Enhancement of dopamine release from striatal slices of rats that were subchronically treated with methamphetamine

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Enhancement of Dopamine Release from Striatal Slices of Rats that Were Subchronically Treated with Methamphetamine S. Yamada, H. Kojima, H. Yokoo, T. Tsutsumi, K. Takamuki, S. An&u,

S. Nishi, and K. Inanaga

The effect of dopamine (DA) uptake inhibitors (methamphetamine, nomifensine, and phenylethylamine) on the release of endogenous DAfrom striatal slices of rats pretreated with methamphetamine (6 mglkglday for 9 days) was investigated. The exposure of me&hetamine-pretreated rat striatal slices to a low concentration (le7 M, 5 x 1P7 M) of methamphetamine caused a greater increase in DA e&x than that of saline-treated rat striatal slices. The drug-treated rats displayed an enhanced stereotyped behavioral response to a small dose of methamphetamine (1 mglkg). Removal of CaZ+ from the supetjusion medium did not aflect the difference in the rates of methamphetamine (lt37 M) induced DA release between methamphetamine-treated and saline-treated rat striatal slices. Nomifensine- and phenylethylamine-induced DA release from striatal slices was also enhanced by repeated administration of methamphetamine. On the other hand, there was no diaerence in K+ -induced DA release between the two groups. Moreover, repeated administration of methamphetamine caused a significant increase in 3H-dopamine uptake in rat striatal synaptosomes. These results suggest that the behavioral sensitization produced by the repeated administration of methamphetamine is accompanied by an enhancement in the release of DA induced by methamphetamine, nomifensine, and phenylethylamine in vitro and is also accompanied by increased DA uptake into striatal synaptosomes.

Introduction After repeated administration of amphetamine to rats for several days, followed by a drug-free period, a marked stereotyped behavior characterized by compulsive sniffing, head movement, and rearing was evoked by a single small dose of amphetamine. The same dose of amphetamine failed to cause any stereotyped behavior in saline-treated rats (Peachey et al. 1977). This sensitized state of the rat to amphetamine has been considered to be an experimental model for the psychotic state caused by a single small dose of amphetamine in humans suffering from chronic amphetamine abuse (Snyder 1973). Ste-

t+om the Indtute of Brain Dkeases and the Depimcnt of Neuropsychiatry, (K.T., K.I.), Kumme University School of Medicine, K-e, Japan. Address reprint rcqucsts to Dr. Shigeto Yamada, htitute of Brain Diseases, K-e University School of Medicine, 67, Asahi-Ma&i, Kurume, a30 Japan. Received October 2, 1985; revised August 5, 1987. 0 1988 Society of Biological Psychiatry

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reotyped behavior caused by amphetamine is thought to be due to the release of dopamine (DA) from the nerve terminals and the subsequent activation of DA receptors in the striatum. Robinson and Becker (1982) recently reported that the DA efflux caused by amphetamine from amphetamine-pretreated rat striatal slices was greater than that from saline-pretreated rat striatal slices. Kolta et al. (1985) showed that the enhancement of DA release by amphetamine pretreatment could be correlated with the development of behavioral sensitization to amphetamine. In the present study, the effects of subchronic methamphetamine on methamphetamine-, nomifensine-, and phenylethyl-amine-induced DA release from striatal slices and on 3H-DA uptake in striatal synaptosomes were observed in order to define clearly any functional alterations of striatal DA terminals that might be associated with the behavioral sensitization to methamphetamine seen after pretreatment with methamphetamine.

