- Email: [email protected]
Effect of NO synthase inhibition on behavioral changes induced by a single administration of methamphetamine
BRAIN RESEARCH ELSEVIER
Brain Research 666 (1994) 147-150
Short communication
Effect of NO synthase inhibition on behavioral changes induced by a single administration of methamphetamine Tomohiro Abekawa *, Tetsuro Ohmori, Tsukasa Koyama Department of Psychiatry, Hokkaido University School of Medicine, Sapporo, Japan Accepted 27 September 1994
Abstract
The present study examined the effects of nitric oxide synthase inhibitor, Nto-nitro-L-arginine methyl ester (L-NAME; 10, 30, 60 mg/kg, i.p.) on behavioral changes induced by a single administration of methamphetamine (MA) (3.22 and 0.805 mg free base/kg, s.c.). MA increased locomotion-stereotypy rating scores and motor activity counts measured by an infrared sensor. L-NAME administerd prior to MA significantly decreased the level of locomotion stereotypy rating and motor activity induced by MA. An inactive optical isomer, Nto-nitro-D-arginine methyl ester (D-NAME) had no effects on MA-induced behavioral changes. The results suggest that NO synthesis is involved in the full expression of behavioral effects of MA.
Keywords: Methamphetamine; Nitric oxide; Nitric oxide synthase inhibitor; L-NAME
Nitric oxide (NO) was initially identified as a mediator for macrophage and endothelial cells, but has recently been recognized as a novel neuronal messenger, which acts both as an intracellular messenger and neurotransmitter. Stimulation of N-methyl-D-aspartate (NMDA) receptors induces influx of extracellular Ca 2+, which binds to calmodulin and consequently activates NO synthase. NO binds to hem, conforming guanylate cyclase, and activates this enzyme to form cyclic guanosine monophosphate (cGMP). These processes suggest a relationship between N M D A receptor activation and NO formation [2-4,8,14,21,22]. Involvement of NMDA receptors in the behavioral and neurochemical effects of psychostimulants has been reported [10,11,17,23,25]. Recently, Pudiak et al. [18] have presented that Nto-nitro-L-arginine methyl ester (L-NAME) blocked locomotor activity induced by a single administration of cocaine. Furthermore, Stewart et al. [24] revealed that L-NAME reduced lomotor activity induced by amphetamine. The present study examined the effects of NO synthase inhibition on not only locomotor activity but also
* Corresponding author. Department of Psychiatry and Neurology, Hokkaido University School of Medicine, Kita 15, Nishi 7, Kitaku, Sapporo, Japan. Fax: (81) (11) 736-0956. 0006-8993/94/$07.00 © 1994 Elsevier Science B.V. All rights reserved SSDI 0 0 0 6 - 8 9 9 3 ( 9 4 ) 0 1 133-8
stereotyped behavior induced by a single administration of methamphetamine (MA). Locomotor activity and stereotyped behavior are generally thought to be mediated by the activity of the nucleus accumbens and striatum, respectively. Since the interaction of dopamine and glutamate in the two regions have different features [1], the effect of NO synthase inhibition on the two MA-induced behaviors should be examined separately. Male Wistar-King rats (200-260 g) were housed individually in conditions of constant temperature (24°C) and controlled light (light period 06.30 h to 18.30 h) and given food and water ad libitum. Methamphetamine hydrochloride (MA) and Ntonitro-L-arginine methyl ester hydrochloride (L-NAME) were purchased from Dainippon Pharmaceuticals Ltd., Japan and Sigma Chemical (St.Louis, MO), respectively. Both agents were dissolved in sterile physiological saline. Experiment 1. Rats received one subcutaneous injection of MA (3.22 mg free base/kg) or saline (1 ml/kg). L-NAME (10, 30 and 60 mg/kg) were administered intraperitoneally 1 h prior to injection of MA or saline. Effects of each dose of L-NAME were examined in separate experiments. Locomotion-stereotypy rating was performed every 10 min according to the method of Dougerty and Ellinwood [6]. Ratings were made by
7". Abekawa
148
et al./Brain Research 666 (1994) 147-150
two observers; one was unaware of the treatment condition. In short, definition of each score was as follows. Score 1: lying down, eyes closed. Score 2: lying down, eyes open. Score 3: normal gnowing or chewing cage
LNAME(
10
mg/kg
)
8
'!i
0)
'~
~. i -----¢P'---
O,
MA LNAME
~.
