Persistent supersensitivity of σ receptors develops during repeated methamphetamine treatment

European Journal of Pharmacology, 211 (1992) 323-328

2

© 1992 Elsevier Science Publishers B.V. All rights reserved 0014-2999/92/$05.00

EJP 52290

Persistent supersensitivity of o- receptors develops during repeated methamphetamine treatment H i r o s h i Ujike, K a z u y a O k u m u r a , Y o s h i f u m i Z u s h i , K a z u f u m i A k i y a m a a n d S a b u r o O t s u k i Department of Neuropsychiatry, Okayama University Medical School, 2-5-1 Shikata-cho, Okayama 700, Japan

Received 10 June 1991, revised MS received 20 November 1991, accepted 26 November 1991

Functional changes in cr receptors were examined after behavioral sensitization induced by repeated methamphetami treatment. Rats received either saline or 4 mg/kg methamphetamine for 14 days. (+)3-(3-hydroxyphenyl)-N-(1-propyl)piperidi ((+)-3-PPP), a ~ receptor agonist, was given as challenge after various periods of abstinence. (+)-3-PPP at doses greater than mg/kg stimulated several forms of behavior in naive rats. (+)-3-PPP at 12 and 24 mg/kg produced more frequent rearing a more intense stereotyped sniffing and repetitive head movements in rats previously sensitized with methamphetamine than saline-pretreated rats. The augmented response to (+)-3-PPP in methamphetamine-treated rats was maintained for at least o month. The augmented response to (+)-3-PPP was reversed by the combined administration of 100 mg/kg (+)-sulpiride, a i dopamine receptor antagonist, and 30 mg/kg BMY 14802, a ~r receptor antagonist. These results suggest that repeat methamphetamine treatment induces persistent supersensitivity in o- receptors and that it may subsequently activate t dopamine system. o- Receptors; ( + )-3-PPP ((+)-3-(3-hydroxyphenyl)-N-propylpiperidine); Behavioral sensitization; Methamphetamine; BMY 14802

1. Introduction The o- receptor was designated a novel putative subtype of opiate receptor by Martin et al. (1976) and may mediate some of the actions of benzomorphans, Later, binding assay and autoradiography studies with radiolabeled selective or ligands revealed that ~r receptors are widely distributed in the central nervous systern, but that they should not be classified as a opiate receptor subtype and differ from phencyclidine (PCP) receptors (Largent et al., 1984; W e b e r et al., 1986). The possible involvement of ~r receptors in the psychopharmacology of schizophrenia was suggested by the finding that haloperidol, a prototype butyrophenone-type neuroleptica, has significant affinity for ~r receptors at nanomolar concentrations (Largent et al., 1984; T a m and Cook, 1984; H a r a d a et al., 1989). Recently developed atypical neuroleptics such as rimcazole, B M Y 14802, remoxipride and tiospirone share a high affinity for o- receptors (Largent et al., 1988). Although rimcazole and BMY 14802 do not show significant affinity for D 2 dopamine receptors, they

showed potent antipsychotic effects both in preclink screening tests and in early clinical trials (Ferris et 1982; Davidson et al., 1982; Chouinard and Annab 1984; Taylor et al., 1985; Ujike, 1991). Recently, Wei: man et al. (1991) reported that cerebral cortex receptors were reduced in patients with schizophren These findings suggest that or receptors may be J volved in the antipsychotic effects of neuroleptics a: in the pathogenesis of schizophrenia. It is well documented that behavioral sensitizati or reverse tolerance after repeated m e t h a m p h e t a m i administration is an animal model of vulnerability acute exacerbation in m e t h a m p h e t a m i n e psychosis a schizophrenia (Ellinwood et al., 1973; Angrist, 191 Robinson and Becker, 1986). In view of the significz affinity of some atypical neuroleptics for ~ receptc and the modulating effects of cr receptor-related co: pounds on dopamine neurons (Ceci et al., 1988; Ste: fels and Tam, 1989), a receptors might be involved psychosis and methamphetamine-induced behavio: sensitization. However, as yet there have been no stt ies examining whether cr receptors are involved methamphetamine-induced sensitization. The pres~ study investigated behavioral changes in response tc

Correspondence to: H. Ujike, Department of Neuropsychiatry, Okayama University Medical School, 2-5-1 Sbikata-cho, Okayama 700, Japan. Tel. 81.862.23 7151 (ext. 2444), fax 81.862.32 1534.

o" receptor agonist, (+)-3-(3-hydroxyphenyl)-N-(1-p~ pyl)piperidine ((+)-3-PPP), in m e t h a m p h e t a m i r sensitized rats.

