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Tripelennamine: Enhancement of brain-stimulation reward
Life Sciences, Vol. 34, pp. 149-153 Printed in the U.S.A.
TRIPELENNAMINE:
ENHANCEMENT
Pergamon Pres:
OF B R A I N - S T I M U L A T I O N
REWARD
Ellen M. Unterwald, L. Thomas Kucharski, J o s e p h E.G. W i l l i a m s and Conan K o r n e t s k y L a b o r a t o r ~ of B e h a v i o r a l P h a r m a c o l o g y , Boston U n i v e r s i t y School of Medicine, 80 E. C o n c o r d Street Boston, MA 02118 (Received in final form October 28, 1983) Summary T h r e s h o l d s for r e i n f o r c i n g e l e c t r i c a l s t i m u l a t i o n to the m e d i a l f o r e b r a i n b u n d l e were d e t e r m i n e d in rats by means of a r a t e - f r e e p s y c h o p h y s i c a l method. The acute a d m i n i s t r a t i o n of t r i p e l e n n a m i n e lowered the t h r e s h o l d for r e w a r d i n g brain s t i m u l a t i o n in a d o s e - d e p e n d e n t manner. These results suggest that the abuse liability of t r i p e l e n n a m i n e may be r e l a t e d to its a b i l i t y to sensitize the c e n t r a l neural p a t h w a y that m e d i a t e s reward. A n t i h i s t a m i n e s are g e n e r a l l y b e l i e v e d to be w i t h o u t significant abuse liability. However, recent c l i n i c a l and l a b o r a t o r y f i n d i n g s suggest that the a n t i h i s t a m i n e , t r i p e l e n n a m i n e (Pyribenzamine R, PBZR), has unique p o t e n t i a l for abuse e s p e c i a l l y w h e n combined w i t h opioids. R e p o r t s from n u m e r o u s urban centers have d o c u m e n t e d w i d e s p r e a d abuse of the c o m b i n a t i o n of t r i p e l e n n a m i n e and p e n t a z o c i n e (i). This combination, known as "T's and Blues," is f r e q u e n t l y s u b s t i t u t e d for h e r o i n in p e r i o d s of low heroin availability. In animals t r i p e l e n n a m i n e has been shown to potentiate several of the p h a r m a c o l o g i c e f f e c t s of p e n t a z o c i n e (2,3). In order to further c h a r a c t e r i z e its abuse liability, we studied the e f f e c t s of t r i p e l e n n a m i n e on brain s t i m u l a t i o n reward. It has p r e v i o u s l y b e e n shown that n u m e r o u s drugs of abuse including morphine, cocaine, a m p h e t a m i n e and p h e n c y c l i d i n e lower the t h r e s h o l d for r e w a r d i n g brain s t i m u l a t i o n s u g g e s t i n g that this is a useful m o d e l for p r e d i c t i n g ab~se l i a b i l i t y (4). Thus a lowering of this t h r e s h o l d by t r i p e l e n n a m i n e w o u l d suggest that this d r u g alone m a y p r o d u c e e u p h o r i a and abuse l i a b i l i t y in man. Methods Six m a l e a l b i n o rats (CDF - C h a r l e s River Laboratory) weighing a p p r o x i m a t e l y 300 gms, w e r e a n e s t h e t i z e d w i t h E q u i - T h e s i n R (0.9 ml) and s t e r e o t a x i c a l l y i m p l a n t e d b i l a t e r a l l y w i t h b i p o l a r s t a i n l e s s steel e l e c t r o d e s (0.0127 cm in d i a m e t e r and i n s u l a t e d e x c e p t at the tips) aimed at the lateral h y p o t h a l a m i c region of the m e d i a l f o r e b r a i n b u n d l e (MFB-LH c o o r d i n a t e s - 4.0 m m p o s t e r i o r
0024-3205/84 $3.00 + .00 Copyright (c) 1984 Pergamon Press Ltd.