-50
I~ Time
510
100
after
injection(
150
200
rain
Saline
250
)
LNAME( 30 mg/kg )
==
° ° •
•
>,
o u) LNAME+MA
o
o E o
: ----o-.-
2
o, 1
-
i 0
-50
-
Time
i 50
•
after
i 100
-
• J 150
injection(
-'
i 200
mln
•
-
MA LNAME
,,
Saline
250
)
LNAME( 60 mg/kg ) 8
=.
71 C
.",,''""
re
61 ,
e o
LNAME+MA MA
LNAME "J -50
= 0 Time
Fig.
1. E f f e c t s
• so
100
after
injection(
of MA,
Is0
L-NAME+MA,
200
min
Saline
2s0
) L-NAME
and
saline
on
locomotion-stereotypy rating. Each value represents the mean+ S.E.M. L-NAME was given 1 h before the administration of MA (3.22 mg free base/kg). A: 10 mg/kg L-NAME, n = 9 for each group. B: 30 mg/kg L-NAME, n = 9 for each group. C: 60 mg/kg L-NAME, n = 6 for each group. *P < 0.05 MA group vs L-NAME+ MA group•
litter. Score 4: sniffing or rearing intermittently. Score 5: increased locomotion, jerky movement. Score 6: nearly continuous sniffing, gnawing, or licking, normal level of locomotor activity, but repetitive. Sore 7: nearly continuous sniffing, gnawing, or licking with hyperactive, repetitive exploration of cage. Score 8: rapid, intense, continuous head a n d / o r foreleg activity-sniffing, licking, or gnawing in the same place. Score 9: dyskinetic-reactive: backing up, jumping, seizures, abnormally maintained postures, dyskinetic movements. Experiment 2. Rats received M A (0.805 mg free b a s e / k g , s.c.) or saline (1 m g / k g , s.c). I.-NAME (10, 30 and 60 m g / k g , i.p.) was administered 1 h prior to injection of MA or saline. Motor activity was measured by an apparatus with an infrared sensor as previously described [17]. The apparatus was a slight modification of that of Shirakawa and Oikawa [20]. Horizontal movements of the rat were digitized and fed into a computer every 10 rain. Measurement was started 2 h after the home cage of the rat was placed under the sensor. Experiment 3. D-NAME (30 m g / k g ) was administered 1 h prior to injection of MA (3.22 and 0.805 mg free b a s e / k g , s.c.). Locomotion-stereotypy rating and motor activity measurement were conducted using the rats who had received 3.22 and 0.85 mg free b a s e / k g MA, respectively. A one-way A N O V A with a post-hoe Duncan new multiple range test was performed at each time to determine when a significant difference was observed. The level of significance was set at P < 0.05. Fig. 1 shows effects of MA, L-NAME + MA, LN A M E and saline on locomotion-stereotypy rating scores. As shown in Fig. 1A, one-way A N O V A with the post-hoc tests revealed that locomotion-stereotypy rating scores were not different between MA and LN A M E (10 m g / k g ) + MA group. However, pretreatment with a higher dose of L-NAME (30 and 60 m g / k g ) significantly reduced MA-induced behavioral change from 10 to 110 rain (Fig. 1B,C). L-NAME (10, 30 and 60 m g / k g ) administerd alone did not have any significant behavioral effects compared with saline group. Fig. 2 shows effects of MA, L-NAME + MA and saline on motor activity measured by the infrared sensor. One-way A N O V A with the post-hoe tests revealed that motor activity did not change in L-NAME (10 m g / k g ) + MA group compared with MA group. 30 m g / k g E-NAME significantly decreased motor activity induced by M A from 10 to 40 and at 130 min. 60 m g / k g L-NAME also significantly reduced motor activity induced by MA from 10 to 50, and at 70, 90, 110, 120 and 130 rain. Fig. 3A, B shows effects of D-NAME on MA-induced changes in locomotion-stereotypy rating scores and motor activity, respectively. As shown in Fig. 3A,B,
T. Abekawa et al. / Brain Research 666 (1994) 147-150
100 -
8O 6O LNAME(10)+MA
40
LNAME(30)+MA
=t
LNAME(60)+MA
20-
MA Saline
0 -S0
0
50
100
Time
after
2OO
150
Injection(
mln
)
Fig. 2. Effects of MA, L-NAME (10, 30 and 60 m g / k g ) + M A , and saline on motor activity, n = 8, respectively. Each value represents the m e a n + S.E.M. L-NAME was given 1 h before the administration of MA (0.805 mg free base/kg).
