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The dopamine hypothesis of opiate reward challenged
European Journal of Pharmacology, 134 (1987) 239-243 Elsevier
239
EJP 146SC
Short communication
The dopamine hypothesis of opiate reward challenged J a n M V a n Ree * a n d N i c k R a m s e y Rudolf Magnus Institute for Pharmacology, Medt~al Fa~ultv, Unwer~ltv of Utrecht, Vondellaan 6, 3521 GD Utre~ht The Netherlands Received 14 November 1986, accepted 16 December 1986
The d o p a r m n e hypothesis of opiate reward was darectly tested b y blockang d o p a m m e receptor h a l o p e n d o l H a l o p e n d o l was a d n u m s t e r e d either systemically or locally into different b r a i n areas with ternunals an rats allowed to amtmte a n d maantaan intravenous heroin self-adm~mstratmn H a l o p e n d o l n o t block heroin reward It as concluded that d o p a m l n e as not cntacally involved m opmte reward a n d e n d o g e n o u s reward systems are present m the b r a i n
systems with dopamlnerglc t r e a t m e n t dad that multiple
Halopendol, Dopanune terrmnal areas, Heroin self-admxmstratmn, Opiate reward, Dopanune 1. Introduction D u n n g the last decade theories have been presented concerning a common endogenous system in the brain that medmtes the reward from various sources, including intracramal electrical stimulation, different types of addictive drugs and even natural reinforcers (Flbiger, 1978, Wise, 1983) Indeed, evidence suggests that central catecholamines are concerned in behaviors aimed to obtain a reward to brain stimulation (German and Bowden, 1974) and involved in the reinforcing properties of psychoactive stimulants (Wise, 1983) In particular, activation of central dopamine receptor systems has been lmphcated as a common factor in different sources of reward This has lead to the dopamane hypothesis of reward which suggests that dopamlne plays a critical and unique role in brain reward in general, and thus also in opiate reward (Wise, 1983) Although activation of opiate receptor mechanisms certainly interferes with brain doparmne function (Schwartz et al, 1977), direct evidence for the involvement of bram dopamlne in opiate reward is lacking We have
* To whom all correspondence should be addressed
tested this possible dopamme involvement by blocking doparmne receptor systems with the doparmne antagonist haloperidol administered either systemically or into speclflC brain areas in animals allowed to inmate and maintain intravenous (i v ) heroin self-administration This is a test system directly measuring heroin reward (Van Ree, 1979) The selected brain areas were terrmnal areas of doparmnerglc pathways the nucleus caudatus, where terminals of the nlgrostrlatal pathway are present, the nucleus accumbens and central amygdala with ternunals of the mesohmblc dopamlne pathway and the medial prefrontal cortex and the pyriform cortex where terminals of the mesocortical dopamlne pathway are located
2. Materials and methods Male Wlstar rats (TNO, Zelst, The Netherlands) from our own breeding stock, weighing 200-240 g at the time of operation were, under H y p n o r m® anesthesia, equipped with an i v cannula system of silicone plastic, prepared in such a way that infusion fluid could be injected into the vene, but that blood could not enter the cannula
0014-2999/87/$03 50 © 1987 Elsevier Science Pubhshers B V (Blome&cal Division)
240 system Thus, contact between infusion fluid a n d blood was only present d u r i n g the time of mfusion This permits d i s c o n n e c t i o n of this infuston system a n d prevents blood coagulation without using a n t i c o a g u l a n t s In the same session, in which the m t r a v e n o u s c a n n u l a system was i m p l a n t e d the rats were prepared for intracerebral mjections Rats were secured in a stereotax~c i n s t r u m e n t a n d stainless steel guide c a n n u l a s (0 6 m m outer diameter, 0 3 m m i n n e r dmmeter) were i m p l a n t e d on each side of the b r a i n (bilaterally) a n d aimed at various areas of the brain, l e the nucleus caudatus, nucleus accumbens, central amygdala, medial prefrontal cortex a n d pyriform cortex The rats were allowed to recover from the o p e r a t i o n procedure for 5-7 days before testing was started The test cages were s t a n d a r d o p e r a n t c o n d i t i o n i n g cages placed in s o u n d - a t t e n u a t e d rooms and e q m p p e d with two levers, one of whtch was marked by an lllurmnated light placed just above the lever The IV c a n n u l a of the rat was c o n n e c t e d to an i n f u s i o n p u m p via a swtvel, perm