150
Tripelennamine and Brain-stimulation Reward
Vol. 34, No. 2, ]984
to bregma, ~1.4 m m from the m i d l i n e suture, and 8.5 m m v e n t r a l to the skull surface). The e l e c t r o d e s w e r e p l a c e d t h r o u g h small burr h o l e s in the skull and a t t a c h e d p e r m a n e n t l y to the surface w i t h an a c r y l i c platform. A f t e r surgery, a n i m a l s r e c e i v e d 60,000 u n i t s of p e n i c i l l i n (Bicillin R) i.m. and w e r e given at least one w e e k for p o s t - o p e r a t i v e r e c o v e r y b e f o r e b e h a v i o r a l t e s t i n g was begun. A n i m a l s w e r e m a i n t a i n e d on a 12 hour l i g h t / d a r k cycle, h o u s e d in s t a n d a r d steel c a g e s and had ad l i b i t u m a c c e s s to food and water. A n i m a l s w e r e t r a i n e d and t e s t e d on a r a t e - i n d e p e n d e n t threshold p r o c e d u r e (5) in a P l e x i g l a s c h a m b e r (20 x 20 cm). A wheel m a n i p u l a n d u m w a s located w i t h i n one w a l l of the test chamber. F o u r e q u a l l y spaced cams on one e n d p l a t e of the w h e e l m a n i p u l a n d u m o p e r a t e d a m i c r o s w i t c h w h i c h r e s u l t e d in i m m e d i a t e d e l i v e r y of a s t i m u l a t i o n w h e n the w h e e l w a s r o t a t e d o n e - q u a r t e r of a turn. A c o n s t a n t c u r r e n t s t i m u l a t o r (Sunrise Systems, P e m b r o k e , MA) was used to d e l i v e r the b i p h a s i c s y m m e t r i c a l pulses. Each stimulus c o n s i s t e d of a 500 m s e c train w i t h a p u l s e w i d t h of 0.2 m s e c and a d e l a y of 0.2 m s e c b e t w e e n the p o s i t i v e and n e g a t i v e p u l s e s at a f r e q u e n c y of 160 Hz. T h r e s h o l d s w e r e d e t e r m i n e d by a p r o c e d u r e i n v o l v i n g the use of d i s c r e t e trials s y s t e m a t i c a l l y p r e s e n t e d over a r a n g e of stimulus i n t e n s i t i e s . A trial b e g a n w i t h the d e l i v e r y of a n o n c o n t i n g e n t stimulus. A r e s p o n s e of o n e - q u a r t e r w h e e l turn w i t h i n 7.5 sec of this stimulus r e s u l t e d in the d e l i v e r y of a c o n t i n g e n t stimulus, i d e n t i c a l in all p a r a m e t e r s to the n o n c o n t i n g e n t stimulus, and t e r m i n a t e d the trial. F a i l u r e to r e s p o n d had no schedu l e d c o n s e q u e n c e s and the trial was t e r m i n a t e d after 7.5 sec. The i n t e r v a l b e t w e e n t r i a l s v a r i e d a r o u n d an a v e r a g e of 15 sec and r e s p o n s e s d u r i n g the i n t e r t r i a l i n t e r v a l (error responses) resulted in a 15 sec d e l a y b e f o r e the start of the next trial. S t i m u l u s i n t e n s i t i e s w e r e v a r i e d u s i n g a m o d i f i c a t i o n of the c l a s s i c a l m e t h o d of limits. S t i m u l i w e r e p r e s e n t e d in an altern a t i n g d e s c e n d i n g and a s c e n d i n g series w i t h a step size of 3, 5 or 10 ~A (depending on the s e n s i t i v i t y of the i n d i v i d u a l animal) w i t h 5 trials at e a c h i n t e n s i t y level b e f o r e the next lower or higher intensity was presented. S u b j e c t s c o m p l e t e d 4 series (i.e. d e s c e n d i n g , a s c e n d i n g , d e s c e n d i n g , and ascending) p r i o r to i n j e c t i o n then 8 s e r i e s p o s t - i n j e c t i o n , w i t h the e n t i r e pre- posts e s s i o n l a s t i n g 2.5 to 3 hours. All e x p e r i m e n t a l data was collected and s t o r e d by an o n - l i n e m i c r o c o m p u t e r . E a c h series' threshold v a l u e w a s d e f i n e d as the m i d p o i n t in m i c r o a m p e r e s b e t w e e n the level at w h i c h the a n i m a l m a d e 3 or m o r e r e s p o n s e s out of 5 stimulus p r e s e n t a t i o n s (a p l u s score) and the level w h e r e less than 3 r e s p o n s e s (a m i n u s score) w a s made. A n i m a l s r e q u i r e d a p p r o x i m a t e l y 6 one h o u r t r a i n i n g s e s s i o n s to learn the task and a p p r o x i m a t e l y 4 a d d i t i o n a l s e s s i o n s for the e s t a b l i s h m e n t of a s t a b l e t h r e s h o l d level w h e r e u p o n i n t r a - p e r i t o n e a l saline i n j e c t i o n s w e r e initiated. Animals were tested w i t h s a l i n e i n j e c t i o n s for 5 days b e f o r e d r u g a d m i n i s t r a t i o n was initiated. Also, saline days w e r e a l w a y s i n t e r s p e r s e d b e t w e e n e a c h day of d~ug t r e a t m e n t so that a n i m a l s r e c e i v e d d r u g o n l y twice weekly.
Vol. 34, No. 2, 1 9 8 4
Tripelennamine and Brain-stimulation Reward
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T r i p e l e n n a m i n e w a s d i s s o l v e d in i s o t o n i c saline and i n j e c t e d i n t r a - p e r i t o n e a l l y in a v o l u m e of 1.0 m g / k g of body weight. The p o s t - i n j e c t i o n t e s t i n g w a s b e g u n 10 m i n u t e s after a d m i n i s t r a t i o n of e i t h e r s a l i n e or t r i p e l e n n a m i n e . The s e q u e n c e of doses of t r i p e l e n n a m i n e (0.625 - 20.0 mg/kg) was b a l a n c e d b e t w e e n animals. T h r e s h o l d v a l u e s w e r e c a l c u l a t e d for b o t h the p r e - i n j e c t i o n and the p o s t - i n j e c t i o n sessions, w i t h the d i f f e r e n c e b e t w e e n the two s c o r e s t a k e n as the d e p e n d e n t measure. These difference scores w e r e t r a n s f o r m e d to s t a n d a r d s c o r e s (Z scores) b a s e d on the s t a n d a r d d e v i a t i o n of the d i f f e r e n c e scores for all saline days. A Z score of ± 2.0 (95% c o n f i d e n c e level) was p r e - s e l e c t e d as the level of s i g n i f i c a n c e . Results The r e s u l t s are s u m m a r i z e d in Fig. 1 w h i c h d i s p l a y s the effects of 0.625 to 20.0 m g / k g t r i p e l e n n a m i n e . A l l six a n i m a l s s h o w s i g n i f i c a n t r e d u c t i o n s in the r e i n f o r c i n g t h r e s h o l d w i t h the o p t i m a l l y e f f e c t i v e dose v a r y i n g f r o m a n i m a l to animal. Significant d e c r e a s e s in the t h r e s h o l d for r e w a r d i n g b r a i n s t i m u l a t i o n w e r e seen at d o s e s of 1.25 to 10.0 m g / k g of t r i p e l e n n a m i n e for rat #183, at 7.5 to I0.0 m g / k g for #67, at 2.5 to 5.0 m g / k g for #71, at 1.25 for #70, at 2.5 to 20.0 m g / k g for #99, and at 20.0 m g / k g for #15. H i s t o l o g i c a l a n a l y s i s r e v e a l e d all e l e c t r o d e s to be l o c a t e d in the M F B - L H area.
