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Accelerated communication α2-adrenoceptor antagonists block the stimulant effects of cocaine in mice
Life Sciences, Vol. 50, pp. PL-155- PL-159 Printed
Pergamon
Press
in t h e U S A
PHARMACOLOGY Accelerated
~2-ADRENOCEPTOR
LETTERS
Communication
ANTAGONISTS BLOCK THE STIMULANT COCAINE IN MICE
EFFECTS OF
Helen C. Jackson*, Ian J. Griffin and David J. Nutt Reckitt & Colman Psychopharmacology Unit, Department of Pharmacology, School of Medical Sciences, University Walk, Bristol, BS8 ITD, U.K. (Submitted January 22, 1992; accepted February 14, 1992; received in final form March 3, 1992) Abstract. In the present study we have investigated the effects of the u2-adrenoceptor antagonist idazoxan and its 2-ethoxy derivative RX811059 on the locomotor activity induced by cocaine in mice. The stimulant effects of cocaine (15 mg/kg i.p.) were s i g n i f i c a n t l y antagonised by idazoxan (3 mg/kg i.p.) and RX811059 (i mg/kg i.p.) and also initially suppressed by idazoxan (i mg/kg i.p.) and RX811059 (0.3 mg/kg i.p.). The u2-adrenoceptor antagonists had no effect on locomotion when given alone. These results suggest that noradrenergic mechanisms may play a role in the stimulant effects of cocaine and that u2-adrenceptor antagonists like idazoxan may be of some benefit in the clinical management of cocaine abuse. Introduction The consequences of chronic cocaine use such as craving and crash are major clinical problems that are thought to contribute to the addictive properties of this stimulant drug (i). A commonly used treatment is the tricyclic antidepressant desipramine, which has been shown to alleviate both cocaine craving and crash in man (2). Because desipramine is thought to increase synaptic availability of noradrenaline by blocking its re-uptake (3-5) it is possible that other compounds which similarly elevate noradrenaline levels in the synaptic cleft might also be efficacious. One class of compounds with this property are the e2adrenoceptor antagonists which increase noradrenaline release by blocking inhibitory pre-synaptic autoreceptors (3). Idazoxan is an ~2-adrenoceptor antagonist (6) which has been used successfully in a large number of depressed patients (7). This clinical experience with idazoxan coupled with our previous d e m o n s t r a t i o n that it did not increase cocaine toxicity (8) raises the p o s s i b i l i t y that if effective idazoxan could be used clinically in the treatment of cocaine abuse. In this study we have investigated the effects of idazoxan in a simple model of the psychomotor stimulant effects of cocaine: locomotor activity. * Author for correspondence at: CNS Division, Novo N o r d i s k Park, 2760 Malov, Denmark.
Novo
Nordisk
0024-3205/92 $5.00 + .00 Copyright © 1992 Pergamon Press Ltd All rights reserved.
A/S,
PL-156
u2-adrenoceptor Antagonists and C o c a i n e
Vol. 50, No. 19, 1992
In addition, since idazoxan is also a ligand at nona d r e n o c e p t o r idazoxan binding sites (NAIBS, 9) we have used the more p o t e n t and selective ~2-adrenoceptor a n t a g o n i s t RX811059 (2e t h o x y idazoxan; i0), which has over 3-fold h i g h e r a f f i n i t y for central ~ 2 - a d r e n o c e p t o r s than idazoxan, is over three times more ~ 2 / ~ l - s e l e c t i v e (i0) and has only low affinity for NAIBS (ii). Methods
were 23 ± with were
M a l e TO mice (Bantin & Kingman) in the w e i g h t range 28-35 g used in all experiments. Mice were housed in groups of 30 at 2°C under a 14:10 h light-dark cycle (lights on at 05.00 h) free access to standard rat and mouse diet and water. Mice used on only one occasion.