l t t m g the a n i m a l s to move relatively freely The rats were o n a reversed dark-light schedule a n d testing was performed d u r i n g the dark phase They were tested o n 5 consecutive days for 6 h per day The rest of the day they were housed in home cages, one rat per cage Water was avadable ad h b l t u m in the h o m e cages only As food deprlvan o n has b e e n shown to facilitate acqulsttion of h e r o m self-admlnlstratton, food was restricted to such an extent that the body weight of the rats was a b o u t 80% (_+5%) of their original b o d y weight Pressmg the lever marked by the ill u m i n a t e d light, resulted in a 0 25 ml infuston of heroin ( d t a c e t y l m o r p h i n e hydrochloride, dissolved in saline, p H 7 35, 0 15 m g / k g per injectton), u s m g a c o n t i n u o u s r e m f o r c e m e n t schedule Ourmg the time of i n f u s i o n (15 s) the hght above the lever was t u r n e d off and pressing the lever was not reinforced b y a d d i t i o n a l injection At the first day of testing the rats received every hour an infusion with heroin by the e x p e r l m e n t a t o r a n d two infusions were given every day at the start of the e x p e r i m e n t a l session These infusions were not c o u n t e d Details of the experimental procedure have been p u b h s h e d (Van Ree, 1982)
In the first experiment, groups of animals (n = 8-11) were pretreated s u b c u t a n e o u s l y (s c ) every day 1 h before the experimental session with placebo or graded doses of haloperldol (Haldol~L diluted with saline, 0 125-1 125 m g / k g ) I n subseq u e n t experiments, rats were injected lntracerebrally using a H a m d t o n syringe, the needle (0 25 m m outer diameter) was mserted into the gutde c a n n u l a O n e mlcroliter s o l u n o n was mjected at a rate of 2 /~1 m l n l G r o u p s of rats (n = 6-17) were pretreated btlaterally m the indicated areas of the b r a i n with saline a n d graded doses of haloperidol (0 01-1 /~g) 0 5 h before each experim e n t a l session Each a m m a l was tested only once After experiments were completed the injection sttes were evaluated histologically the rats were kdled a n d the brains fixed In 4% f o r m a h n Serial sections (100 /~m thick) were cut on a cryostat The sites of injection were d e t e r m i n e d microscopically usmg the atlas of K o m g a n d K h p p e l (1963) Stattstical analysis was performed using a multiple analysis of variance (repeated m e a s u r e m e n t design) (SPSS c o m p u t e r program)
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Fig 1 The influence of subcutaneous halopendol pretreatment on intravenous heroin self-admamstranonof rats Nmve anamals were allowed to self-admlmster heroin (0 15 mg/kg per mjecnon) for 6 h dunng 5 consecunve days Groups of rats were pretreated with sahne (O, n = 11) or graded doses of halopendol ( x , 0 125 mg/kg, n = 9, O, 0 375 mg/kg, n = 10, D, 1 125 mg/kg, n = 8) 1 h before the dmly experimental sessaon The mean number of self lnjecnons is plotted versus the days of testing Vertical bars represent S E M of two groups on the last test day The S E M s of the other groups and on the other test days were comparable to those presented * Different from saline pretreatment (MANOVA, treatment effect, * P < 0 05, • * P < 001, mean hme effect (P < 0001), no interaction between treatment and tame)
241 CAUDATUS
ACCUMBENS
AMYGDALA
4O
o
B
30
10
7
Z
1
2
3
4
5
2
3
4
1
2
3
4
5
LI,J
:[
MEDIAL PREFRONTAL ODRTEX
PYRIFORM 03RTEX
40
30
1
2
oys
Fig 2 The influence of mtracerebral halopendol pretreatment on intravenous heroin self-admlmstrat:on of rats Naave ammals were allowed to self-admlmster heroin (0 15 m g / k g per m lecnon) for 6 h dunng 5 consecutive days Groups of rats (n = 6-17) were bdaterally pretreated with sahne (m) or graded doses of halopendol (D, 0 01 #g, I~, 0 1 pg, [], 1 p.g) into the indicated braan areas 0 5 h before the daaly experimental session The top of the figures represents examples of the p o s m o n of the top of the cannula as revealed from lustologlcal evaluahon Drawings are taken from Komg and Khppel (15) At the bottom of the figures the mean number of self mject:ons is plotted versus the days of testing Vertical bars represent S E M on the last test day The S E M s on the other days were comparable to those of the last day MANOVA revealed that the middle dose of haloperldol (0 1 p.g) increased heroin intake m the medial prefrontal cortex (P < 0 02), a maan time effect for all areas (P < 0 01), and no interaction between treatment and time in any area
242 3. Results
4. Discussion