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S t a n d a r d score (Z score) c h a n g e s in t h r e s h o l d v a l u e s f r o m pre- to p o s t - d r u g as a f u n c t i o n of d o s e of t r i p e l e n n a m i n e for e a c h of six animals. S h a d i n g i n d i c a t e s the 95% c o n f i d e n c e limits b a s e d on the ~ and SD of all s a l i n e days.
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Tripelennamine and Brain-stimulation Reward
Vol. 34, No. 2, 1984
Discussion The results of this study demonstrate that tripelennamine significantly lowered the threshold for rewarding brain stimulation to the MFB-LH area. Animals given tripelennamine consistently responded at intensity levels that were too low to maintain responding during saline treatment. While significant enhancement of the reward system was observed with tripelennamine, the magnitude of this facilitation was substantially less then what was observed in previous studies with morphine, cocaine, amphetamine or other highly abused substances ( 4 ) . This suggests that compared to other drugs of abuse, tripelennamine is only weakly euphorigenic when given alone. The mechanism by which tripelennamine enhances the reward system is unclear. Tagashira, et al. (6) and Hui, et al. (7) report that tripelennamine has weak analgesic activity which can be antagonized by naloxone, suggesting that tripelennamine may possess opiate-like activity. However, Shannon and Su (2) report that tripelennamine has no effect on 3H-naloxone binding in the brain synaptosomal preparation nor did it affect the pentazocine inhibition of twitch height in the electrically stimulated guinea pig ileum. Together, these results suggest that tripelennamine may have indirect opiate effects at best. Numerous other possible mechanisms for tripelennamine's enhancement of the reward system exist. Issac and Goth (8) report that certain antihistamines including tripelennamine, d-chlorpheneramine and phenindamine inhibit norepinephrine uptake and thus possess a cocaine-like effect. Alternatively, tripelennamine's anticholinergic activity may be related to its abuse liability. Anticholinergics, used to treat neuroleptic induced extrapyramidal symptoms, are known to be abused ( 9 ) . Additionally, scopolamine has been shown to enhance rate-dependent intracranial self-stimulation behavior in rats (i0). In conclusion, the results of this study demonstrate that tripelennamine significantly lowered the threshold for rewarding brain stimulation to the MFB-LH area in the rat. These results suggest that tripelennamine may have abuse liability in and of itself. In this regard, our results are consistant with those of D. Jasinski who found that human subjects given tripelennamine report an increase in euphoria as measured by the Addiction Research Center Inventory (personal communication), and the report by O'Driscoll and Lindley (ii) of the i.v. administration of tripelennamine by a heroin addict. Acknowledgements .This research was supported Drug Abuse grant DA 02326.
in part by National
Institute
on
References i.
H.W. LAHMEYER (1980).
and R.G.
STEINGOLD,
Int.
J. Addict.
15 1219-1221
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2.
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H.E. S H A N N O N and T.P. SU, P h a r m a c o l . Biochem. Behav. 17 789795 (1982). 3. D.P. WALLER, N.L. KATZ and R.W. MORRIS, Clino Toxicol. 16 1723 (1980). 4. C. K O R N E T S K Y , R.U. E S P O S I T O , S. M C L E A N and J.O. J A C O B S O N , Arch. Gen. P s y c h i a t . 36 289-292 (1979). 5. R.U. E S P O S I T O and C. K O R N E T S K Y , S c i e n c e 195 189-191 (1977). 6. E. T A G A S H I R A , J.F. K A C H U R and W.L. DEWEY, P h a r m a c o l o g i s t , 24 188 (1982). 7. F.W. HUI, C.J. SUN, E.C. TOCUS and J.P. HANIG, Life Sci. 32 1 5 3 1 - 1 5 3 8 (1983). 8. L. ISAAC and A. GOTH, Lif Sci. 4 1 8 9 9 - 1 9 0 4 (1965). 9. J.M. SMITH, J. Clin. P s y c h i a t . 4 1 351-354 (1980). 10. M.E. OLDS, N e u r o p h a r m a c o l o g y 9 519-532 (1970). ii. W.G. O ' D R I S C O L L and G.R. LINDLEY, N. Eng. J. Med. 257 376377 (1957).