324 2. Materials and methods Male Sprague-Dawley rats weighing 180-200 g at the start of drug administration were used. The animals were housed in group, with free access to food and water, at constant temperature (24°C) and humidity (65%) under a standard 12 h - 1 2 h light-dark cycle (lights on at 07:00 h). After a 1-week handling period, rats were subjected to the following experiments, 2.1. Experiment 1: behavioral effects of various doses of (+)-3-PPP in naive rats Thirty naive rats were divided into five groups. Each group of six rats received intraperitoneal (i.p.) injections of saline, or 3, 6, 12 or 24 m g / k g of (+)-3-PPP, and induced behaviors were observed, 2.2. Experiment 2: behavioral effects of ( + )-3-PPP in methamphetamine-sensitized rats Two groups, each consisting of 12 rats, received i.p. injections of either saline or 4 m g / k g methamphetamine, respectively, once daily for 14 days. We have previously shown that this schedule of methamphetamine administration results in behavioral sensitization (Akiyama et al., 1982; Ujike et al., 1989). After a short period of abstinence (5 days), both groups received a challenge dose of 12 m g / k g (+)-3-PPP (i.p.). After an additional 3-day period of abstinence, these groups received a further injection of 24 m g / k g (+)-3PPP. The two other groups, each consisting of six rats that had received the same repeated administration of saline or 4 m g / k g methamphetamine, now received a challenge dose of 6 m g / k g (+)-3-PPP after an abstinence of 5 days, and also received a challenge dose of 24 m g / k g (+)-3-PPP after a long abstinence of 30 days. 2.3. Experiment 3: effects of an antagonist of or or dopamine D 2 receptor on ( + )-3-PPP-induced behaviors in sensitized rats

175 mm, and allowed 1 h for acclimatization prior drug challenge. The behavior of each rat was recor& on videotape for 30 s every 5 or 10 min for 45 min aft the injection. Behavior was scored by a single train, rater, who was unaware of the pretreatments, accor ing to the rating system reported previously (Ujike al., 1990). Briefly, grooming and rearing were es mated in terms of the total duration these forms behavior were evident. Locomotion was scored as t] number of times an animal moved from one corner the cage to the other. Stereotypy of sniffing and repe tive head movements was rated using a 0-5 score reported previously (Ujike et al., 1990). In experimer 1 and 3, the durations and scores recorded every 5 10 min were summed and analyzed for statistical sign icance using a one-way A N O V A and the lower-ord analysis was done with Student's t-test. In experime 2, each form of behavior was analyzed using a two-w ANOVA.

3. Results

Experiment 1 (fig. 1): (+)-3-PPP at 3 m g / k g t duced all five forms of behavior compared with tl effects of saline. (+)-3-PPP at 6 m g / k g induced slight enhancement of sniffing and repetitive he~ movements, which, however, did not differ significanl from saline-treated rats. (+)-3-PPP at 12 m g / k g sign icantly enhanced the intensity of sniffing and he~ movements, and 24 m g / k g (+)-3-PPP enhanced t] intensity of rearing, locomotion, sniffing and he~ movements by 98.8, 235.5, 213.2 and 202.5%, respe tively, compared with the effects of saline. Groomi] was reduced by (+)-3-PPP in a dose-dependent ma ner, and was completely abolished at a dose o f ' mg/kg.

[] ~a1~ne 1~ [] 3 ~/kg • 6

Five groups, each consisting of six rats, received 4 m g / k g methamphetamine once daily for 14 days. After a 5-day abstinence, each group was pretreated with saline, 10 and 30 m g / k g BMY 14802, which is a selective antagonist of tr receptors, or 50 and 100 m g / k g (+)-sulpiride, which is a selective antagonist of dopamine D 2 receptors. One hour after pretreatment, rats of all five groups received an injection of 24 m g / k g ( + )-3-PPP (i.p.). 2.4. Behavior rating Rats were individually placed in an observation cage of transparent plastic with the dimensions 310 x 360 x

mg/kg

~ 12~g/~ I[~-: mZ4mg/k~~

1 ~e

~

sec s0

20 :**

I

~

~

sc0re_~ :*~ • i0

[~t : .

.