At the start of each experiment animals were r e m o v e d to a quiet, a i r - c o n d i t i o n e d laboratory (23 ± 2°C) and a c c l i m a t i z e d to these c o n d i t i o n s for at least 1 h before use. All p r o c e d u r e s were c a r r i e d out b e t w e e n 09.00 h and 16.00 h. L o c o m o t o r a c t i v i t y was m e a s u r e d using 4 automated activity boxes. Each c o n s i s t e d of an open t r a n s p a r e n t - p e r s p e x arena (60 cm X 60 cm X 30 cm high). A r o u n d the arena (at floor level) were located 15 sets of infrared e m i t t e r s and detectors which were interfaced to a c o m p u t e r w h i c h r e c o r d e d c o n t i n u o u s l y the number of beam breaks per unit time. Four identical sets of equipment were used so that the locomotor a c t i v i t y of animals from each of 4 different t r e a t m e n t groups could be m o n i t o r e d c o n c u r r e n t l y to control for any v a r i a t i o n s due to the time of day of the experiment. Animals were tested i n d i v i d u a l l y and 2 animals from each treatment group were tested in each of the 4 boxes to account for any variability in either the a c t i v i t y boxes or their environment. The 4 treatment groups (n=8) c o n s i s t e d of a control group which received 2 injections of vehicle; a g r o u p given c o c a i n e (15 mg/kg) and vehicle and 2 groups given cocaine and 1 of 2 doses of the test drug. Animals were h a b i t u a t e d to the a c t i v i t y boxes for 40 min. The ~2-adrenoceptor antagonists were given 5 min before v e h i c l e or cocaine. Locomotor activity was then m o n i t o r e d in 5 min periods for 30 min. Cocaine h y d r o c h l o r i d e (Sigma), idazoxan h y d r o c h l o r i d e and RX811059 h y d r o c h l o r i d e (synthesized at Reckitt & Colman, Hull) were d i s s o l v e d in 0.9 % saline and injected i n t r a p e r i t o n e a l l y in a dose v o l u m e of i0 ml/kg. Doses are expressed as the h y d r o c h l o r i d e salt and were based on those shown to be p h a r m a c o l o g i c a l l y active in other studies in our laboratory (unpublished observations). T r e a t m e n t group means were statistically compared using K r u s k a l Wallis and the M a n n - W h i t n e y U-test (two-tailed). Results Cocaine (15 mg/kg) significantly increased locomotor a c t i v i t y (Figs 1 and 2). This effect was of quick onset and o c c u r r e d m a i n l y in the first 15 min. Idazoxan (i, 3 mg/kg; Fig. i) d e c r e a s e d c o c a i n e - i n d u c e d locomotion in a d o s e - r e l a t e d manner. L o c o m o t o r a c t i v i t y scores of animals given idazoxan (3 mg/kg) and cocaine were s i g n i f i c a n t l y lower than the group given cocaine alone d u r i n g the first i0 min after injection. Furthermore, a c t i v i t y scores of mice given this dose of idazoxan and cocaine were s i m i l a r to the v e h i c l e - t r e a t e d controls throughout the experiment. The a c t i v i t y
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Effect of idazoxan on the locomotor activity induced by cocaine. Mice were injected i.p. with vehicle (open circles); cocaine 15 m g / k g (closed circles); cocaine 15 mg/kg plus idazoxan 1 m g / k g (open squares) or cocaine 15 mg/kg plus idazoxan 3 mg/kg (closed squares). Values are mean scores (n=8). * P <0.05 versus vehiclet r e a t e d controls; t P <0.05 versus the c o c a i n e - t r e a t e d controls.
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T i m e (rain) FIG. 2 Effect of RX811059 on the locomotor activity induced by cocaine. Mice were injected i.p. with vehicle (open circles); cocaine 15 mg/kg (closed circles); cocaine 15 mg/kg plus RX811059 0.3 m g / k g (open squares) or cocaine 15 mg/kg plus RX811059 1 m g / k g (closed squares). V a l u e s are mean scores (n=8). * P <0.05 versus v e h i c l e t r e a t e d controls; % P <0.05 versus the c o c a i n e - t r e a t e d controls.