TRIPELENNAMINE:
ENHANCEMENT
Pergamon Pres:
OF B R A I N - S T I M U L A T I O N
REWARD
Ellen M. Unterwald, L. Thomas Kucharski, J o s e p h E.G. W i l l i a m s and Conan K o r n e t s k y L a b o r a t o r ~ of B e h a v i o r a l P h a r m a c o l o g y , Boston U n i v e r s i t y School of Medicine, 80 E. C o n c o r d Street Boston, MA 02118 (Received in final form October 28, 1983) Summary T h r e s h o l d s for r e i n f o r c i n g e l e c t r i c a l s t i m u l a t i o n to the m e d i a l f o r e b r a i n b u n d l e were d e t e r m i n e d in rats by means of a r a t e - f r e e p s y c h o p h y s i c a l method. The acute a d m i n i s t r a t i o n of t r i p e l e n n a m i n e lowered the t h r e s h o l d for r e w a r d i n g brain s t i m u l a t i o n in a d o s e - d e p e n d e n t manner. These results suggest that the abuse liability of t r i p e l e n n a m i n e may be r e l a t e d to its a b i l i t y to sensitize the c e n t r a l neural p a t h w a y that m e d i a t e s reward. A n t i h i s t a m i n e s are g e n e r a l l y b e l i e v e d to be w i t h o u t significant abuse liability. However, recent c l i n i c a l and l a b o r a t o r y f i n d i n g s suggest that the a n t i h i s t a m i n e , t r i p e l e n n a m i n e (Pyribenzamine R, PBZR), has unique p o t e n t i a l for abuse e s p e c i a l l y w h e n combined w i t h opioids. R e p o r t s from n u m e r o u s urban centers have d o c u m e n t e d w i d e s p r e a d abuse of the c o m b i n a t i o n of t r i p e l e n n a m i n e and p e n t a z o c i n e (i). This combination, known as "T's and Blues," is f r e q u e n t l y s u b s t i t u t e d for h e r o i n in p e r i o d s of low heroin availability. In animals t r i p e l e n n a m i n e has been shown to potentiate several of the p h a r m a c o l o g i c e f f e c t s of p e n t a z o c i n e (2,3). In order to further c h a r a c t e r i z e its abuse liability, we studied the e f f e c t s of t r i p e l e n n a m i n e on brain s t i m u l a t i o n reward. It has p r e v i o u s l y b e e n shown that n u m e r o u s drugs of abuse including morphine, cocaine, a m p h e t a m i n e and p h e n c y c l i d i n e lower the t h r e s h o l d for r e w a r d i n g brain s t i m u l a t i o n s u g g e s t i n g that this is a useful m o d e l for p r e d i c t i n g ab~se l i a b i l i t y (4). Thus a lowering of this t h r e s h o l d by t r i p e l e n n a m i n e w o u l d suggest that this d r u g alone m a y p r o d u c e e u p h o r i a and abuse l i a b i l i t y in man. Methods Six m a l e a l b i n o rats (CDF - C h a r l e s River Laboratory) weighing a p p r o x i m a t e l y 300 gms, w e r e a n e s t h e t i z e d w i t h E q u i - T h e s i n R (0.9 ml) and s t e r e o t a x i c a l l y i m p l a n t e d b i l a t e r a l l y w i t h b i p o l a r s t a i n l e s s steel e l e c t r o d e s (0.0127 cm in d i a m e t e r and i n s u l a t e d e x c e p t at the tips) aimed at the lateral h y p o t h a l a m i c region of the m e d i a l f o r e b r a i n b u n d l e (MFB-LH c o o r d i n a t e s - 4.0 m m p o s t e r i o r
0024-3205/84 $3.00 + .00 Copyright (c) 1984 Pergamon Press Ltd.