Self-administration b e h a v i o r was readily acquired and increased during the first days reaching a ceiling on the 4th and 5th test day. The lowest dose of haloperldol (0 125 m g / k g ) did not affect the heroin intake of the rats, but the two highest doses decreased this intake (fig 1, MANOVA F(3,34)=44, P<001) A significant effect of time was observed (P < 0 001), but no interaction between treatment and time was present (P > 0.05), indicating that the rate of acquisition of heroin self-admimstration was slmalar in all treatment groups. Thus, although a decrease of heroin intake was found after relatively high doses of haloperldol, the rats still acquired and maintained responding for heroin reward, but at a somewhat lower level. In subsequent experiments, haloperldol was injected into different t e r m i n a l areas of dopaminergic pathways in the brain The positions of the top of the cannula as revealed from histological evaluation are shown in fig 2 In all sahne-pretreated groups the rats acqmred and maintained i v heroin self-administration (fig. 2) The level of heroin intake varied among the groups, the lowest and highest heroin intake was found in rats with cannulas in the medial prefrontal cortex and the nucleus accumbens respectively Treatment with haloperldol did not affect heroin intake in any of the brain areas under investigation, except that m the medial prefrontal cortex the middle dose of haloperldol (0 1 ~g) increased responding for heroin reward ( M A N O V A F(3, 34) = 4 1, P < 0 02) In all tested areas a mean time effect and no interaction between treatment and time was present, indicating that heroin intake increased over the test days but the intake increased similarly for the different treatment groups Thus, in none of the areas did relatively high doses of halopendol decrease heroin intake Additional experiments showed that also lower doses of haloperldol (10 pg-1 ng) injected into the nucleus accumbens did not change 1 v heroin self-adrmmstratlon
The present data suggest that haloperldol administered s c m a dose of 0 4-1 m g / k g decreased heroin Intake, but that thus treated rats still engaged m selfadmlnlstenng behavior, Indicating that heroin reward is not blocked in these rats Since the dose of haloperldol required to decrease heroin intake is 2-3 orders of magnitude higher than that needed to counteract behavioral changes induced by the dopanune agonlst apomorptune (Serra et al, 1983), and to decrease exploration behavior, the effect of haloperldol on heroin reward is most likely not mediated by the blocking action of this drug of dopamlne systems. Accordingly, in none of the Investigated dopamlne terminal areas of the brain a decreasing effect of haloperldol was observed Also the dose of haloperldol injected lntracramally was quite high, since, e g 1-10 pg of this drug can completely antagonize apomorphlne-lnduced behavioral changes following local injection into the nucleus accumbens (Van Ree et al, 1982) and pyriform cortex (unpubhshed data) Maybe haloperidol did not block dopamlne receptors for the entire period of the 6 h lasting session However, in a separate experiment it was shown that stereotyped sniffing elicited by mjecUon of apomorphine into the nucleus caudatus was completely antagonized by local haloperldol (1 t~g) pretreatment 6 h before apomorphine (unpubhshed data). The present investigation challenged the hypothesis that d o p a m m e is critically involved m heroin reward (Flbxger, 1978, Wise, 1983) Thus, the reward mechamsm implicated in opiate reward may be different from those concerned in other types of reward Accordingly, it has been shown that destruction of doparmne systems m the nucleus accumbens selectively attenuates cocaine, but not heroin reward in rats, and that opiate and dopamine receptor antagonists differentially affect heroin and cocaine self-administration (Pettit et al, 1984) Following the same procedure as outlined in this paper, we found that when naltrexone (100 /~g/rat) was injected s c instead of haloperidol, the heroin self-administration was gradually decreased during the 5 days test period (number of self-injections on last test day 6 1 + 1 9)
243 T h u s , at is m o r e likely t h a t r e c e p t o r s y s t e m s f o r e n d o g e n o u s o p l o l d s rather t h a n d o p a m l n e are a critical substrate for o p m t e reward. Multiple endogenous reward systems may therefore be present m the brain, which suggestion has consequences for the underlying mechamsm
of reward
a n d a d d i c t i o n b u t also for the t r e a t m e n t of various types of addlcuon.
