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The effect of repeated amphetamine treatment on striatal DA transporter and rotation in rats
BRAIN RESEARCH ELSEVIER
Brain Research 668 (1994) 239-242
Short communication
The effect of repeated amphetamine treatment on striatal D A transporter and rotation in rats Matti Mintz b,, Irit Gordon a
a
Netta Roz
a
Moshe Rehavi a
Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel b Psychobiology Research Unit, Department of Psychology, Tel-Aviv University, Tel-Aviv 69978, Israel
Accepted 4 October 1994
Abstract
The effect of repeated amphetamine treatment on the involvement of the striatal DA transporters in rotation behavior was tested in rats. Repeated amphetamine treatment had no effect on [3H]DA uptake or [3H]GBR-12935 binding density. However, unlike the naive rats who rotated away from the striatum with a lower density of DA transporters, rats sensitized to amphetamine rotated toward the striatum with a lower density of DA transporters. These findings imply that repeated amphetamine augments the subcortical involvement in behavioral output. Keywords: Rotation; Repeated amphetamine; Sensitization; Striatum; DA; DA transporter; DA uptake
Recent studies have shown that female rats challenged with amphetamine rotate toward the striatum with a higher extracellular D A level [7] and a higher density of D A transporters [8]. Given that excess of DA transporters contribute to increase in extracellular D A level in response to amphetamine, the above findings imply that asymmetry in the density of DA transporters may be causally related to rotation asymmetry. The present study attempts to further assess the relationship between the asymmetries of striatal D A transporter and rotation. Repeated amphetamine treatment has been shown to change rotation asymmetry [6,16] but has no effect on the density of striatal D A transporters [1,12]. We, therefore, predicted that repeated amphetamine treatment would change the relationship between the asymmetry in striatal D A transporters and the asymmetry in rotation. Expt. 1: Female Wistar rats were treated with either D-amphetamine (3 m g / k g i.p.) or saline for 5 days. Rotation [8] was recorded only in response to the first injection (presensitization). Amphetamine stimulated only a moderate level of rotation, due to interference by stereotypy (Fig. 1A). Nevertheless, it caused a clear
* Corresponding author. Fax: (972) (21) 931-7810. 0006-8993/94/$07.00 © 1994 Elsevier Science B.V. All rights reserved SSDI 0006-8993(94)01180-X
side preference in comparison to the effect of saline (group by side interaction; Fl,10 = 12.9, P < 0.005). Rats were sacrificed after 2 days of withdrawal from the repeated injections (Fig. 3A,C). The specific binding of [3H]GBR-12935 [8,10] to striatal membranes (2 nM) was similar in both amphetamine-treated and control rats (group effect P = 0.23; Fig. 1B). In five out of six rats in each group, binding was lower in the striatum contralateral to the preferred side of full circle rotations (hemisphere effect; F],10 --- 2.9, P < 0.12). The rate of [3H]DA uptake 3 (5 × 10 -7) into striatal synaptosomes was similar in both amphetamine-treated and control rats (group effect; P = 0.20; Fig. 1C). In five out of six rats in each group, D A uptake was lower in the striatum contralateral to the preferred side of rotation (hemisphere effect; F~,10 = 8.7, P < 0.014). Expt. 2: Rats were treated with either amphetamine (3 m g / k g i.p.) or saline for 5 days. Presensitization rotation was tested in response to either amphetamine (1.5 m g / k g ) or saline, respectively. Rotation to amphetamine (1.5 m g / k g ) was retested both 2 and 14 days after withdrawal from the repeated amphetamine regime (postsensitization). Amphetamine-treated rats were sacrificed 2 days later, i.e., 16 days after withdrawal from repeated amphetamine (Fig. 3E). Saline-
M. Mintz et al. / Brain Research 668 (1994) 239-242
240 AMPHETAMINE GROUP
"~ ,o o
~0
E
20
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nonpreferred
i~pref . . . . d
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2
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8 6
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SESSION
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HEMISPHERE contralateral ipsilaterol
1 ] J
2
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0
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40
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2o
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30
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o!