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to bregma, ~1.4 m m from the m i d l i n e suture, and 8.5 m m v e n t r a l to the skull surface). The e l e c t r o d e s w e r e p l a c e d t h r o u g h small burr h o l e s in the skull and a t t a c h e d p e r m a n e n t l y to the surface w i t h an a c r y l i c platform. A f t e r surgery, a n i m a l s r e c e i v e d 60,000 u n i t s of p e n i c i l l i n (Bicillin R) i.m. and w e r e given at least one w e e k for p o s t - o p e r a t i v e r e c o v e r y b e f o r e b e h a v i o r a l t e s t i n g was begun. A n i m a l s w e r e m a i n t a i n e d on a 12 hour l i g h t / d a r k cycle, h o u s e d in s t a n d a r d steel c a g e s and had ad l i b i t u m a c c e s s to food and water. A n i m a l s w e r e t r a i n e d and t e s t e d on a r a t e - i n d e p e n d e n t threshold p r o c e d u r e (5) in a P l e x i g l a s c h a m b e r (20 x 20 cm). A wheel m a n i p u l a n d u m w a s located w i t h i n one w a l l of the test chamber. F o u r e q u a l l y spaced cams on one e n d p l a t e of the w h e e l m a n i p u l a n d u m o p e r a t e d a m i c r o s w i t c h w h i c h r e s u l t e d in i m m e d i a t e d e l i v e r y of a s t i m u l a t i o n w h e n the w h e e l w a s r o t a t e d o n e - q u a r t e r of a turn. A c o n s t a n t c u r r e n t s t i m u l a t o r (Sunrise Systems, P e m b r o k e , MA) was used to d e l i v e r the b i p h a s i c s y m m e t r i c a l pulses. Each stimulus c o n s i s t e d of a 500 m s e c train w i t h a p u l s e w i d t h of 0.2 m s e c and a d e l a y of 0.2 m s e c b e t w e e n the p o s i t i v e and n e g a t i v e p u l s e s at a f r e q u e n c y of 160 Hz. T h r e s h o l d s w e r e d e t e r m i n e d by a p r o c e d u r e i n v o l v i n g the use of d i s c r e t e trials s y s t e m a t i c a l l y p r e s e n t e d over a r a n g e of stimulus i n t e n s i t i e s . A trial b e g a n w i t h the d e l i v e r y of a n o n c o n t i n g e n t stimulus. A r e s p o n s e of o n e - q u a r t e r w h e e l turn w i t h i n 7.5 sec of this stimulus r e s u l t e d in the d e l i v e r y of a c o n t i n g e n t stimulus, i d e n t i c a l in all p a r a m e t e r s to the n o n c o n t i n g e n t stimulus, and t e r m i n a t e d the trial. F a i l u r e to r e s p o n d had no schedu l e d c o n s e q u e n c e s and the trial was t e r m i n a t e d after 7.5 sec. The i n t e r v a l b e t w e e n t r i a l s v a r i e d a r o u n d an a v e r a g e of 15 sec and r e s p o n s e s d u r i n g the i n t e r t r i a l i n t e r v a l (error responses) resulted in a 15 sec d e l a y b e f o r e the start of the next trial. S t i m u l u s i n t e n s i t i e s w e r e v a r i e d u s i n g a m o d i f i c a t i o n of the c l a s s i c a l m e t h o d of limits. S t i m u l i w e r e p r e s e n t e d in an altern a t i n g d e s c e n d i n g and a s c e n d i n g series w i t h a step size of 3, 5 or 10 ~A (depending on the s e n s i t i v i t y of the i n d i v i d u a l animal) w i t h 5 trials at e a c h i n t e n s i t y level b e f o r e the next lower or higher intensity was presented. S u b j e c t s c o m p l e t e d 4 series (i.e. d e s c e n d i n g , a s c e n d i n g , d e s c e n d i n g , and ascending) p r i o r to i n j e c t i o n then 8 s e r i e s p o s t - i n j e c t i o n , w i t h the e n t i r e pre- posts e s s i o n l a s t i n g 2.5 to 