Groo~ing Rearln

. . LocomotionSniffing

Head Move~nt

Fig. 1. Dose-dependent effects of (+)-3-PPP on behaviors of na rats. Rats received an i.p. injection of saline or 3, 6, 12 or 24 mg/ (+)-3-PPP, and induced behaviors were observed and rated for rain. (N=6, means+_S.E.M., + P<0.1, * P<0.05, * * P < 0 J comparedwith saline-treated rats, analyzedwith a one-wayANO'~ and Student's t-test.)

a) 12 mg/kg of (+)-3-PPP rearing

b) 24 mg/kg of (+)-3-PPP

locomotion

rearing

20

locomotion

20

15

I

•

~,

15

,

I

~2

5

z

0

0

sniffing u~3

0 .... 0

,

~o3'

15

_

head movement

30

/J,5 MIN.

0 ,';' T , , . 0 15

sniffing

head movement

~3

~3

0 30

45 I','lr4. l

0 0

15

30

45 MIN.

0

15

30

45 MIN.

Fig. 2. (a, b) Behavioral effects of a challenge dose of (+)-3-PPP in rats previously sensitized by repeated methamphetamine treatment. R received either saline or 4 mg/kg methamphetamine once daily for 14 days. After an abstinence of 5 and 8 days, ( + ) - 3 - P P P at dose of 12 mg/ (a) or 24 m g / k g (b) was given as challenge. Open circle: saline-pretreated rats, closed circle: methamphetamine-pretreated rats. (N = means_+ S.E.M. Statistical analysis was done with a two-way ANOVA, See text for F values.)

Experiment 2 (fig. 2a and b and table 1): there was no significant difference between methamphetamineand saline-pretreated rats in the intensity of 6 mg/kg (+)-3-PPP-induced behaviors with the exception of locomotion (table 1). (+)-3-PPP at 12 mg/kg induced significantly more frequent rearing (F(1,176)= 4.691, P < 0.05), more intense sniffing (F(1,176) --- 21.586, P < 0.01) and repetitive head movements (F(1,176)= 20.824, P < 0.01) in the methamphetamine-pretreated rats than in the saline-pretreated rats after 5 days of abstinence (fig. 2a). (+)-3-PPP at 24 mg/kg also induced significantly more frequent rearing (F(1,176)= 6.733, P < 0.05) and more intense sniffing (F(1,176) =

92.742, P < 0.01) and repetitive head movemei (F(1,176) = 85.734, P < 0.01) in th methamphetamine-pretreated rats than in the salir pretreated rats after 8 days of abstinence (fig. 2b). T mean scores for sniffing and head movements indue by 24 mg/kg (+)-3-PPP in the sensitized rats we higher than 2, indicating that these types of behavi were the result of stereotypy. As a result of inter stereotypy, locomotion induced by 12 and 24 rag/ (+)-3-PPP was decreased in methamphetamine-pJ treated rats compared with saline-pretreated rats. t ter 1 month of abstinence, (+)-3-PPP produced J tense stereotypy in sensitized rats similar to that se

TABLE 1

Summary of the effects by a challenge with ( + ) - 3 - P P P in methamphetamine-sensitized rats. Behavior

Pretreatment

Period of abstinence

component

condition

Short (5 days)

Long (30 days)

6 mg/kg d

12 m g / k g d

24 m g / k g d

24 m g / k g d

23.3 _+5.5 a 14.3 -+6.6

31.6 _+10.3 51.3 _+ 13.4 b

59.7 -+12.5 91.6 _+22.4 b

15.8 -+ 5.0 172.7 -+16.0 c

Rearing

Saline

(s)

Methamphetamine

Locomotion (numbers)

Saline Methamphetamine

4.92-+ 1.37 1.75_+0.70 c

Sniffing (scores)

Saline Methamphetamine

7.3 _+ 1.5 5.3 _+0.7

Head movement (scores)

Saline Methamphetamine

6.5 _+1.7 4.8 + 1 . 0

5.75-+ 1.60 3.63_+ 0.84 b

14.80_+ 3.27 3.63_+ 1.02 c

15.58_+ 1.83 4.00_+ 1.69 c

8.9 -+ 2.0 14.5 _+ 1.6 c

13.7 + 1.4 26.4 _+ 2.3 c

15.2 -+ 0.72 30.2 _+ 1.5 c

7.6 _+ 1.9 12.4 -+ 1.6 c

9.5 + 1.4 21.8 + 2.2 c

9.6 -+ 2.0 21.2 -+ 1.6 c

All values are expressed as means-+ S.E.M. of sums of each score or duration for 45 min after the challenge with (+)-3-PPP. b p < 0.~ c p < 0.01 as compared with corresponding saline-pretreated group analyzed by two-way A N O V A . d Challenge dose of (+)-3-PPP.