one-way ANOVA with the post-hoe tests revealed that behavioral changes were not different between MA (3.22 and 0.805 mg free base/kg) and D-NAME (30 mg/kg) + MA group. The present study indicated that L-NAME attenu-
MA( 3.22 mg free base/kg
)
g
S4 3
! g
DNAME+MA
2
MA
..J
1 -50
•
w
-
|
•
)
-
i
•
;
•
0 50 100 150 200 Time efter Injection( mln )
250
MA ( 0.805 mg free beselkg ) 120 • In0 .
i '° 6O
20 0 -50
~
DNAME+MA MA
0 Time
$0 •fter
100 Injection(
150 mln
200 )
Fig. 3. Effects of M A (3.22 and 0.805 mg free b a s e / k g ) and D-NAME (30 m g / k g ) + M A on locomotion-stereotypy rating and motor activity, respectively. A: 3.22 mg free b a s e / k g MA, n = 6 for each group. B: 0.805 mg free b a s e / k g MA, n = 6 for each group.
149
ated in a dose-related manner both locomotion induced by a small dose of/VIA and stereotypy induced by a moderate dose of the agent. The attenuation produced by 30 mg/kg of L-NAME was greater than that produced by 10 mg/kg of the agent, although no apparent difference was observed between the effects of 30 and 60 mg/kg of L-NAME. Our results are consistent with those of Stewart et al. [24] and Pudiak et al. [18] who reported that L-NAME attenuated locomotor activity induced by amphethamine or cocaine. In addition, the present results revealed that L-NAME also reduced stereotyped behavior induced by MA. In contrast to L-NAME, D-NAME, an inactive optical isomer, had no effects on MA-induced behavioral changes, suggesting that NO synthesis inhibition was related to the effect of L-NAME. These results suggest that NO synthesis inhibition attenuates MA-induced behavioral changes. The mechanism of these effects of L-NAME remains unknown. It has been widely accepted that MAinduced increase in motor activity is related to the enhancement of DA release in the striatum (ST) or nucleus accumbens (NA) [5,12]. Gough et al. [9] reported that L-NAME prevented MA-induced DA release in ST in vivo. Therefore, it is possible that LNAME may inhibit MA-induced stereotyped behavior by attenuating DA release in ST. In contrast to the case with ST, Stewart et al. [24] presented that L-NAME did not have any effects on DA release in nucleus accumbens. This finding suggest that the effect of NO synthesis inhibition on MA-induced locomotor activity may be related to the neural process caused by the activation of postsynaptic DA receptor. Although the primary pharmacological effect of amphethamine or MA is to cause DA release from DA nerve terminals, stimulation of NMDA receptors has been shown to be involved in the behavioral and neurochemical effects of the stimulant [10,11,17,23]. Specifically, microdialysis studies [1,16] and a push-pull perfusion study [15] have shown that MA increased extracellular concentrations of glutamate in ST. Considering recent demonstration that stimulation of NMDA receptor activates NO synthesis [7,8], it is possible that the NO synthase inhibition attenuated MA-induced behavioral changes by blocking the intracellular NO formation initiated by activation of NMDA receotors. In summary, L-NAME (30, 60 mg/kg) significantly reduced behavioral changes induced by a single administration of MA. The results suggest that formation of NO is involved in the full expression of the behavioral effect of MA. This study was supported in part by Grant-in Aid 05670796 for Scientific Research from Ministry Education, Science and Culture, Japan.