Fig. 1. A: presensitization rotation (mean_+ S.E.M.) to 3.0 m g / k g of d - a m p h e t a m i n e (n = 6) or saline (n = 6). B: [3HlGBR-12935 (2 nM) binding. C: [3H]DA ( 5 × 10 -7 M) uptake in striati either contra- or ipsilateral to the preferred direction of presensitization rotation to a m p h e t a m i n e or saline. Rats were decapitated after 2 days of withdrawal from repeated a m p h e t a m i n e treatment.
treated rats were sacrificed 2 days after their last saline injection (Fig. 3A). Repeated amphetamine treatment increased the rats' activity (total count of an eights of a circle in the rotometer) in response to the challenge dose of amphetamine (1528 + 298 vs. 1930 + 275 and 1938 + 135; in presensitization vs. 2 and 14 days postsensitization sessions, respectively; session effect, Fz,10= 5.6, P < 0.03). During the presensitization session, amphetamine stimulated a robust and highly asymmetrical rotation (Fig. 2A; group by side interaction; F I A 4 = 23.2, P < 0.001). Sensitization reversed the preferred side of rotation in four out of eight rats. Membranes of the bilateral striati were assessed for a saturable binding of [3H]GBR-12935 (0.5-8.0 nM final concentration) using the Scatchard plot analysis. The K~ values of [3H]GBR-12935 binding were higher in rats treated repeatedly with amphetamine (Fla 4 = 6.0, P < 0.03) but Bm~ values were similar in both groups ( P = 0.10). Bilateral values of Bmax and K~ were similar in both groups when the striati were designated according to the preferred side of rotation to amphetamine in the presensitization session (0.99 >
P > 0.79; Fig. 2B). However, when the striati were defined according to the preferred side of rotation in the postsensitization session, higher Brnax value was found in the striatum contralateral to the preferred side of rotation ( t 6 = 3.4, P < 0.02, two-tailed). Among control rats 75% of those with reliable asymmetry in [3H]GBR-12935 binding rotated spontaneously away from the striatum with a lower density of DA transporters. Repeated amphetamine treatment sensitized the rats' activity response to amphetamine challenge and in half of the animals reversed the preferred side of rotation to amphetamine. In line with others, the behavioral sensitization to amphetamine was not associated with change in DA transporters density or DA uptake [1,12]. Unlike Shapiro et al. [18], we have shown that [3H]DA uptake or [3H]GBR-12935 binding [8] is lower in the striatum contralateral to either the spontaneous or amphetamine-stimulated rotation in female rats (Fig. 3A,B). In the present study, these findings were replicated in spontaneously rotating naive females. Furthermore, 2 days after the withdrawal from the repeated amphetamine treatment, the transporters density was still lower contralaterally to the presensitization preferred side of rotation (Fig. 3C). The emergence of the permanent effects of sensitization may require, however, longer withdrawal periods [11]. Indeed, after 16 days of withdrawal, the asymmetry of DA transporters was no longer associated with a specific pattern of presensitization side preference (Fig. 3D). Loosening A
18,0
SALINE
AMPHETAMINE
150
I
SiDE
|~
nonpreferred pref . . . . d
L. ~
120
I
90 60
o
pre
B o
o.
pre
14 days post
Hemisphere effect
SESSION
HE~,SdHERE [ ~ ] contralateral
8
E -6 E x fib
0
Fig. 2. A: presensitization rotation (mean + S.E.M.) to saline (n = 8) and pre- and postsensitization rotation to 1.5 m g / k g of d-amphetamine (n = 8). B: [3H]GBR-12935 maximal binding capacity to striatal m e m b r a n e s classified as either contra- or ipsilateral to the preferred side of rotation at each test represented in A.