3 hours. All e x p e r i m e n t a l data was collected and s t o r e d by an o n - l i n e m i c r o c o m p u t e r . E a c h series' threshold v a l u e w a s d e f i n e d as the m i d p o i n t in m i c r o a m p e r e s b e t w e e n the level at w h i c h the a n i m a l m a d e 3 or m o r e r e s p o n s e s out of 5 stimulus p r e s e n t a t i o n s (a p l u s score) and the level w h e r e less than 3 r e s p o n s e s (a m i n u s score) w a s made. A n i m a l s r e q u i r e d a p p r o x i m a t e l y 6 one h o u r t r a i n i n g s e s s i o n s to learn the task and a p p r o x i m a t e l y 4 a d d i t i o n a l s e s s i o n s for the e s t a b l i s h m e n t of a s t a b l e t h r e s h o l d level w h e r e u p o n i n t r a - p e r i t o n e a l saline i n j e c t i o n s w e r e initiated. Animals were tested w i t h s a l i n e i n j e c t i o n s for 5 days b e f o r e d r u g a d m i n i s t r a t i o n was initiated. Also, saline days w e r e a l w a y s i n t e r s p e r s e d b e t w e e n e a c h day of d~ug t r e a t m e n t so that a n i m a l s r e c e i v e d d r u g o n l y twice weekly.
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T r i p e l e n n a m i n e w a s d i s s o l v e d in i s o t o n i c saline and i n j e c t e d i n t r a - p e r i t o n e a l l y in a v o l u m e of 1.0 m g / k g of body weight. The p o s t - i n j e c t i o n t e s t i n g w a s b e g u n 10 m i n u t e s after a d m i n i s t r a t i o n of e i t h e r s a l i n e or t r i p e l e n n a m i n e . The s e q u e n c e of doses of t r i p e l e n n a m i n e (0.625 - 20.0 mg/kg) was b a l a n c e d b e t w e e n animals. T h r e s h o l d v a l u e s w e r e c a l c u l a t e d for b o t h the p r e - i n j e c t i o n and the p o s t - i n j e c t i o n sessions, w i t h the d i f f e r e n c e b e t w e e n the two s c o r e s t a k e n as the d e p e n d e n t measure. These difference scores w e r e t r a n s f o r m e d to s t a n d a r d s c o r e s (Z scores) b a s e d on the s t a n d a r d d e v i a t i o n of the d i f f e r e n c e scores for all saline days. A Z score of ± 2.0 (95% c o n f i d e n c e level) was p r e - s e l e c t e d as the level of s i g n i f i c a n c e . Results The r e s u l t s are s u m m a r i z e d in Fig. 1 w h i c h d i s p l a y s the effects of 0.625 to 20.0 m g / k g t r i p e l e n n a m i n e . A l l six a n i m a l s s h o w s i g n i f i c a n t r e d u c t i o n s in the r e i n f o r c i n g t h r e s h o l d w i t h the o p t i m a l l y e f f e c t i v e dose v a r y i n g f r o m a n i m a l to animal. Significant d e c r e a s e s in the t h r e s h o l d for r e w a r d i n g b r a i n s t i m u l a t i o n w e r e seen at d o s e s of 1.25 to 10.0 m g / k g of t r i p e l e n n a m i n e for rat #183, at 7.5 to I0.0 m g / k g for #67, at 2.5 to 5.0 m g / k g for #71, at 1.25 for #70, at 2.5 to 20.0 m g / k g for #99, and at 20.0 m g / k g for #15. H i s t o l o g i c a l a n a l y s i s r e v e a l e d all e l e c t r o d e s to be l o c a t e d in the M F B - L H area.
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S t a n d a r d score (Z score) c h a n g e s in t h r e s h o l d v a l u e s f r o m pre- to p o s t - d r u g as a f u n c t i o n of d o s e of t r i p e l e n n a m i n e for e a c h of six animals. S h a d i n g i n d i c a t e s the 95% c o n f i d e n c e limits b a s e d on the ~ and SD of all s a l i n e days.