Methods Male Wistar rats, weighing 200-250 g, were used in all the experiments. They were kept in a temperature-, humidity-, and light-controlled environment. Rats were injected intraperitoneally with 6 mg/kg methamphetamine hydrochloride (MAP) (Dainihon Seiyaku Co.) per day for 9 days. After the drug period, they were kept for another 9 days without the drug. Control rats were injected with saline instead of methamphetamine, following the same schedule as the test group. After the drug-free period, rats were killed by decapitation between lo:30 and 11:OOAM. The brains were rapidly removed and 4 slices of 0.4~mm thickness were made with a Micro Slicer (Dohan E. M., Co.) at A 9760 to A 7630, according to the atlas of Kiinig and Klippel(1963) in an ice-cold Krebs solution that was aerated with OZ. The striatal regions of the slices were punched out with a metal tube (3 mm internal diameter) and were placed in a superfusion chamber made from a Teflon syringe. The chamber was continuously irrigated with an oxygenized Krebs solution at 0.3 ml/mm in a water bath at 37°C. The composition of the Krebs solution was (in 37°C. The composition of the Krebs solution was (in mu): NaCl 118.0, KC1 4.9, NaHP04 1.25, NaHC03 25.0, CaCl* 2.5, MgC& 1.18, glucose 11.0. Pargyline (0.1 mu) was always added to the Krebs solution to inhibit the monoamine oxidase (MAO) and to cancel the effect of the different MAO activity on DA efflux between methamphetamine and saline-treated rat striatum. The overflowing superfusate was collected in a tube at lo- or 20-min intervals. The tissues were superfused with Krebs solution for 90 min and then exposed for 10 or 20 min to Krebs solution containing various concentrations of methamphetamine, nomifensine, and phenylethylamine. When the DA release by a high concentration of K+ was observed, the slices were super-fused for 3 min with a Krebs solution in which 15 or 30 mu NaCl had been replaced with an equimolar concentration of KCI. Following exposure to these drugs or to high KC, the slices were super-fused with control Krebs solution for an additional 30 min. The DA released by each test was absorbed with 50 mg alumina, eluted with 300 ~1 phosphate buffer (pH 2. l), and measured by high-performance liquid chromatography (Yanaco L2000, Yanagimoto, Japan) with electrochemical detection (Yanaco, VMD-101) according to the method of Kissinger et al. (1973). The details of the analytical conditions were described in a previous report (Yamada et al. 1983). A 3H-DA uptake study was performed according to the method of Nwanze and Jonsson (1981). In short, 9 days after the drug withdrawal, rats were decapitated and the brain was removed. The striatal region of the brain was dissected manually and homogenized

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with 1 ml of 0.25 M sucrose using a grass homogenizer with a Teflon pestle running at a speed of 1000 rpm (8 stroke). The original homogenate was centrifuged at 3000 x g for 10 min. The supematant (containing synaptosome, 50 ~1.1was diluted with 1 ml of 02-saturated Krebs solution containing 0.1 mu pargyline a&was preincubated at 37°C for 5 min; after addition of ‘H-DA (final concentration 160 no) , the mixture was incubated for another 5 min. After the termination of the incubation by addition of 4 ml of cold Krebs solution, the samples were centrifuged at 10,000 rpm for 10 min to precipitate the synaptosomes, then the supematant was discarded. After addition of toluene phospher, radioactivity taken up and retained in the precipitate was determined by liquid scintilation spectrophotometry. The DA level in the striatal synaptosome was determined by highperformance liquid chromatography combined with electrochemical detector according to the method of Yokoo et al. (1985). Protein in the synaptosomes was determined by Lowry et al. (1951). To check the development of behavioral hypersensitivity to methamphetamine, the stereotyped behavior was scored every 10 min for 60 min after the administration of 1 mg/kg methamphetamine to saline-treated and methamphetamine-treated rats. The score of stereotyped behaviors, according to Creese and Iversen (1973), was as follows: 0, asleep or stationary; 1, active; 2, predominantly active but with bursts of stereotyped sniffing or rearing; 3, stereotyped activity, such as sniffing along a fixed path in the cage; 4, stereotyped sniffing or rearing maintained in one location; 5, stereotyped behavior in one location with bursts of gnawing or licking; 6, continual gnawing or licking of the cage bars. The data were expressed as nanograms dopamine per milligram protein per 10 min for basal dopamine release and as percent of basal DA efflux for the drugs or high K+-induced DA release. The amount of 3H-DA incorporated into the striatal synaptosomes was expressed as 1000 dpm/mg protein/5 min and was corrected for extraneural uptake by subtracting uptake values obtained performing identical incubations at 4°C. Statistical comparisons were performed with the Student’s c-test for the DA release and the uptake study and with the Mann-Whitney U-test for the stereotyped rating.

Results Stereotyped Behavior The administration of methamphetamine (1 mg/kg) to saline-treated rats produced an enhancement of locomotor activity, with a burst of stereotyped sniffing and rearing, 2060 min after injection of the drug. In contrast, administration of methamphetamine to methamphetamine-pretreated rats induced continuous stereotyped behaviors characterized by compulsive sniffing, head moving, and licking in one location or fixed path, 20-60 min after the injection. The rating scores of the methamphetamine-evoked behavioral changes were significantly greater for methamphetamine-treated rats than for saline-treated rats @ < 0.025). The latency to the onset of the stereotyped behavior was shorter in the rats pretreated with methamphetamine (Figure 1).