a

326 rearing "''"'- .............. ~ " ~ ; --,* locomotion ..................... ~ : ~ * ~ sniffing h

e

a

d

~

~

........ d ! ~ - -

[] ~,~po24mg,,'k~ [] ~0 [ ] +BM, +BN~s~ [] +SUEs~ • +SUE180

movement ~i~=:/~-.. * 58

, 180

158

258

% against (+)-3ppp alone

Fig. 3. Effects of BMY 14802 or ( +_)-sulpiride on ( + )-3-PPP-induced behavior of sensitized rats. Five groups of rats received 4 mg/kg methamphetamine once daily for 14 days. After a 5-day period of abstinence, each group was pretreated with saline, BMY 14802 (10 and 30 mg/kg) or (+_)-sulpiride (50 and 100 mg/kg). One hour after pretreatment all rats received 24 mg/kg (+)-3-PPP. (N = 6, means+ S.E.M., * P < 0.05, ** P < 0.01, *** P < 0.001 analyzed with a o n e way ANOVAand Student's t-test.)

after ( + ) - 3 - P P P challenge after a short abstinence, Thus, even after such a long period of abstinence, the challenge dose of 24 m g / k g ( + ) - 3 - P P P produced more frequent rearing (F(1,80) = 214.745, P < 0.01), more intense sniffing (F(1,80) 160.714, P < 0.01) and repetitive head m o v e m e n t s (F(1,80) = 81.666, P < 0.01) in m e t h a m p h e t a m i n e - p r e t r e a t e d rats than in saline-pretreated rats (table 1). Experiment 3 (fig. 3): BMY 14802 at 10 m g / k g reduced (-F)-3-PPP-induced sniffing and head movements in sensitized rats, but this effect did not reach statistical significance. BMY 14802 at 30 m g / k g significantly reduced ( + )-3-PPP-induced locomotion, sniffing and head movements in m e t h a m p h e t a m i n e - p r e t r e a t e d rats. (+)-Sulpiride at 50 and 100 m g / k g also significantly attenuated (+)-3-PPP-induced behavior,

4. Discussion The rationale of using ( + ) - 3 - P P P as a selective agonist of tr receptors is based upon the relative affinity of ( + ) and ( - ) enantiomers for o- receptors versus dopamine D 2 receptors. Thus, [3H]spiperone binding has shown that the IC50 values for the displacement of ( + ) - and ( - ) - 3 - P P P are only 10-100 and 0.8-7.0 ~ M , respectively (Arnt et al., 1983; Koch et al., 1983; Mikuni et al., 1984). Dopamine agonist binding, using [ 3 H ] ( - ) - N - n - p r o p y l n o r a p o m o r p h i n e , also showed a weak displacement by ( + ) - 3 - P P P , with an IC50 value of more than 1 / z M (Mikuni et al., 1984). In contrast, tr receptor binding, using [3H] 1,3-di(2tolyl)guanidine showed that the ICs0 values of ( + ) and ( - ) - 3 - P P P for displacement were 76 and 135 nM, respectively (Weber et al., 1986). Another report in which the same ligand was used indicated the K i of ( + ) - 3 - P P P to be 74 nM (Kavanaugh et al., 1989).