150
T. Abekawa et al. /Brain Research 666 (1994) 147-150
[1[ Abekawa, T., Ohmori, T. and Koyama, T., Effects of repeated administration of a high dose of methamphetamine on dopamine and glutamate release in rat striatum and nucleus accumbens, Brain Res., 643 (1994) 276-281. [2] Bredt, D.S. and Snyder, S.H., Nitric oxide mediates glutamatelinked enhancement of cGMP levels in the cerebellum, Proc. Natl. Acad. Sci. USA, 86 (1989) 9030-9033. [3] Bredt, D.S., Hwang, P.M. and Snyder, S.H., Localization of nitric oxide synthase indicating a neural role for nitric oxide, Nature, 347 (1990) 768-770. [4] Bredt, D.S. and Snyder, S.H., Nitric oxide, a novel neuronal messenger, Neuron, 8 (1992) 3-11. [5] Chueh, C.C. and Moore, K.E., d-Amphetamine-induced release of newly synthetized and stored dopamine from the caudate nucleus in vivo, J. Pharmacol. Exp. Then, 192 (1975) 642-653. [6] Dougherty, G.G. and Ellinwood, E.H., Influence of gammabutyrolactone on behavior due to dopaminergic drugs, Physiol. Behat% 30 (1983) 607-612. [7] Garthwaite, J., Garthwaite, G., Palmer, R.M. and Moncada, S., NMDA receptor activation nitric oxide synthesis from arginine in rat brain slices, Eur. Z Pharmacol., 172 (1989) 413-416. [8] Garthwaite, J., Glutamate, nitric oxide and cell-cell signalling in the nervous system, Trends Neurosci., 14 (1991) 60-67. [9] Gough, B., Holson, R.R., Slikker, W.JR. and Bower, J.F., Effects of nitric oxide synthetase inhibition and adenosine receptor antagonism on extracellular dopamine levels during methamphetamine exposure, Soc. Neurosci. Abstr., (1993) 1679. [10] Karler, R., Calder, L.D., Chaudhry, I.A. and Turkanis, S.A., Blockade of reverse tolerance to cocaine and amphetamine by MK-801, Life Sci., 45 (1989) 599-606. [11] Karler, R., Chaudhry, I.A., Calder, LD. and Turkanis, S.A., Amphetamine sensitization and the excitatory amino acids, Brain Res., 537 (1990) 76-82. [12] Kelly, P.H., Seviour, P.W. and Iversen, S.D., Amphetamine and apomorphine response in the rat following 6-OHDA lesions of the nucleus aecumbens septi and corpus striatum, Brain Res., 94 (1975) 507-522. [13] Macrae, I.M., Dawson, D.A., Norrie, J.D. and McCulloch, J., Inhibition of nitric oxide synthesis: effects on cerebral blood flow and glucose utilisation in the rat, J. Cereb. Blood Flow Metab., 13 (1993) 985-992.
[14] MacVicar, B.A., Samanani, S.A., Dully, S. and Weiss, S., Nitric oxide (NO) induces the release of intracellular calcium ([Ca ~+ ]) in striatal neurons, Soc. Neurosci. Abstr., (1993) 1351. [15] Mora, F and Porras, A., Effects of amphetamine on the release of excitatory amino acid neurotransmitters in the basal ganglia of the conscious rat, Can. J. physiol. Pharmacol., 71 (1993) 348-351. [16] Nash, J.F. and Yamamoto, B.K., Methamphetamine neurotoxicity and striatal glutamate release: comparison to 3,4-methylenedioxymethamphetamine, Brain Res., 581 (1992) 237-243. [17] Ohmori, T., Abekawa, T., Muraki, A. and Koyama, T., Competitive and noncompetitive NMDA antagonists block sensitization to methamphetamine, PharmacoL Bioehem. Behat,., 48 (1994) 587-591. [18] Pudiak, C.M. and Bozarth, M.A., L-NAME and MK-801 attenuate sensitization to to the locomotor-stimulating effect of cocaine, Life Sci., 53 (1993) 1517-1524. [19] Roberts, P.J. and Anderson, S.D., Stimulatory effect of Lglutamate and related amino acid on [3H]dopamine release from rat striatum: an in vitro model for glutamate actions, Neurochemistry, 32 (1979) 1539-1545. [20] Shirakawa, T. and Oikawa, K., An actograph sensing thermal radiation from animals, Sapporo Symposium on Biological Rhythm, Abstracts, 1988, pp. 39. [21] Snyder, S.H. and Bredt, D.S., Nitric oxide as a neuronal messenger, Trends Pharmacol. Sci., 12 (1991) 125-128. [22] Snyder, S.H., Nitric oxide: first in a new class of neurotransmitter, Science, 257 (1992) 494-496. [23] Stewart, J., and Druhan, J., Development of both conditioning and sensitization of the behavioral activating effects of amphetamine is blocked by the non-competitive NMDA receptor antagonist, MK-801, Psychopharmacology, 110 (1993) 125-132. [24] Stewart, J., Deschamps, S.E. and Amir, S., Inhibition of nitric oxide synthase does not block the developement of sensitization to the behavioral activating effects of amphetamine, Brain Res., 641 (1994) 141-144. [25] Wolf, M.E. and Khasa, M.R., Repeated administration of MK801 produces sensitization to its own locomotor stimulant effects but block sensitization to amphetamine, Brain Res., 562 (1991) 164-168.