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~2-adrenoceptor Antagonists and Cocaine
Vol. 50, No. 19, 1992
scores of mice treated with cocaine and idazoxan (i mg/kg) were not s i g n i f i c a n t l y d i f f e r e n t from the cocaine-control group. H o w e v e r , t h e l o c o m o t o r a c t i v i t y of these animals was not s i g n i f i c a n t l y g r e a t e r than c o n t r o l s at the 5 min reading suggesting that some initial a n t a g o n i s m of c o c a i n e - i n d u c e d locomotion had occurred. R X 8 1 1 0 5 9 (0.3, 1 mg/kg) antagonised c o c a i n e - h y p e r l o c o m o t i o n in a s i m i l a r d o s e - d e p e n d e n t fashion (Fig. 2). R X 8 1 1 0 5 9 (i mg/kg) s i g n i f i c a n t l y a t t e n u a t e d c o c a i n e - i n d u c e d locomotion in the first i0 min of the e x p e r i m e n t and reduced the locomotor scores of this group back to control levels. The activity scores of mice injected with c o c a i n e and a lower dose of RX811059 (0.3 mg/kg) were not s i g n i f i c a n t l y d i f f e r e n t from the cocaine controls. On the other hand, c o c a i n e did not significantly increase l o c o m o t i o n in these animals until the i0 min reading, indicating that R X 8 1 1 0 5 9 (0.3 mg/kg) a n t a g o n i s e d the stimulant effects of cocaine to some extent. I n h i b i t i o n of the locomotor effects of cocaine by the ~2adrenoceptor a n t a g o n i s t s was confirmed by direct b e h a v i o u r a l observation. The doses of idazoxan and RX811059 used in this study did not alter locomotor activity when given alone (for e x a m p l e in the 5 min following injection the mean locomotor a c t i v i t y score of mice t r e a t e d with the highest dose of idazoxan was 1023 c o m p a r e d with a control value of 1319 whereas the mean score of mice injected with the highest dose of RX811059 was 682 c o m p a r e d with a control value of 962; P>0.05). Discussion The major finding of this study is that the ~ 2 - a d r e n o c e p t o r a n t a g o n i s t s idazoxan and RX811059 inhibited the s t i m u l a n t effects of cocaine in mice. A l t h o u g h idazoxan also has high a f f i n i t y for NAIBS (9), this is u n l i k e l y to be of any c o n s e q u e n c e in the current study, since RX811059 which has only low affinity at these sites (ii), p r o d u c e d equivalent actions to idazoxan. Hence the results of this study implicate noradrenergic m e c h a n i s m s in c o c a i n e - i n d u c e d locomotion. Other evidence for this is p r o v i d e d by c o m p a r a b l e e x p e r i m e n t s showing inhibition of the locomotor effects of cocaine in mice by the n o r a d r e n a l i n e uptake blocker n i s o x e t i n e (12). What m e c h a n i s m s may underlie attenuation of the s t i m u l a n t effects of cocaine by ~ 2 - a d r e n o c e p t o r antagonists? One p o s s i b i l i t y derives from the w e l l - e s t a b l i s h e d property of cocaine to increase n o r a d r e n a l i n e a v a i l a b i l i t y (13). Perhaps this can i n d i r e c t l y lead to l o c o m o t o r s t i m u l a t i o n via activation of p o s t - s y n a p t i c ~2a d r e n o c e p t o r s ? This explanation is supported by o b s e r v a t i o n s on the b e h a v i o u r a l effects of the ~ 2 - a d r e n o c e p t o r agonist clonidine. A l t h o u g h at low doses it p r e f e r e n t i a l l y activates p r e - s y n a p t i c ~2adrenoceptors and causes sedation at high doses it p r o d u c e s behavioural activation, which is presumably mediated posts y n a p t i c a l l y (14, 15). Similar reasons have been used to account for the activating effects of clonidine in patients with K o r s a k o f f ' s p s y c h o s i s (16) in which there is d e g e n e r a t i o n of pres y n a p t i c n o r a d r e n e r g i c terminals. A second p o s s i b i l i t y stems from the current v i e w that d o p a m i n e plays an important role in the locomotor effects of cocaine (17). It may be that n o r a d r e n e r g i c ~ 2 - m e d i a t e d inputs have a p e r m i s s i v e role in d o p a m i n e r g i c function, and this is b l o c k e d by
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~ 2 - a d r e n o c e p t o r antagonists. There is c o n s i d e r a b l e e v i d e n c e for a noradrenergic-dopaminergic link as revealed by behavioural, b i o c h e m i c a l and electrophysiological means (18). However, there appear to have been few if any studies on the effects of s e l e c t i v e ~ 2 - a d r e n o c e p t o r antagonists on these phenomena in mice. In c o n c l u s i o n therefore the current findings suggest that n o r a d r e n e r g i c processes may be involved in the s t i m u l a n t effects of cocaine. W h e t h e r this is a direct interaction or an indirect m o d u l a t i o n of cocaines action on dopamine systems is still to be resolved. There is very little literature on the effects of cocaine on brain n o r a d r e n e r g i c systems despite its well e s t a b l i s h e d u p t a k e b l o c k i n g p r o p e r t i e s (13). Most studies have focussed on the action of cocaine on the dopaminergic system. The present findings suggest that ~ 2 - a d r e n o c e p t o r antagonists may have some role in r e d u c i n g the s t i m u l a n t and r e i n f o r c i n g effects of cocaine, and this may be of use in the clinical management of cocaine addiction. References 1.
