b b i t [17] a n d increased half-life o f i n j e c t e d DMT in the b r a i n a n d liver of rat [15] p r e t r e a t e d w i t h iproniazid uphold our proposition. T h e f i n d i n g t h a t p r e t r e a t m e n t w i t h CPZ b l o c k e d t h e DMT effects is in a c c o r d w i t h t h a t o f M o o r e et al. [17] w h o r e p o r t e d a partial a n t a g o n i s m o f D M T - i n d u c e d h y p e r t h e r m i a , m y d r i a s i s a n d E E G a c t i v a t i o n in rats b y CPZ at a dose o f 1 mg/kg. In a related s t u d y , h y p e r a c t i v i t y i n d u c e d in rats b y a c o m b i n a t i o n of t r a n y l c y p r o m i n e a n d 5 - m e t h o x y - N , N - d i m e t h y l t r y p t a m i n e , a derivative o f DMT, was s h o w n to be p r e v e n t e d in a dose related m a n n e r b y p r i o r a d m i n i s t r a t i o n o f 10 or 30 m g / k g CPZ [ 1 0 ] . It is i n t e r e s t i n g to n o t e t h a t CPZ a n d several p h e n o t h i a z i n e s are effective a n t a g o n i s t s of m e s c a l i n e previously s h o w n b y o n e of us [ 2 7 , 3 3 ] . Increased tissue levels o f DMT at 1 h r in CPZ p r e t r e a t e d mice seem to be i n d e p e n d e n t o f t h e m e t a b o l i c c o n v e r s i o n of D M T b y MAO. In fact CPZ has b e e n s h o w n t o p r o d u c e

355 little o r n o effect o n t h e MAO activity [ 8 , 1 2 ] . A few studies have s h o w n a m a r k e d p r o l o n g a t i o n o f t h e disappearance o f i n j e c t e d m e l a t o n i n [43] a n d a m p h e t a m i n e [ 1,13] in rats a n d m e s c a l i n e [27, 29, 30, 33, 34] in mice p r e t r e a t e d w i t h CPZ ( 1 5 - 2 0 mg/kg). Increased a c c u m u l a t i o n o f m e s c a l i n e in t h e b r a i n a n d o t h e r tissues o f mice p r e t r e a t e d w i t h CPZ [34] has b e e n previously a t t r i b u t e d to t h e m e m b r a n e stabilizing effect o f CPZ [ 2 6 ] . C P Z - i n d u c e d m a r k e d h y p o t h e r m i a c o u l d affect t h e a m i n e m e t a b o l i s m in vivo [ 11 ]. T h e r e is e v i d e n c e t h a t CPZ effects t h e m e m b r a n e p e r m e a b i l i t y to various a m i n e s [6, 14, 2 0 ] . E i t h e r or b o t h of t h e s e effects c o u l d a c c o u n t for small increases in DMT levels f o l l o w i n g CPZ a d m i n i s t r a t i o n . These possibilities are c u r r e n t l y b e i n g i n v e s t i g a t e d b o t h in vitro a n d in vivo studies. B i o c h e m i c a l l y CPZ evokes a m u l t i t u d e o f effects o n various m e t a b o l i c p a t h w a y s a n d o n m e m b r a n e p e r m e a b i l i ties. P h a r m a c o l o g i c a l l y , it exerts a n t a g o n i s m t o b o t h c a t e c h o l a m i n e a n d i n d o l e a m i n e h a l l u c i n o g e n s . T h e fact t h a t CPZ b l o c k s t h e p h a r m a c o l o g i c a l effects o f s t r u c t u r a l l y u n r e l a t e d h a l l u c i n o g e n s suggests t h a t e i t h e r t h e hallucinogens m a y have a c o m m o n site of a c t i o n in t h e CNS or t h a t t h e a c t i o n o f CPZ m a y be n o n s p e c i f i c so far as p h a r m a c o logic a n t a g o n i s m o f h a l l u c i n o g e n s is c o n c e r n e d . ACK NOWLEDGEMENTS Sincere thanks are due to Alexander G. Donald, M. D., Director and Joe E. Freed, M. D., Associate Director Training and Research, William S. Hall Psychiatric Institute for continued interest in the study. The authors acknowledge the assistance of Ms. Dianne Eargle in calculation and statistical analysis.

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