Brain Research 666 (1994) 147-150
Short communication
Effect of NO synthase inhibition on behavioral changes induced by a single administration of methamphetamine Tomohiro Abekawa *, Tetsuro Ohmori, Tsukasa Koyama Department of Psychiatry, Hokkaido University School of Medicine, Sapporo, Japan Accepted 27 September 1994
Abstract
The present study examined the effects of nitric oxide synthase inhibitor, Nto-nitro-L-arginine methyl ester (L-NAME; 10, 30, 60 mg/kg, i.p.) on behavioral changes induced by a single administration of methamphetamine (MA) (3.22 and 0.805 mg free base/kg, s.c.). MA increased locomotion-stereotypy rating scores and motor activity counts measured by an infrared sensor. L-NAME administerd prior to MA significantly decreased the level of locomotion stereotypy rating and motor activity induced by MA. An inactive optical isomer, Nto-nitro-D-arginine methyl ester (D-NAME) had no effects on MA-induced behavioral changes. The results suggest that NO synthesis is involved in the full expression of behavioral effects of MA.
Keywords: Methamphetamine; Nitric oxide; Nitric oxide synthase inhibitor; L-NAME
Nitric oxide (NO) was initially identified as a mediator for macrophage and endothelial cells, but has recently been recognized as a novel neuronal messenger, which acts both as an intracellular messenger and neurotransmitter. Stimulation of N-methyl-D-aspartate (NMDA) receptors induces influx of extracellular Ca 2+, which binds to calmodulin and consequently activates NO synthase. NO binds to hem, conforming guanylate cyclase, and activates this enzyme to form cyclic guanosine monophosphate (cGMP). These processes suggest a relationship between N M D A receptor activation and NO formation [2-4,8,14,21,22]. Involvement of NMDA receptors in the behavioral and neurochemical effects of psychostimulants has been reported [10,11,17,23,25]. Recently, Pudiak et al. [18] have presented that Nto-nitro-L-arginine methyl ester (L-NAME) blocked locomotor activity induced by a single administration of cocaine. Furthermore, Stewart et al. [24] revealed that L-NAME reduced lomotor activity induced by amphetamine. The present study examined the effects of NO synthase inhibition on not only locomotor activity but also
* Corresponding author. Department of Psychiatry and Neurology, Hokkaido University School of Medicine, Kita 15, Nishi 7, Kitaku, Sapporo, Japan. Fax: (81) (11) 736-0956. 0006-8993/94/$07.00 © 1994 Elsevier Science B.V. All rights reserved SSDI 0 0 0 6 - 8 9 9 3 ( 9 4 ) 0 1 133-8
stereotyped behavior induced by a single administration of methamphetamine (MA). Locomotor activity and stereotyped behavior are generally thought to be mediated by the activity of the nucleus accumbens and striatum, respectively. Since the interaction of dopamine and glutamate in the two regions have different features [1], the effect of NO synthase inhibition on the two MA-induced behaviors should be examined separately. Male Wistar-King rats (200-260 g) were housed individually in conditions of constant temperature (24°C) and controlled light (light period 06.30 h to 18.30 h) and given food and water ad libitum. Methamphetamine hydrochloride (MA) and Ntonitro-L-arginine methyl ester hydrochloride (L-NAME) were purchased from Dainippon Pharmaceuticals Ltd., Japan and Sigma Chemical (St.Louis, MO), respectively. Both agents were dissolved in sterile physiological saline. Experiment 1. Rats received one subcutaneous injection of MA (3.22 mg free base/kg) or saline (1 ml/kg). L-NAME (10, 30 and 60 mg/kg) were administered intraperitoneally 1 h prior to injection of MA or saline. Effects of each dose of L-NAME were examined in separate experiments. Locomotion-stereotypy rating was performed every 10 min according to the method of Dougerty and Ellinwood [6]. Ratings were made by
7". Abekawa
148
et al./Brain Research 666 (1994) 147-150
two observers; one was unaware of the treatment condition. In short, definition of each score was as follows. Score 1: lying down, eyes closed. Score 2: lying down, eyes open. Score 3: normal gnowing or chewing cage
LNAME(
10
mg/kg
)
8
'!i
0)
'~
~. i -----¢P'---
O,
MA LNAME
~.