2.
3o
4. 5.
F.H. GAWIN, Science 2 5 1 1 5 8 0 - 1 5 8 6 (1991). F.H. GAWIN, H.D. KLEBER, R. BYCK, B.J. ROUNSAVILLE, T.R. KOSTEN, P.I. JATLOW and C. MORGAN, Arch. Gen. P s y c h i a t r y 46 117-121 (1989). T. DENNIS, R. L'HEUREUX, C. CARTER and B. SCATTON, J. Pharmacol. Exp. Ther. 2 4 1 6 4 2 - 6 4 9 (1987). A. CARLSSON, K. FUXE, B. HAMBERGER and M. LINDQVIST, Acta Physiol. Scand. 6/7481-489 (1966). K. FUXE and U. UNGERSTEDT, Europ. J. Pharmacol. 4 1 3 5 - 1 4 4
(1968). 7. 8.
J.C. DOXEY, A.G. ROACH and C.F.C. SMITH, Brit. J. Pharmacol. 78489-505 (1983). S.L. DICKINSON, Drug News & Perspectives 4 1 9 7 - 2 0 3 (1991). H.C. JACKSON, D.M. BALL and D.J. NUTT, Life sci. 4/7353-359
9.
M.C. M I C H E L and P.A. INSEL, Trends Pharmacol. Sci. 1 0 3 4 2 - 3 4 4
i0.
J.C. DOXEY, A.C. LANE, A.G. ROACH, C.F.C. SMITH and D.S. WALTER, In: Pharmacology of Adrenoceptors, E. Szabadi, C.M. B r a d s h a w and S.R. Nahorski Eds., pp. 13-22, M a c m i l l a n Press, New York, 1985. N.J. MALLARD, R. TYACKE, A.L. HUDSON and D.J. NUTT, Brit. J. Pharmacol. 1 0 2 2 2 1 P (1991). T.D. T Y L E R and R.E. TESSEL, P s y c h o p h a r m a c o l o g y 6_99 27-34
6.
(1990) . (1989).
ii. 12.
(1980).
15.
L.L. IVERSEN, In: Handbook of Psychopharmacology 3. B i o c h e m i s t r y of Biogenic Amines, L.L. Iversen, S.D. Iversen and S.H. Snyder Eds., pp. 381-442, Plenum Press, N e w York, 1975. D.J. HEAL, M.R. PROW and W.R. BUCKETT, Europ. J. Pharmacol. 17019-28 (1989). U. STROMBOM, N a u n y n - S c h m i e d e b e r g ' s Arch. Pharmacol. 292
16.
R.G.
13.
14.
167-176 (1976). MAIR
and
W.J.
MCENTEE,
Psychopharmacology
88374-380
(1986). 17.
C-E.
JOHANSON
and
M.W.
FISCHMAN,
Pharmacol.
Rev.
4_!i 3-52
(1989). 18.
MAVRIDIS, A.-D. DEGRYSE, A.J. LATEGAN, M.R. F.C. COLPAERT, Neuroscience 4_!i 507-523 (1991).
M.