Acknowledgements The authors wish to thank Emdxe Burbach-Bloemarts for her skdlful techmcal assistance and the Mlmstry of Welfare, Health and Cultural Affa_trs, The Netherlands, for financial support
References Flbxger, H C , 1978, Drugs and reinforcement mechamsms A critical review of the catecholamxne theory, Ann Rev Pharmacol Toxacol 18, 37 German, D C and D M Bowden, 1974, Catecholamme systems as the neuronal substrate for lntracranlal self-stlmulauon A hypothesis, Braun Res 73,381 Komg, J F R and R A Khppel, 1963, The Rat Brain, a Stereotaxac Atlas (Wllhams and Wdkms Co, Baltamore)
Pettlt, H O, A Ettenberg, F E Bloom and G F Koob, 1984, Destruction of dopamlne in the nucleus accumbens selectively attenuates cocaane but not heroin self-administration m rats, Psychopharmacology 84, 167 Schwartz, J C , H Pollard, C Llorens, B Malfroy, C Gros, P Pradelles and F Dray, 1977, Endorphlns and endorphln receptors in stnatum Relationships with dopamlnerglc neurons, in Advances in Biochemical Psychopharmacology, ed E Costa (Raven Press, New York) p 245 Serra, G , J M Van Ree and D De Wled, 1983, Influence of classtcal and atypical neuroleptlcs on apomorphlne-xnduced behavioral changes and on extinction of a conditioned avoidance response, J Pharm Pharmacol 35, 255 Van Ree, J M , 1979, Reinforcing stimulus properties of drugs, Neuropharmacology 18, 963 Van Ree, J M , 1982, Neurohypophyseal hormones and addiction, m Advances in Pharmacology and Therapeutics II, Vol 1, eds H Yoshada, Y Haglhara and S Ebashl (Pergamon Press, Oxford) p 199 Van Ree, J M , A M Caffd and G Woltennk, 1982, Non-opiate fl-endorphln fragments and dopamme III T-Type endorphlns and various neuroleptlcs counteract the hypoactXVltyehcited by rejection of apomorphine into the nucleus accumbens, Neuropharmacology 21, 1111 Wise, R A , 1983, Braan neuronal systems mediating reward processes, m The Neurobaology of Opiate Reward Processes, eds J E Smith and J D Lane (Elsevier Biomedical Press, Amsterdam) p 405
239
EJP 146SC
Short communication
The dopamine hypothesis of opiate reward challenged J a n M V a n Ree * a n d N i c k R a m s e y Rudolf Magnus Institute for Pharmacology, Medt~al Fa~ultv, Unwer~ltv of Utrecht, Vondellaan 6, 3521 GD Utre~ht The Netherlands Received 14 November 1986, accepted 16 December 1986
The d o p a r m n e hypothesis of opiate reward was darectly tested b y blockang d o p a m m e receptor h a l o p e n d o l H a l o p e n d o l was a d n u m s t e r e d either systemically or locally into different b r a i n areas with ternunals an rats allowed to amtmte a n d maantaan intravenous heroin self-adm~mstratmn H a l o p e n d o l n o t block heroin reward It as concluded that d o p a m l n e as not cntacally involved m opmte reward a n d e n d o g e n o u s reward systems are present m the b r a i n
systems with dopamlnerglc t r e a t m e n t dad that multiple
Halopendol, Dopanune terrmnal areas, Heroin self-admxmstratmn, Opiate reward, Dopanune 1. Introduction D u n n g the last decade theories have been presented concerning a common endogenous system in the brain that medmtes the reward from various sources, including intracramal electrical stimulation, different types of addictive drugs and even natural reinforcers (Flbiger, 1978, Wise, 1983) Indeed, evidence suggests that central catecholamines are concerned in behaviors aimed to obtain a reward to brain stimulation (German and Bowden, 1974) and involved in the reinforcing properties of psychoactive stimulants (Wise, 1983) In particular, activation of central dopamine receptor systems has been lmphcated as a common factor in different sources of reward This has lead to the dopamane hypothesis of reward which suggests that dopamlne plays a critical and unique role in brain reward in general, and thus also in opiate reward (Wise, 1983) Although activation of opiate receptor mechanisms certainly interferes with brain doparmne function (Schwartz et al, 1977), direct evidence for the involvement of bram dopamlne in opiate reward is lacking We have