-50
I~ Time
510
100
after
injection(
150
200
rain
Saline
250
)
LNAME( 30 mg/kg )
==
° ° •
•
>,
o u) LNAME+MA
o
o E o
: ----o-.-
2
o, 1
-
i 0
-50
-
Time
i 50
•
after
i 100
-
• J 150
injection(
-'
i 200
mln
•
-
MA LNAME
,,
Saline
250
)
LNAME( 60 mg/kg ) 8
=.
71 C
.",,''""
re
61 ,
e o
LNAME+MA MA
LNAME "J -50
= 0 Time
Fig.
1. E f f e c t s
• so
100
after
injection(
of MA,
Is0
L-NAME+MA,
200
min
Saline
2s0
) L-NAME
and
saline
on
locomotion-stereotypy rating. Each value represents the mean+ S.E.M. L-NAME was given 1 h before the administration of MA (3.22 mg free base/kg). A: 10 mg/kg L-NAME, n = 9 for each group. B: 30 mg/kg L-NAME, n = 9 for each group. C: 60 mg/kg L-NAME, n = 6 for each group. *P < 0.05 MA group vs L-NAME+ MA group•
litter. Score 4: sniffing or rearing intermittently. Score 5: increased locomotion, jerky movement. Score 6: nearly continuous sniffing, gnawing, or licking, normal level of locomotor activity, but repetitive. Sore 7: nearly continuous sniffing, gnawing, or licking with hyperactive, repetitive exploration of cage. Score 8: rapid, intense, continuous head a n d / o r foreleg activity-sniffing, licking, or gnawing in the same place. Score 9: dyskinetic-reactive: backing up, jumping, seizures, abnormally maintained postures, dyskinetic movements. Experiment 2. Rats received M A (0.805 mg free b a s e / k g , s.c.) or saline (1 m g / k g , s.c). I.-NAME (10, 30 and 60 m g / k g , i.p.) was administered 1 h prior to injection of MA or saline. Motor activity was measured by an apparatus with an infrared sensor as previously described [17]. The apparatus was a slight modification of that of Shirakawa and Oikawa [20]. Horizontal movements of the rat were digitized and fed into a computer every 10 rain. Measurement was started 2 h after the home cage of the rat was placed under the sensor. Experiment 3. D-NAME (30 m g / k g ) was administered 1 h prior to injection of MA (3.22 and 0.805 mg free b a s e / k g , s.c.). Locomotion-stereotypy rating and motor activity measurement were conducted using the rats who had received 3.22 and 0.85 mg free b a s e / k g MA, respectively. A one-way A N O V A with a post-hoe Duncan new multiple range test was performed at each time to determine when a significant difference was observed. The level of significance was set at P < 0.05. Fig. 1 shows effects of MA, L-NAME + MA, LN A M E and saline on locomotion-stereotypy rating scores. As shown in Fig. 1A, one-way A N O V A with the post-hoc tests revealed that locomotion-stereotypy rating scores were not different between MA and LN A M E (10 m g / k g ) + MA group. However, pretreatment with a higher dose of L-NAME (30 and 60 m g / k g ) significantly reduced MA-induced behavioral change from 10 to 110 rain (Fig. 1B,C). L-NAME (10, 30 and 60 m g / k g ) administerd alone did not have any significant behavioral effects compared with saline group. Fig. 2 shows effects of MA, L-NAME + MA and saline on motor activity measured by the infrared sensor. One-way A N O V A with the post-hoe tests revealed that motor activity did not change in L-NAME (10 m g / k g ) + MA group compared with MA group. 30 m g / k g E-NAME significantly decreased motor activity induced by M A from 10 to 40 and at 130 min. 60 m g / k g L-NAME also significantly reduced motor activity induced by MA from 10 to 50, and at 70, 90, 110, 120 and 130 rain. Fig. 3A, B shows effects of D-NAME on MA-induced changes in locomotion-stereotypy rating scores and motor activity, respectively. As shown in Fig. 3A,B,
T. Abekawa et al. / Brain Research 666 (1994) 147-150
100 -
8O 6O LNAME(10)+MA
40
LNAME(30)+MA
=t
LNAME(60)+MA
20-
MA Saline
0 -S0
0
50
100
Time
after
2OO
150
Injection(
mln
)
Fig. 2. Effects of MA, L-NAME (10, 30 and 60 m g / k g ) + M A , and saline on motor activity, n = 8, respectively. Each value represents the m e a n + S.E.M. L-NAME was given 1 h before the administration of MA (0.805 mg free base/kg).