Endogenous DA Eflu from Rat Striatal Slices ‘Ihe spontaneous DA effIux was 420 + 89 pg/mg protein/IO min (n = 24). The average amount of striatal tissue in the chamber was approximately 2 mg protein, so the basal DA release in a lo-min fraction was detectable (Figure 2). As shown in Table 1, the

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score

Figure 1. Stereotypyfrom I mgi kg methamphetamine-HCI in methamphetamine-pretreated rats and control rats (n = 6 each). The stereotypy was quantitated with the stereotypy rating scale reported by Creese and Iversen f 1973) as the mean stereotypy responses per 10 min. The distribution of scores from the stereotypy rating categories was analyzed using the MannWhitney U-test. *p < 0.025 0

10

20

30

40

50

* p*ao25

60 min.

exposure of the slices to 15 u&i and 30 mu K’ for 3 min caused 2.2-fold and l&fold increases in DA efflux, respectively. The K+-evoked DA release was completely suppressed by the removal of Ca2’ from the Krebs solution. The addition of methamphetamine (1W6 M and 1W5 M) to the Krebs solution caused a concentrationdependent increase in DA efflux (6.2-fold and 20-fold, respectively) from striatal slices of saline-treated animals. ~e~~phe~ne at a concen~ation lower than 1c7 M failed to enhance the DA eftlux. The me~amphet~ne (lad M) induced DA efflux was observed even in a Ca2’-free medium (Table 1). Nomifensine, at a concentration of lO_’ M, caused a marked increase in DA efflux; however, the amount of released DA was much smaller than that caused by the same concentrations of methamphetamine. Pheny~e~yl~ine, at concentrations of 5 x lt3’ and lob M also caused significant increases in basal DA efflux (Figure 3 and Table 1) from striatal slices of seine-feats animals.

Effects of Pretreatment with Methamphetamine on DA Eflux from Striatal Slices There was no si~i~c~t difference in the basal DA efflux from me~~phe~ine-heard and saline-treated rat striatal slices (methamphetamine-treated, 420 +_ 85 pg/mg protein/ lo-min fraction, n = 14; saline-treated, 440 + 90 pg/mg protein/lO-min traction, n = 16). The exposure of methamphetamine-treated rat striatal slices to 1W7 M or 5 X 1c7 M methamphetamine caused a greater increase in DA efflux than that of saline-treated rat striatal slices (Figure 2, Table 1). The enhancement of DA efflux by 1W7 M methamphetamine from me~~phe~ne-panty rat striatal slices could still be observed after the removal of Ca2’ from the superfusion medium (Table 1). The higher concentrations of methamphetamine (1W M and lO_’ M) caused marked increases in the DA

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o saline treated a MAP treated *

300 t \

I

500

9 ’

100

/a

I

/ *--_--_l-

100

110

130 ld7M

150min

110

130

15Omin

110

5~10-~M

130

150min

1Ci6M **

PCO.01

* RO.05

Figure 2. Effects of methamphetamine (l(r’ M, 5 X l&’ M, lo-6 M) on endogenous DA efflux from methamphetamine-treated and saline-treated rat striatal slices. The DA release from each fraction is expressed as percent of the basal DA release. Following superfusion with Krebs solution for 90 min, each concentration of methamphetamine (indicated by the open bar) was added to the superfusion medium. Note that methamphetamine-treated rat striatal slices had significantly greater DA release with 10-’ M and 5 X l&’ M methamphetamine than saline-treated rat striatal slices (*p < 0.05, **p C 0.01, Student’s r-test).

efflux; however, there were no significant differences in the DA efflux from methamphetamine-treated and saline-treated rat striatal slices. Nomifensine (1V M and 10-5 M) produced greater significant increases in DA release from methamphetamine-treated slices than from saline-treated rat striatal slices (Figure 3). Phenylethylamine (5 x 1W7M and lo-6 M) induced DA effluxes from methamphetamine-pretreated striatal slices were also significantly greater than the effluxes from saline-treated slices (Figure 3). On the other hand, there were no significant differences in the K+ (15 mrvrand 30 mu) induced DA effluxes of methamphetamine- and saline-treated rat striatal slices (Table 1).

3H-DA Uptake into Striatal Synaptosomes 3H-DA was rapidly taken up into the striatal synaptosomes, and the level of radioactivity reached plateau within 5 min. Synaptosomal 3H-DA uptake level in the striatum following 5-min incubation with Krebs solution containing 160 no 3H-DA is shown in Table 2. As can be seen, the repetitive administration of methamphetamine caused a significant increase in tritium radioactivity taken up into the striatal synaptosomes ( + 25%, p < 0.01, n = 15), without any effect on synaptosomal DA concentration.