* To whom all correspondence should be addressed
tested this possible dopamme involvement by blocking doparmne receptor systems with the doparmne antagonist haloperidol administered either systemically or into speclflC brain areas in animals allowed to inmate and maintain intravenous (i v ) heroin self-administration This is a test system directly measuring heroin reward (Van Ree, 1979) The selected brain areas were terrmnal areas of doparmnerglc pathways the nucleus caudatus, where terminals of the nlgrostrlatal pathway are present, the nucleus accumbens and central amygdala with ternunals of the mesohmblc dopamlne pathway and the medial prefrontal cortex and the pyriform cortex where terminals of the mesocortical dopamlne pathway are located
2. Materials and methods Male Wlstar rats (TNO, Zelst, The Netherlands) from our own breeding stock, weighing 200-240 g at the time of operation were, under H y p n o r m® anesthesia, equipped with an i v cannula system of silicone plastic, prepared in such a way that infusion fluid could be injected into the vene, but that blood could not enter the cannula
0014-2999/87/$03 50 © 1987 Elsevier Science Pubhshers B V (Blome&cal Division)
240 system Thus, contact between infusion fluid a n d blood was only present d u r i n g the time of mfusion This permits d i s c o n n e c t i o n of this infuston system a n d prevents blood coagulation without using a n t i c o a g u l a n t s In the same session, in which the m t r a v e n o u s c a n n u l a system was i m p l a n t e d the rats were prepared for intracerebral mjections Rats were secured in a stereotax~c i n s t r u m e n t a n d stainless steel guide c a n n u l a s (0 6 m m outer diameter, 0 3 m m i n n e r dmmeter) were i m p l a n t e d on each side of the b r a i n (bilaterally) a n d aimed at various areas of the brain, l e the nucleus caudatus, nucleus accumbens, central amygdala, medial prefrontal cortex a n d pyriform cortex The rats were allowed to recover from the o p e r a t i o n procedure for 5-7 days before testing was started The test cages were s t a n d a r d o p e r a n t c o n d i t i o n i n g cages placed in s o u n d - a t t e n u a t e d rooms and e q m p p e d with two levers, one of whtch was marked by an lllurmnated light placed just above the lever The IV c a n n u l a of the rat was c o n n e c t e d to an i n f u s i o n p u m p via a swtvel, perm l t t m g the a n i m a l s to move relatively freely The rats were o n a reversed dark-light schedule a n d testing was performed d u r i n g the dark phase They were tested o n 5 consecutive days for 6 h per day The rest of the day they were housed in home cages, one rat per cage Water was avadable ad h b l t u m in the h o m e cages only As food deprlvan o n has b e e n shown to facilitate acqulsttion of h e r o m self-admlnlstratton, food was restricted to such an extent that the body weight of the rats was a b o u t 80% (_+5%) of their original b o d y weight Pressmg the lever marked by the ill u m i n a t e d light, resulted in a 0 25 ml infuston of heroin ( d t a c e t y l m o r p h i n e hydrochloride, dissolved in saline, p H 7 35, 0 15 m g / k g per injectton), u s m g a c o n t i n u o u s r e m f o r c e m e n t schedule Ourmg the time of i n f u s i o n (15 s) the hght above the lever was t u r n e d off and pressing the lever was not reinforced b y a d d i t i o n a l injection At the first day of testing the rats received every hour an infusion with heroin by the e x p e r l m e n t a t o r a n d two infusions were given every day at the start of the e x p e r i m e n t a l session These infusions were not c o u n t e d Details of the experimental procedure have been p u b h s h e d (Van Ree, 1982)