241
M. Mintz et aL / Brain Research 668 (1994) 239-242
of the above association was caused by a change in the preferred side of rotation in a half of the sample and possibly by a change in the asymmetry of the D A transporter's density in other rats. As a result of these changes, rats retested for rotation after 14 days of withdrawal preferred to rotate away from the striatum with a higher, rather than lower, density of D A transporters (Fig. 3E). In line with Glick et al. [6], these results support the hypothesis of asymmetric sensitization of rotation behavior. The following is a working hypothesis concerning the site of the sensitizing effect. The endogenous asymmetry of D A transporters may contribute to a bilateral imbalance in extracellular D A levels, causing spontaneous rotation away from the striatum with lower DA uptake and higher levels of extracellular DA [7] (Fig. 3A). In the context of amphetamine challenge, a lower density of DA transporters implies lower intraterminal uptake of amphetamine [5,17] and less effective D A release [14]. It seems, therefore, that amphetamine interacting with an asymmetric DA uptake systems, generates asymmetric increase in extracellular D A levels. The direction of this asymmetry is reversed in comparison to that observed during spontaneous conditions. Thus, rotation
to amphetamine directed away from the striatum with lower density of DA transporters [8] corresponds to amphetamine-stimulated rotation directed away from the striatum with lower extracellular D A levels [7] (Fig. 3B). Based on the same reasoning, rotation to amphetamine of rats previously treated repeatedly with amphetamine is directed away from the striatum with higher D A uptake and higher extracellular DA levels (Fig. 3E). According to the above reasoning, rotation away from the striatum with higher D A activity characterizes the spontaneous conditions (Fig. 3A); however, in response to amphetamine, it prevails only in sensitized (Fig. 3E) and not in naive rats (Fig. 3B). We assume that the spontaneous rotation is determined preferentially by the nigrostriatal D A asymmetry. Amphetamine challenge to naive rats expands the extrastriatal involvement in rotation. Indeed, acute amphetamine activates preferentially the mesocortical vs. the nigrostriatal DA terminals. This may be inferred from the findings that amphetamine increases extracellular DA in the accumbens more than in the caudate [4] although it increases the extracellular DA in the accumbens and medial prefrontal cortex to the same
REPEATED AMPH 14 DAYS OFF ROTATION
SALINE
AMPH
AMPH
AMPH
REPEATED AMPH
REPEATED AMPH
2 DAYS OFF
16 DAYS OFF
AMPH
2 DAYS OFF
. . . .
Fig. 3. A schematic representation of the striatal DA terminals involvement in rotation. Arrows represent the preferred side of rotation stimulated by i.p. saline (A) or amphetamine (B-E). Rotation test was followed (C,D) or preceded (E) by repeated amphetamine treatment. Pump symbols represent the density of the striatal DA transporter. Dots represent the quantity of the extracellular DA.