one-way ANOVA with the post-hoe tests revealed that behavioral changes were not different between MA (3.22 and 0.805 mg free base/kg) and D-NAME (30 mg/kg) + MA group. The present study indicated that L-NAME attenu-
MA( 3.22 mg free base/kg
)
g
S4 3
! g
DNAME+MA
2
MA
..J
1 -50
•
w
-
|
•
)
-
i
•
;
•
0 50 100 150 200 Time efter Injection( mln )
250
MA ( 0.805 mg free beselkg ) 120 • In0 .
i '° 6O
20 0 -50
~
DNAME+MA MA
0 Time
$0 •fter
100 Injection(
150 mln
200 )
Fig. 3. Effects of M A (3.22 and 0.805 mg free b a s e / k g ) and D-NAME (30 m g / k g ) + M A on locomotion-stereotypy rating and motor activity, respectively. A: 3.22 mg free b a s e / k g MA, n = 6 for each group. B: 0.805 mg free b a s e / k g MA, n = 6 for each group.
149
ated in a dose-related manner both locomotion induced by a small dose of/VIA and stereotypy induced by a moderate dose of the agent. The attenuation produced by 30 mg/kg of L-NAME was greater than that produced by 10 mg/kg of the agent, although no apparent difference was observed between the effects of 30 and 60 mg/kg of L-NAME. Our results are consistent with those of Stewart et al. [24] and Pudiak et al. [18] who reported that L-NAME attenuated locomotor activity induced by amphethamine or cocaine. In addition, the present results revealed that L-NAME also reduced stereotyped behavior induced by MA. In contrast to L-NAME, D-NAME, an inactive optical isomer, had no effects on MA-induced behavioral changes, suggesting that NO synthesis inhibition was related to the effect of L-NAME. These results suggest that NO synthesis inhibition attenuates MA-induced behavioral changes. The mechanism of these effects of L-NAME remains unknown. It has been widely accepted that MAinduced increase in motor activity is related to the enhancement of DA release in the striatum (ST) or nucleus accumbens (NA) [5,12]. Gough et al. [9] reported that L-NAME prevented MA-induced DA release in ST in vivo. Therefore, it is possible that LNAME may inhibit MA-induced stereotyped behavior by attenuating DA release in ST. In contrast to the case with ST, Stewart et al. [24] presented that L-NAME did not have any effects on DA release in nucleus accumbens. This finding suggest that the effect of NO synthesis inhibition on MA-induced locomotor activity may be related to the neural process caused by the activation of postsynaptic DA receptor. Although the primary pharmacological effect of amphethamine or MA is to cause DA release from DA nerve terminals, stimulation of NMDA receptors has been shown to be involved in the behavioral and neurochemical effects of the stimulant [10,11,17,23]. Specifically, microdialysis studies [1,16] and a push-pull perfusion study [15] have shown that MA increased extracellular concentrations of glutamate in ST. Considering recent demonstration that stimulation of NMDA receptor activates NO synthesis [7,8], it is possible that the NO synthase inhibition attenuated MA-induced behavioral changes by blocking the intracellular NO formation initiated by activation of NMDA receotors. In summary, L-NAME (30, 60 mg/kg) significantly reduced behavioral changes induced by a single administration of MA. The results suggest that formation of NO is involved in the full expression of the behavioral effect of MA. This study was supported in part by Grant-in Aid 05670796 for Scientific Research from Ministry Education, Science and Culture, Japan.