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o sali l

treated

MAP treated

l8

-7 i0g

o saline treated 0 MAP treated

-4 -6 (NOM) M

a

b

Figure 3, Effects of various concentrations of nomifensin (a) and phenylethylamine (b) on DA efflux from methamphetamine-treated and saline-treated rat striatal slices. The exposure of methamphetamine-treated rat striatal slices to lob M and l(r5 M nomifensine (a) or lad M and 5 X 10-7 M phenylethylamine (b) produced greater increases in DA efflux than that of saline-treated rat striatai slices f*p < 0.05, **p < 0.01).

Discussion Repeated administration of methamphetamine enhances the stereotyped behavior induced by a single small dose of methamphetamine, if the single dose of methamphetamine is given at the appropriate time following the reagent (Figure 1). This result is in agreement with previous reports (Wallach and Gerson 1971; Segal and Mandel 1974; Conway and Uretsky 1982; Nishikawa et al. 1983). This effect has been considered to be due to an increased responsiveness to methamphetamine or amphetamine of nigrostriatal dopaminergic neurons that are primarily involved in mediating stereotyped behavior. Administration of large doses of methamphetamine, more than 25 mg/kg/day for more than 14 days, caused a conside~ble reduction in striatal DA con~n~tions in rats (Morgan and Gibb 1980), although others report no significant change in striatal DA content after the administration of the small doses of methamphetamine, < 12.5 mg/kg/day for 40 days (Wagner et al. 1980), that were used in the present study. During this state of sensitization to methamphetamine, the striatal 3H-spiroperidol binding activity is decreased (Howlett and Nahorski 1978; Kaneno and Shimazono 1981). These findings suggest that the behavioral sensit~tion to rne~~phet~~e or sphere is not due to a h~~nsitivity of the postsynaptic DA receptors. There have also been reports that these behavioral

Chronic Me~~phe~ne:

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‘t@

Table 1. Effect of MAP Pretreatment on Drug-InducedDopamine Release from Striatal Slices DA Drugs

Conw&tion

release(% of

basal release)

Saline-tSWWJ

MAP-bated

High K+ High K+ High K+

15 IuM 30 InhS (30 mht, Ca*+-free)

220 -r- 52 1010 zk 270 102 + 11’

226 2 40 1170 f 290 -

MAP MAP MAP MAP MAP

0.1 ph4 0.5 )LM 1.0 PM 10.0 ph4 (1 pbt, Caz’-free)

104 186 620 2070 605

rt + k + r?

6 25 78 595 92

142 283 669 2154

MAP NOM NOM PEA PEA

(0.1 PM, Ca*+-free) 1.0 PM 10.0 PM 0.5 JLM 1.0 p,M

102 108 196 132 175

f rt ir f f

7 13 37 17 33

128 162 332 317 515

+ 2 + +

11’ 32* 111 315

?z + t f +

96 1Y 47* 100 121*

-

MAP, v; NOM, nomifeasine;PEA, ~nyle~yl~. Valuesamshovmastbemean f REM. “p < 0.001 as compared with Ca2+ presence. “p < 0.05, p < 0.01 as wmpared with saline group.

changes were accompanied by an enh~cement of rne~~phet~e-induce increases in DA metaholites in several regions, including the striatum (Matsumoto et al. 1983; Nishikawa et al. 1983). These reports suggest that the repeated administration of methamphetamine results in a hypersensitivity of the striatum to the DA-releasing action of methamphetamine. In the present study, repeated administration of methamphetamine produced an element of the DA-releasing response to low con~n~ations of methamphetamine (Figure 2). This is in agreement with the results of Robinson and Becker (1982) and Kolta et al. (1985), who demonstrated that D-amphetamine-induced (IV M, IO-’ M) DA release from striatal slices is enhanced by repeated administration of amphetamine (5 mg/kg/l2 hr for 5 day). However, they reported that the difference in DA eftlux was observed even with high concentrations of amphetamine, whereas high concen~tions of rne~~phe~ne in the present study failed to produce any differences in the DA efflux between methamphetamine-treated and saline-treated striatum. This discrepancy could be explained by differences in the drug potencies of methamphetamine and amphetamine to induce DA release or block DA uptake, and/or to a difference in experimental conditions, for instance, the presence of pargyline in the Krebs solution in the present study but not in the previous studies (Robinson et al. 1982; Kolta et al. 1985).