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152
Tripelennamine and Brain-stimulation Reward
Vol. 34, No. 2, 1984
Discussion The results of this study demonstrate that tripelennamine significantly lowered the threshold for rewarding brain stimulation to the MFB-LH area. Animals given tripelennamine consistently responded at intensity levels that were too low to maintain responding during saline treatment. While significant enhancement of the reward system was observed with tripelennamine, the magnitude of this facilitation was substantially less then what was observed in previous studies with morphine, cocaine, amphetamine or other highly abused substances ( 4 ) . This suggests that compared to other drugs of abuse, tripelennamine is only weakly euphorigenic when given alone. The mechanism by which tripelennamine enhances the reward system is unclear. Tagashira, et al. (6) and Hui, et al. (7) report that tripelennamine has weak analgesic activity which can be antagonized by naloxone, suggesting that tripelennamine may possess opiate-like activity. However, Shannon and Su (2) report that tripelennamine has no effect on 3H-naloxone binding in the brain synaptosomal preparation nor did it affect the pentazocine inhibition of twitch height in the electrically stimulated guinea pig ileum. Together, these results suggest that tripelennamine may have indirect opiate effects at best. Numerous other possible mechanisms for tripelennamine's enhancement of the reward system exist. Issac and Goth (8) report that certain antihistamines including tripelennamine, d-chlorpheneramine and phenindamine inhibit norepinephrine uptake and thus possess a cocaine-like effect. Alternatively, tripelennamine's anticholinergic activity may be related to its abuse liability. Anticholinergics, used to treat neuroleptic induced extrapyramidal symptoms, are known to be abused ( 9 ) . Additionally, scopolamine has been shown to enhance rate-dependent intracranial self-stimulation behavior in rats (i0). In conclusion, the results of this study demonstrate that tripelennamine significantly lowered the threshold for rewarding brain stimulation to the MFB-LH area in the rat. These results suggest that tripelennamine may have abuse liability in and of itself. In this regard, our results are consistant with those of D. Jasinski who found that human subjects given tripelennamine report an increase in euphoria as measured by the Addiction Research Center Inventory (personal communication), and the report by O'Driscoll and Lindley (ii) of the i.v. administration of tripelennamine by a heroin addict. Acknowledgements .This research was supported Drug Abuse grant DA 02326.
in part by National
Institute
on
References i.
H.W. LAHMEYER (1980).
and R.G.
STEINGOLD,
Int.
J. Addict.
15 1219-1221
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2.
Tripelennamine and Brain-stimulation Reward
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H.E. S H A N N O N and T.P. SU, P h a r m a c o l . Biochem. Behav. 17 789795 (1982). 3. D.P. WALLER, N.L. KATZ and R.W. MORRIS, Clino Toxicol. 16 1723 (1980). 4. C. K O R N E T S K Y , R.U. E S P O S I T O , S. M C L E A N and J.O. J A C O B S O N , Arch. Gen. P s y c h i a t . 36 289-292 (1979). 5. R.U. E S P O S I T O and C. K O R N E T S K Y , S c i e n c e 195 189-191 (1977). 6. E. T A G A S H I R A , J.F. K A C H U R and W.L. DEWEY, P h a r m a c o l o g i s t , 24 188 (1982). 7. F.W. HUI, C.J. SUN, E.C. TOCUS and J.P. HANIG, Life Sci. 32 1 5 3 1 - 1 5 3 8 (1983). 8. L. ISAAC and A. GOTH, Lif Sci. 4 1 8 9 9 - 1 9 0 4 (1965). 9. J.M. SMITH, J. Clin. P s y c h i a t . 4 1 351-354 (1980). 10. M.E. OLDS, N e u r o p h a r m a c o l o g y 9 519-532 (1970). ii. W.G. O ' D R I S C O L L and G.R. LINDLEY, N. Eng. J. Med. 257 376377 (1957).