150
T. Abekawa et al. /Brain Research 666 (1994) 147-150
[1[ Abekawa, T., Ohmori, T. and Koyama, T., Effects of repeated administration of a high dose of methamphetamine on dopamine and glutamate release in rat striatum and nucleus accumbens, Brain Res., 643 (1994) 276-281. [2] Bredt, D.S. and Snyder, S.H., Nitric oxide mediates glutamatelinked enhancement of cGMP levels in the cerebellum, Proc. Natl. Acad. Sci. USA, 86 (1989) 9030-9033. [3] Bredt, D.S., Hwang, P.M. and Snyder, S.H., Localization of nitric oxide synthase indicating a neural role for nitric oxide, Nature, 347 (1990) 768-770. [4] Bredt, D.S. and Snyder, S.H., Nitric oxide, a novel neuronal messenger, Neuron, 8 (1992) 3-11. [5] Chueh, C.C. and Moore, K.E., d-Amphetamine-induced release of newly synthetized and stored dopamine from the caudate nucleus in vivo, J. Pharmacol. Exp. Then, 192 (1975) 642-653. [6] Dougherty, G.G. and Ellinwood, E.H., Influence of gammabutyrolactone on behavior due to dopaminergic drugs, Physiol. Behat% 30 (1983) 607-612. [7] Garthwaite, J., Garthwaite, G., Palmer, R.M. and Moncada, S., NMDA receptor activation nitric oxide synthesis from arginine in rat brain slices, Eur. Z Pharmacol., 172 (1989) 413-416. [8] Garthwaite, J., Glutamate, nitric oxide and cell-cell signalling in the nervous system, Trends Neurosci., 14 (1991) 60-67. [9] Gough, B., Holson, R.R., Slikker, W.JR. and Bower, J.F., Effects of nitric oxide synthetase inhibition and adenosine receptor antagonism on extracellular dopamine levels during methamphetamine exposure, Soc. Neurosci. Abstr., (1993) 1679. [10] Karler, R., Calder, L.D., Chaudhry, I.A. and Turkanis, S.A., Blockade of reverse tolerance to cocaine and amphetamine by MK-801, Life Sci., 45 (1989) 599-606. [11] Karler, R., Chaudhry, I.A., Calder, LD. and Turkanis, S.A., Amphetamine sensitization and the excitatory amino acids, Brain Res., 537 (1990) 76-82. [12] Kelly, P.H., Seviour, P.W. and Iversen, S.D., Amphetamine and apomorphine response in the rat following 6-OHDA lesions of the nucleus aecumbens septi and corpus striatum, Brain Res., 94 (1975) 507-522. [13] Macrae, I.M., Dawson, D.A., Norrie, J.D. and McCulloch, J., Inhibition of nitric oxide synthesis: effects on cerebral blood flow and glucose utilisation in the rat, J. Cereb. Blood Flow Metab., 13 (1993) 985-992.
[14] MacVicar, B.A., Samanani, S.A., Dully, S. and Weiss, S., Nitric oxide (NO) induces the release of intracellular calcium ([Ca ~+ ]) in striatal neurons, Soc. Neurosci. Abstr., (1993) 1351. [15] Mora, F and Porras, A., Effects of amphetamine on the release of excitatory amino acid neurotransmitters in the basal ganglia of the conscious rat, Can. J. physiol. Pharmacol., 71 (1993) 348-351. [16] Nash, J.F. and Yamamoto, B.K., Methamphetamine neurotoxicity and striatal glutamate release: comparison to 3,4-methylenedioxymethamphetamine, Brain Res., 581 (1992) 237-243. [17] Ohmori, T., Abekawa, T., Muraki, A. and Koyama, T., Competitive and noncompetitive NMDA antagonists block sensitization to methamphetamine, PharmacoL Bioehem. Behat,., 48 (1994) 587-591. [18] Pudiak, C.M. and Bozarth, M.A., L-NAME and MK-801 attenuate sensitization to to the locomotor-stimulating effect of cocaine, Life Sci., 53 (1993) 1517-1524. [19] Roberts, P.J. and Anderson, S.D., Stimulatory effect of Lglutamate and related amino acid on [3H]dopamine release from rat striatum: an in vitro model for glutamate actions, Neurochemistry, 32 (1979) 1539-1545. [20] Shirakawa, T. and Oikawa, K., An actograph sensing thermal radiation from animals, Sapporo Symposium on Biological Rhythm, Abstracts, 1988, pp. 39. [21] Snyder, S.H. and Bredt, D.S., Nitric oxide as a neuronal messenger, Trends Pharmacol. Sci., 12 (1991) 125-128. [22] Snyder, S.H., Nitric oxide: first in a new class of neurotransmitter, Science, 257 (1992) 494-496. [23] Stewart, J., and Druhan, J., Development of both conditioning and sensitization of the behavioral activating effects of amphetamine is blocked by the non-competitive NMDA receptor antagonist, MK-801, Psychopharmacology, 110 (1993) 125-132. [24] Stewart, J., Deschamps, S.E. and Amir, S., Inhibition of nitric oxide synthase does not block the developement of sensitization to the behavioral activating effects of amphetamine, Brain Res., 641 (1994) 141-144. [25] Wolf, M.E. and Khasa, M.R., Repeated administration of MK801 produces sensitization to its own locomotor stimulant effects but block sensitization to amphetamine, Brain Res., 562 (1991) 164-168.