Table 2. Effect of Repeated Administrationof MAP on Endogenous DA Concentrationand 3H-DAUptake in Rat Striatal Synaptosomes SaliXl&tIWlted Endogenous DA concentration (HIM) %-DA uptake (1000 dpm/mg protein/S min)

53.6 -e 3.4 252.2 It 10.5

MAP-tI.e.ZItlXl 55.7 2 4.7 314.1 f 12.8a

Values of DA concentration am expressed as nanomolars in incubation medium and arc the mean of 8 dctermhdons f SEM. Values of ‘H-DA uptake we expressed as loo0 dpmhg protein/5 min and are the mean of 15 dete~&~~tions TSIZM. “p < 0.01.

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There are several explanations for the enhancement of DA efflux from the methamphetamine-treated rat striatum by the low concentration ( 1fV7M) of methamphetamine. Methamphetamine pretreatment may cause a long-lasting MAO inhibition, enhancement of DA release, and/or enhancement of DA uptake blockade. The presence of pargyline, an MAO inhibitor, in the Krebs solution and the observation of no difference in the K + induced DA effluxes should exclude the possibility that a reduction in the MAO activity causes an increase in the amount of DA in the superfusate. A greater DA efflux by the 1Cr7M methamphetamine in methamphetamine-pretreated slices compared with the saline-treated slices was still observable following removal of Ca2+ from the superfusion medium (Table 1). This result suggests that the mechanism underlying the activation of DA efflux from the striatal slices in methamphetamine-treated rats is different from the mechanism of DA release induced by K+ . The K+-induced DA efflux was completely suppressed by removal of Ca*+ from the Krebs solution; however, the methamphetamine-induced DA efflux was independent of Ca*+ in the medium (Table l), which is in agreement with previous reports (Raiteri et al. 1979; Kamal et al. 198 1). The DA release induced by methamphetamine is considered to be mediated by the carriermediated DA uptake mechanism, which is a Ca” -independent process. Nomifensine, as well as methamphetamine, caused a greater DA efflux from methamphetamine-pretreated rat striatal slices (Figure 3). According to the results of Lemasson et al. (1984), nomifensine is as potent a DA uptake inhibitor as methamphetamine, whereas the DAreleasing action of nomifensine (up to 1Cr5 M) is negligible (Raiteri et al. 1978). An enhanced DA release from methamphetamine-treated rat striatal slices was also observed during exposure to phenylethylamine. The characteristic that is common to these three drugs (methamphetamine, nomifensine, and phenylethylamine) is a DA uptake inhibition. These results suggest that DA uptake inhibition by the drugs is responsible for the difference of DA efflux between methamphetamine-treated and saline-treated rat striatal slices (Figure 3). Moreover, the results of the 3H-DA uptake study indicates that methamphetamine pretreatment causes an increase in 3H-DA uptake sites in striatal synaptosomes. To our knowledge, this is the first report indicating that repeated administration of methamphetamine causes an increase in DA uptake into striatum. The present finding is compatible with the report by Swann et al. (1985) that presynaptic stimulation by Damphetamine increased desipramine binding, which reflected the number of norepinephrine reuptake sites. Camp and Robinson (1985) and Watanabe (1985) found significantly higher striatal 3,4_dihydroxyphenyl acetic acid to DA ratios in amphetamine- or methamphetamine-pretreated rats than in control rats, suggesting enhanced DA release and uptake. These reports are not incompatible with the present finding of increased DA uptake in methamphetamine-pretreated rat striatum. These data support the hypothesis advanced by Kolta et al. (1985) that repeated administration of amphetamine may increase the number of DA uptake sites in the striatum, leading to an enhanced interaction between amphetamine and the DA uptake sites, thereby resulting in a greater release of DA. A mechanism similar to this hypothesis could be responsible for the enhancement of DA release from mcthamphetamine-treated striatal slices by the exposure to nomifensine and phenylethylamine. However, this does not exclude the possibility that changes in other dopaminergic mechanisms are also involved. For example, it has been suggested that sensitization is due to a subsensitivity of DA autoreceptors (Muller and Seeman 1979; Kaneno and Shimaxono 1981), which would be expected to produce an enhancement in DA release (Robinson and Becker, 1982). In conclusion, the behavioral sensitization produced by the repeated administration of

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is accompanied by an enduring enhancement in the release of DA produced by exposure to methamphetamine, nomifensine, and phenylethylamine in vitro and is also accompanied by increased DA uptake sites in shiatal synaptosomes. These functional changes of striatal nerve endings would be responsible, at least partially, for the behavioral sensitization to methamphetamine after repeated administration of methamphetamine.

methamphetamine

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