In the first experiment, groups of animals (n = 8-11) were pretreated s u b c u t a n e o u s l y (s c ) every day 1 h before the experimental session with placebo or graded doses of haloperldol (Haldol~L diluted with saline, 0 125-1 125 m g / k g ) I n subseq u e n t experiments, rats were injected lntracerebrally using a H a m d t o n syringe, the needle (0 25 m m outer diameter) was mserted into the gutde c a n n u l a O n e mlcroliter s o l u n o n was mjected at a rate of 2 /~1 m l n l G r o u p s of rats (n = 6-17) were pretreated btlaterally m the indicated areas of the b r a i n with saline a n d graded doses of haloperidol (0 01-1 /~g) 0 5 h before each experim e n t a l session Each a m m a l was tested only once After experiments were completed the injection sttes were evaluated histologically the rats were kdled a n d the brains fixed In 4% f o r m a h n Serial sections (100 /~m thick) were cut on a cryostat The sites of injection were d e t e r m i n e d microscopically usmg the atlas of K o m g a n d K h p p e l (1963) Stattstical analysis was performed using a multiple analysis of variance (repeated m e a s u r e m e n t design) (SPSS c o m p u t e r program)
c~
o
30
20 ~D
E
~
S i
I
i
2
J
3
4
5 doys
Fig 1 The influence of subcutaneous halopendol pretreatment on intravenous heroin self-admamstranonof rats Nmve anamals were allowed to self-admlmster heroin (0 15 mg/kg per mjecnon) for 6 h dunng 5 consecunve days Groups of rats were pretreated with sahne (O, n = 11) or graded doses of halopendol ( x , 0 125 mg/kg, n = 9, O, 0 375 mg/kg, n = 10, D, 1 125 mg/kg, n = 8) 1 h before the dmly experimental sessaon The mean number of self lnjecnons is plotted versus the days of testing Vertical bars represent S E M of two groups on the last test day The S E M s of the other groups and on the other test days were comparable to those presented * Different from saline pretreatment (MANOVA, treatment effect, * P < 0 05, • * P < 001, mean hme effect (P < 0001), no interaction between treatment and tame)
241 CAUDATUS
ACCUMBENS
AMYGDALA
4O
o
B
30
10
7
Z
1
2
3
4
5
2
3
4
1
2
3
4
5
LI,J
:[
MEDIAL PREFRONTAL ODRTEX
PYRIFORM 03RTEX
40
30
1
2
oys
Fig 2 The influence of mtracerebral halopendol pretreatment on intravenous heroin self-admlmstrat:on of rats Naave ammals were allowed to self-admlmster heroin (0 15 m g / k g per m lecnon) for 6 h dunng 5 consecutive days Groups of rats (n = 6-17) were bdaterally pretreated with sahne (m) or graded doses of halopendol (D, 0 01 #g, I~, 0 1 pg, [], 1 p.g) into the indicated braan areas 0 5 h before the daaly experimental session The top of the figures represents examples of the p o s m o n of the top of the cannula as revealed from lustologlcal evaluahon Drawings are taken from Komg and Khppel (15) At the bottom of the figures the mean number of self mject:ons is plotted versus the days of testing Vertical bars represent S E M on the last test day The S E M s on the other days were comparable to those of the last day MANOVA revealed that the middle dose of haloperldol (0 1 p.g) increased heroin intake m the medial prefrontal cortex (P < 0 02), a maan time effect for all areas (P < 0 01), and no interaction between treatment and time in any area
242 3. Results
4. Discussion
Self-administration b e h a v i o r was readily acquired and increased during the first days reaching a ceiling on the 4th and 5th test day. The lowest dose of haloperldol (0 125 m g / k g ) did not affect the heroin intake of the rats, but the two highest doses decreased this intake (fig 1, MANOVA F(3,34)=44, P<001) A significant effect of time was observed (P < 0 001), but no interaction between treatment and time was present (P > 0.05), indicating that the rate of acquisition of heroin self-admimstration was slmalar in all treatment groups. Thus, although a decrease of heroin intake was found after relatively high doses of haloperldol, the rats still acquired and maintained responding for heroin reward, but at a somewhat lower level. In subsequent experiments, haloperldol was injected into different t e r m i n a l areas of dopaminergic pathways in the brain The positions of the top