( + ) - 3 - P P P also displaced [3H]pentazocine, another p, tent and selective ligand for ~r receptors, with an IC of 48 nM (De Costa et al., 1989). Thus, ( + ) - 3 - P [ exhibits approximately 1000 times greater affinity for receptors than D 2 dopamine receptors. The present study showed that ( + ) - 3 - P P P exerted bimodal effect on the behaviors investigated. T h t while low doses of ( + ) - 3 - P P P reduced all f o r m s behavior, higher doses enhanced all forms of behavi, except grooming. ( - ) - 3 - P P P , an enantiomer of ( + ) PPP which is reported to reduce behavior in a dose-d pendent manner (Hjorth et al., 1983), exhibits weak and greater affinities for tr and D 2 receptors, respe tively. Pentazocine and SKF-10047, other o- agonisl also stimulate locomotor behavior in a naloxone-r sistant manner (Holtzman and Jewett, 1972; Iwamot 1981; De Costa et al., 1989). Accordingly, the high doses of ( +)-3-PPP used in experiments 2 and 3 in tl~ study to stimulate behavior should be considered to a on tr receptors. The present study clearly showed that ( + ) - 3 - P t induced augmented stereotyped sniffing and he~ movements in rats previously sensitized by repeat( m e t h a m p h e t a m i n e treatment. This augmented r sponse to ( + ) - 3 - P P P in the sensitized rats was repr duced even after 1 month of abstinence. These resul indicate that persistent supersensitivity of or recepto may develop during methamphetamine-induced sensi zation. This hypothesis is supported by evidence th the augmented response to ( + ) - 3 - P P P was reversed 1 BMY 14802, a o- antagonist (Taylor and Deklav 1987). The forms of ( + )-3-PPP-induced behavior, su( as rearing, sniffing and head movements, mimic tho: induced by dopamine agonists such as a D 1 / D 2 mix~ agonist of apomorphine and a selective D 2 agonist quinpirole (Starr and Starr, 1987; Starr, 1988). Ther fore, it is conceivable that the supersensitivity of receptors, which developed during methamphetamil induced sensitization, may result in the a c t i v a t i o n the dopaminergic system. This supposition is in agre ment with the result that (+)-3-PPP-induced behavi, was also reversed by sulpiride, a selective D 2 dopamil antagonist without affinity for or receptors (Ferris al., 1986; H a r a d a et al., 1989). Several studies have indicated that tr receptors i teract closely with dopaminergic systems, especial with the nigrostriatal and mesolimbic dopaminer~ systems, both of which are considered to be key sit for the development of methamphetamine-induc( sensitization, tr Receptors are distributed in the limlz forebrain areas, basal ganglia, substantia nigra al ventral tegmental area (Tam, 1983; Largent e t a 1984; Graybiel et al., 1989). Furthermore, a study which lesions were made with the neurotoxins ibot nate and 6-hydroxydopamine indicated that o- rece tors are located on both cell bodies of nigral dopamil

2 n e u r o n s and striatal intrinsic neurons receiving nigrostriatal p r o j e c t i o n s ( G u n d l a c h et al., 1986). T h i s f i n d i n g suggests t h a t o" r e c e p t o r s m a y d i r e c t l y m o d u l a t e t h e f u n c t i o n of t h e n i g r o s t r i a t a l d o p a m i n e system. I n a d d i tion, b e h a v i o r a l s t u d i e s h a v e s h o w n t h a t r i m c a z o l e ,

another g antagonist, and BMY 14802 attenuate apomorphine-induced hyperlocomotion and climbing (Ferris et al., 1982; T a y l o r et al., 1985). E l e c t r o p h y s i o l o g i c a l studies have revealed that the firing rates of d o p a m i n e n e u r o n s in t h e A 9 a n d A 1 0 a r e a s a r e d e c r e a s e d by 3 - P P P a n d D T G , a n d i n c r e a s e d by B M Y 14802 (Ceci et al., 1988; S t e i n f e l s a n d T a m , 1989). S u c h m o d u l a t i n g effects of ~r d r u g s o n d o p a m i n e n e u r o n s a r e n o t m e d i a t e d via d i r e c t a c t i o n s o n d o p a m i n e a u t o r e c e p t o r s ( M a t t h e w s et al., 1986; W a c h t e l a n d W h i t e , 1988), b u t probably via interactions with ~r receptors located o n d o p a m i n e cell b o d i e s . ( + ) - 3 - P P P has b e e n s h o w n to m o d u l a t e t h e synthesis, m e t a b o l i s m a n d r e l e a s e of

dopamine in terminal areas of the nigrostriatal and m e s o l i m b i c systems in vitro a n d in vivo ( H j o r t h et al., 1983; M u l d e r et al., 1985; l m p e r a t o et al., 1988). T h e s e f i n d i n g s i n d i c a t e t h a t ( + ) - 3 - P P P , as well as o t h e r cr d r u g s , m a y p o t e n t l y affect t h e activity o f d o p a m i n e n e u r o n s in t h e A 9 a n d A 1 0 areas. A c c o r d i n g l y , t h e d e v e l o p m e n t of l a s t i n g s u p e r s e n s i t i v i t y o f g r e c e p t o r s during repeated methamphetamine treatment, as d e m o n s t r a t e d in t h e p r e s e n t study, m a y b e a s s o c i a t e d with mechanisms underlying the methamphetamine-ind u c e d b e h a v i o r a l s e n s i t i z a t i o n , possibly r e s u l t i n g in f a c i l i t a t i o n of d o p a m i n e r g i c t r a n s m i s s i o n a n d a u g m e n -

tation of abnormal behavior,

Acknowledgements The authors wish to thank Fujisawa Co. Ltd. and Bristol-Myers Co. (U.S.A.) for their gifts of sulpiride and BMY 14802, respectively.

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