MARIEN
and
Pergamon
Press
in t h e U S A
PHARMACOLOGY Accelerated
~2-ADRENOCEPTOR
LETTERS
Communication
ANTAGONISTS BLOCK THE STIMULANT COCAINE IN MICE
EFFECTS OF
Helen C. Jackson*, Ian J. Griffin and David J. Nutt Reckitt & Colman Psychopharmacology Unit, Department of Pharmacology, School of Medical Sciences, University Walk, Bristol, BS8 ITD, U.K. (Submitted January 22, 1992; accepted February 14, 1992; received in final form March 3, 1992) Abstract. In the present study we have investigated the effects of the u2-adrenoceptor antagonist idazoxan and its 2-ethoxy derivative RX811059 on the locomotor activity induced by cocaine in mice. The stimulant effects of cocaine (15 mg/kg i.p.) were s i g n i f i c a n t l y antagonised by idazoxan (3 mg/kg i.p.) and RX811059 (i mg/kg i.p.) and also initially suppressed by idazoxan (i mg/kg i.p.) and RX811059 (0.3 mg/kg i.p.). The u2-adrenoceptor antagonists had no effect on locomotion when given alone. These results suggest that noradrenergic mechanisms may play a role in the stimulant effects of cocaine and that u2-adrenceptor antagonists like idazoxan may be of some benefit in the clinical management of cocaine abuse. Introduction The consequences of chronic cocaine use such as craving and crash are major clinical problems that are thought to contribute to the addictive properties of this stimulant drug (i). A commonly used treatment is the tricyclic antidepressant desipramine, which has been shown to alleviate both cocaine craving and crash in man (2). Because desipramine is thought to increase synaptic availability of noradrenaline by blocking its re-uptake (3-5) it is possible that other compounds which similarly elevate noradrenaline levels in the synaptic cleft might also be efficacious. One class of compounds with this property are the e2adrenoceptor antagonists which increase noradrenaline release by blocking inhibitory pre-synaptic autoreceptors (3). Idazoxan is an ~2-adrenoceptor antagonist (6) which has been used successfully in a large number of depressed patients (7). This clinical experience with idazoxan coupled with our previous d e m o n s t r a t i o n that it did not increase cocaine toxicity (8) raises the p o s s i b i l i t y that if effective idazoxan could be used clinically in the treatment of cocaine abuse. In this study we have investigated the effects of idazoxan in a simple model of the psychomotor stimulant effects of cocaine: locomotor activity. * Author for correspondence at: CNS Division, Novo N o r d i s k Park, 2760 Malov, Denmark.
Novo
Nordisk
0024-3205/92 $5.00 + .00 Copyright © 1992 Pergamon Press Ltd All rights reserved.
A/S,
PL-156
u2-adrenoceptor Antagonists and C o c a i n e
Vol. 50, No. 19, 1992
In addition, since idazoxan is also a ligand at nona d r e n o c e p t o r idazoxan binding sites (NAIBS, 9) we have used the more p o t e n t and selective ~2-adrenoceptor a n t a g o n i s t RX811059 (2e t h o x y idazoxan; i0), which has over 3-fold h i g h e r a f f i n i t y for central ~ 2 - a d r e n o c e p t o r s than idazoxan, is over three times more ~ 2 / ~ l - s e l e c t i v e (i0) and has only low affinity for NAIBS (ii). Methods
were 23 ± with were
M a l e TO mice (Bantin & Kingman) in the w e i g h t range 28-35 g used in all experiments. Mice were housed in groups of 30 at 2°C under a 14:10 h light-dark cycle (lights on at 05.00 h) free access to standard rat and mouse diet and water. Mice used on only one occasion.