of the cannula as revealed from histological evaluation are shown in fig 2 In all sahne-pretreated groups the rats acqmred and maintained i v heroin self-administration (fig. 2) The level of heroin intake varied among the groups, the lowest and highest heroin intake was found in rats with cannulas in the medial prefrontal cortex and the nucleus accumbens respectively Treatment with haloperldol did not affect heroin intake in any of the brain areas under investigation, except that m the medial prefrontal cortex the middle dose of haloperldol (0 1 ~g) increased responding for heroin reward ( M A N O V A F(3, 34) = 4 1, P < 0 02) In all tested areas a mean time effect and no interaction between treatment and time was present, indicating that heroin intake increased over the test days but the intake increased similarly for the different treatment groups Thus, in none of the areas did relatively high doses of halopendol decrease heroin intake Additional experiments showed that also lower doses of haloperldol (10 pg-1 ng) injected into the nucleus accumbens did not change 1 v heroin self-adrmmstratlon
The present data suggest that haloperldol administered s c m a dose of 0 4-1 m g / k g decreased heroin Intake, but that thus treated rats still engaged m selfadmlnlstenng behavior, Indicating that heroin reward is not blocked in these rats Since the dose of haloperldol required to decrease heroin intake is 2-3 orders of magnitude higher than that needed to counteract behavioral changes induced by the dopanune agonlst apomorptune (Serra et al, 1983), and to decrease exploration behavior, the effect of haloperldol on heroin reward is most likely not mediated by the blocking action of this drug of dopamlne systems. Accordingly, in none of the Investigated dopamlne terminal areas of the brain a decreasing effect of haloperldol was observed Also the dose of haloperldol injected lntracramally was quite high, since, e g 1-10 pg of this drug can completely antagonize apomorphlne-lnduced behavioral changes following local injection into the nucleus accumbens (Van Ree et al, 1982) and pyriform cortex (unpubhshed data) Maybe haloperidol did not block dopamlne receptors for the entire period of the 6 h lasting session However, in a separate experiment it was shown that stereotyped sniffing elicited by mjecUon of apomorphine into the nucleus caudatus was completely antagonized by local haloperldol (1 t~g) pretreatment 6 h before apomorphine (unpubhshed data). The present investigation challenged the hypothesis that d o p a m m e is critically involved m heroin reward (Flbxger, 1978, Wise, 1983) Thus, the reward mechamsm implicated in opiate reward may be different from those concerned in other types of reward Accordingly, it has been shown that destruction of doparmne systems m the nucleus accumbens selectively attenuates cocaine, but not heroin reward in rats, and that opiate and dopamine receptor antagonists differentially affect heroin and cocaine self-administration (Pettit et al, 1984) Following the same procedure as outlined in this paper, we found that when naltrexone (100 /~g/rat) was injected s c instead of haloperidol, the heroin self-administration was gradually decreased during the 5 days test period (number of self-injections on last test day 6 1 + 1 9)
243 T h u s , at is m o r e likely t h a t r e c e p t o r s y s t e m s f o r e n d o g e n o u s o p l o l d s rather t h a n d o p a m l n e are a critical substrate for o p m t e reward. Multiple endogenous reward systems may therefore be present m the brain, which suggestion has consequences for the underlying mechamsm
of reward
a n d a d d i c t i o n b u t also for the t r e a t m e n t of various types of addlcuon.
Acknowledgements The authors wish to thank Emdxe Burbach-Bloemarts for her skdlful techmcal assistance and the Mlmstry of Welfare, Health and Cultural Affa_trs, The Netherlands, for financial support
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