At the start of each experiment animals were r e m o v e d to a quiet, a i r - c o n d i t i o n e d laboratory (23 ± 2°C) and a c c l i m a t i z e d to these c o n d i t i o n s for at least 1 h before use. All p r o c e d u r e s were c a r r i e d out b e t w e e n 09.00 h and 16.00 h. L o c o m o t o r a c t i v i t y was m e a s u r e d using 4 automated activity boxes. Each c o n s i s t e d of an open t r a n s p a r e n t - p e r s p e x arena (60 cm X 60 cm X 30 cm high). A r o u n d the arena (at floor level) were located 15 sets of infrared e m i t t e r s and detectors which were interfaced to a c o m p u t e r w h i c h r e c o r d e d c o n t i n u o u s l y the number of beam breaks per unit time. Four identical sets of equipment were used so that the locomotor a c t i v i t y of animals from each of 4 different t r e a t m e n t groups could be m o n i t o r e d c o n c u r r e n t l y to control for any v a r i a t i o n s due to the time of day of the experiment. Animals were tested i n d i v i d u a l l y and 2 animals from each treatment group were tested in each of the 4 boxes to account for any variability in either the a c t i v i t y boxes or their environment. The 4 treatment groups (n=8) c o n s i s t e d of a control group which received 2 injections of vehicle; a g r o u p given c o c a i n e (15 mg/kg) and vehicle and 2 groups given cocaine and 1 of 2 doses of the test drug. Animals were h a b i t u a t e d to the a c t i v i t y boxes for 40 min. The ~2-adrenoceptor antagonists were given 5 min before v e h i c l e or cocaine. Locomotor activity was then m o n i t o r e d in 5 min periods for 30 min. Cocaine h y d r o c h l o r i d e (Sigma), idazoxan h y d r o c h l o r i d e and RX811059 h y d r o c h l o r i d e (synthesized at Reckitt & Colman, Hull) were d i s s o l v e d in 0.9 % saline and injected i n t r a p e r i t o n e a l l y in a dose v o l u m e of i0 ml/kg. Doses are expressed as the h y d r o c h l o r i d e salt and were based on those shown to be p h a r m a c o l o g i c a l l y active in other studies in our laboratory (unpublished observations). T r e a t m e n t group means were statistically compared using K r u s k a l Wallis and the M a n n - W h i t n e y U-test (two-tailed). Results Cocaine (15 mg/kg) significantly increased locomotor a c t i v i t y (Figs 1 and 2). This effect was of quick onset and o c c u r r e d m a i n l y in the first 15 min. Idazoxan (i, 3 mg/kg; Fig. i) d e c r e a s e d c o c a i n e - i n d u c e d locomotion in a d o s e - r e l a t e d manner. L o c o m o t o r a c t i v i t y scores of animals given idazoxan (3 mg/kg) and cocaine were s i g n i f i c a n t l y lower than the group given cocaine alone d u r i n g the first i0 min after injection. Furthermore, a c t i v i t y scores of mice given this dose of idazoxan and cocaine were s i m i l a r to the v e h i c l e - t r e a t e d controls throughout the experiment. The a c t i v i t y
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Effect of idazoxan on the locomotor activity induced by cocaine. Mice were injected i.p. with vehicle (open circles); cocaine 15 m g / k g (closed circles); cocaine 15 mg/kg plus idazoxan 1 m g / k g (open squares) or cocaine 15 mg/kg plus idazoxan 3 mg/kg (closed squares). Values are mean scores (n=8). * P <0.05 versus vehiclet r e a t e d controls; t P <0.05 versus the c o c a i n e - t r e a t e d controls.
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T i m e (rain) FIG. 2 Effect of RX811059 on the locomotor activity induced by cocaine. Mice were injected i.p. with vehicle (open circles); cocaine 15 mg/kg (closed circles); cocaine 15 mg/kg plus RX811059 0.3 m g / k g (open squares) or cocaine 15 mg/kg plus RX811059 1 m g / k g (closed squares). V a l u e s are mean scores (n=8). * P <0.05 versus v e h i c l e t r e a t e d controls; % P <0.05 versus the c o c a i n e - t r e a t e d controls.
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scores of mice treated with cocaine and idazoxan (i mg/kg) were not s i g n i f i c a n t l y d i f f e r e n t from the cocaine-control group. H o w e v e r , t h e l o c o m o t o r a c t i v i t y of these animals was not s i g n i f i c a n t l y g r e a t e r than c o n t r o l s at the 5 min reading suggesting that some initial a n t a g o n i s m of c o c a i n e - i n d u c e d locomotion had occurred. R X 8 1 1 0 5 9 (0.3, 1 mg/kg) antagonised c o c a i n e - h y p e r l o c o m o t i o n in a s i m i l a r d o s e - d e p e n d e n t fashion (Fig. 2). R X 8 1 1 0 5 9 (i mg/kg) s i g n i f i c a n t l y a t t e n u a t e d c o c a i n e - i n d u c e d locomotion in the first i0 min of the e x p e r i m e n t and reduced the locomotor scores of this group back to control levels. The activity scores of mice injected with c o c a i n e and a lower dose of RX811059 (0.3 mg/kg) were not s i g n i f i c a n t l y d i f f e r e n t from the cocaine controls. On the other hand, c o c a i n e did not significantly increase l o c o m o t i o n in these animals until the i0 min reading, indicating that R X 8 1 1 0 5 9 (0.3 mg/kg) a n t a g o n i s e d the stimulant effects of cocaine to some extent. I n h i b i t i o n of the locomotor effects of cocaine by the ~2adrenoceptor a n t a g o n i s t s was confirmed by direct b e h a v i o u r a l observation. The doses of idazoxan and RX811059 used in this study did not alter locomotor activity when given alone (for e x a m p l e in the 5 min following injection the mean locomotor a c t i v i t y score of mice t r e a t e d with the highest dose of idazoxan was 1023 c o m p a r e d with a control value of 1319 whereas the mean score of mice injected with the highest dose of RX811059 was 682 c o m p a r e d with a control value of 962; P>0.05). Discussion The major finding of this study is that the ~ 2 - a d r e n o c e p t o r a n t a g o n i s t s idazoxan and RX811059 inhibited the s t i m u l a n t effects of cocaine in mice. A l t h o u g h idazoxan also has high a f f i n i t y for NAIBS (9), this is u n l i k e l y to be of any c o n s e q u e n c e in the current study, since RX811059 which has only low affinity at these sites (ii), p r o d u c e d equivalent actions to idazoxan. Hence the results of this study implicate noradrenergic m e c h a n i s m s in c o c a i n e - i n d u c e d locomotion. Other evidence for this is p r o v i d e d by c o m p a r a b l e e x p e r i m e n t s showing inhibition of the locomotor effects of cocaine in mice by the n o r a d r e n a l i n e uptake blocker n i s o x e t i n e (12). What m e c h a n i s m s may underlie attenuation of the s t i m u l a n t effects of cocaine by ~ 2 - a d r e n o c e p t o r antagonists? One p o s s i b i l i t y derives from the w e l l - e s t a b l i s h e d property of cocaine to increase n o r a d r e n a l i n e a v a i l a b i l i t y (13). Perhaps this can i n d i r e c t l y lead to l o c o m o t o r s t i m u l a t i o n via activation of p o s t - s y n a p t i c ~2a d r e n o c e p t o r s ? This explanation is supported by o b s e r v a t i o n s on the b e h a v i o u r a l effects of the ~ 2 - a d r e n o c e p t o r agonist clonidine. A l t h o u g h at low doses it p r e f e r e n t i a l l y activates p r e - s y n a p t i c ~2adrenoceptors and causes sedation at high doses it p r o d u c e s behavioural activation, which is presumably mediated posts y n a p t i c a l l y (14, 15). Similar reasons have been used to account for the activating effects of clonidine in patients with K o r s a k o f f ' s p s y c h o s i s (16) in which there is d e g e n e r a t i o n of pres y n a p t i c n o r a d r e n e r g i c terminals. A second p o s s i b i l i t y stems from the current v i e w that d o p a m i n e plays an important role in the locomotor effects of cocaine (17). It may be that n o r a d r e n e r g i c ~ 2 - m e d i a t e d inputs have a p e r m i s s i v e role in d o p a m i n e r g i c function, and this is b l o c k e d by
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~ 2 - a d r e n o c e p t o r antagonists. There is c o n s i d e r a b l e e v i d e n c e for a noradrenergic-dopaminergic link as revealed by behavioural, b i o c h e m i c a l and electrophysiological means (18). However, there appear to have been few if any studies on the effects of s e l e c t i v e ~ 2 - a d r e n o c e p t o r antagonists on these phenomena in mice. In c o n c l u s i o n therefore the current findings suggest that n o r a d r e n e r g i c processes may be involved in the s t i m u l a n t effects of cocaine. W h e t h e r this is a direct interaction or an indirect m o d u l a t i o n of cocaines action on dopamine systems is still to be resolved. There is very little literature on the effects of cocaine on brain n o r a d r e n e r g i c systems despite its well e s t a b l i s h e d u p t a k e b l o c k i n g p r o p e r t i e s (13). Most studies have focussed on the action of cocaine on the dopaminergic system. The present findings suggest that ~ 2 - a d r e n o c e p t o r antagonists may have some role in r e d u c i n g the s t i m u l a n t and r e i n f o r c i n g effects of cocaine, and this may be of use in the clinical management of cocaine addiction. References 1.
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