242
M. Mintz et al. / Brain Research 668 (1994) 239-242
extent [15]. Therefore, rotation to amphetamine is modulated by a discordant asymmetry of nigrostriatal [7] and mesocortical [13] DA release, with the latter overriding the effect of the former. As a result, the rats not necessarily rotate away from the striatum with a higher extracellular DA level (Fig. 3B). The critical impact of the nigrostriatal DA asymmetry on rotation is most probably restored in the process of sensitization to amphetamine.. Sensitization is characterized by a selective increase in the reactivity of the nigrostriatal but not the mesocortical DA terminals to amphetamine challenge [2,9]. Thus, in sensitized rats, the rotation to amphetamine is affected by the nigrostriatal rather than the mesocortical DA asymmetry. These considerations suggest that a moderate dose of acute amphetamine suppresses the striatal involvement in rotation and that its involvement may be regained in a process of repeated amphetamine treatment. [1] Allard, P., Eriksson, K., Ross, S.B. and Marcusson, J.O., Unaltered [3H]GBR-12935 binding after chronic treatment with dopamine active drugs, Psychopharmacology, 102 (1990) 291294. [2] Camp, D.M. and Robinson, T.E., Susceptibility to sensitization. I. Sex differences in the enduring effects of chronic Damphetamine treatment on locomotion, stereotyped behavior and brain monoamines, Behav. Brain Res., 30 (1988) 55-68. [3] Coyle, J.T. and Snyder, S.H., Catecholamine uptake by synaptosomes in homogenates of rat brain, J. Pharmacol. Exp. Ther., 170 (1969) 221-231. [4] Di Chiara, G. and Imperato, A., Drugs abused by humans preferentially increase synaptic dopamine concentrations in the mesolimbic system of freely moving rats, Proc. Natl. Acad. Sci. USA, 85 (1988) 5274-5278. [5] Fischer, J.F. and Cho, A.K., Chemical release of dopamine from striatal homogenates: evidence for an exchange diffusion model, J. Pharmacol. Exp. Ther., 208 (1979) 203-209. [6] Glick, S.D., Shapiro, R.M., Drew, K.L., Hinds, P.A. and Carlson, J.N., Differences in spontaneous and amphetamine-in-
[7]
[8]
[9]
[10]
[11]
[12]
[13]
[14] [15]
[16]
[17]
[18]
duced rotational behavior, and in sensitization to amphetamine, among Sprague-Dawley derived rats from different sources, Physiol. Behav., 38 (1986) 67-70. Glick, S.D., Carlson, J.N., Baird, J.L., Maisonneuve, I.M. and Bullock, A.E., Basal and amphetamine-induced asymmetries in striatal dopamine releases and metabolism: bilateral in vivo microdialysis in normal rats, Brain Res., 473 (1988) 161-164. Gordon, I., Rehavi, M. and Mintz, M., Bilateral imbalance in striatal DA-uptake controls rotation behavior, Brain Res., 646 (1994) 207-210. Hamamura, T. and Fibiger, H.C., Enhanced stress-induced dopamine release in the prefrontal cortex of amphetaminesensitized rats, Eur. J. Pharmacol., 237 (1993) 65-71. Janowsky, A., Berger, P., Vocci, F., Labarca, R., Skolnick, P. and Paul, S.M., Characterization of sodium-dependent [3H]GBR-12935 binding in brain: a radioligand for selective labeling of the Dopamine transport complex, J. Neurochem., 46 (1986) 1272-1276. Kalivas, P.W. and Stewart, J., Dopamine transmission in the initiation and expression of drug- and stress-induced sensitization of motor activity, Brain Res. Rev., 16 (1991) 223-244. Kula, N.S. and Baldessarini, R.J., Lack of increase in dopamine transporter binding or function in rat brain tissue after treatment with blockers of neuronal uptake of dopamine, Neuropharmacology, 30 (1991) 89-92. Maisonneuve, I.M., Keller, R.W. and Glick, S.D., Similar effects of d-amphetamine and cocaine on extracellular DA levels in medial prefrontal cortex of rats, Brain Res., 535 (1990) 221-226. McMillen, B.A., CNS stimulants: two distinct mechanisms of action for amphetamine-like drugs, TIPS, (1983) 429-432. Moghaddam, B. and Bunney, B.S., Differential effect of cocaine on extracellular dopamine levels in rat medial prefrontal cortex and nucleus accumbens: comparison to amphetamine, Synapse, 4 (1989)156-161. Robinson, T.E., Becker, J.B. and Presty, S.K., Long-term facilitation of amphetamine-induced rotational behavior and striatal dopamine release produced by a single exposure to amphetamine: sex differences, Brain Res., 253 (1982) 231-241. Seiden, L.S., Sabol, K.E. and Ricaurte, G.A., Amphetamine: effects on catecholamine systems and behavior, Annu. Rev. Pharmacol. Toxicol., 32 (1993) 639-677. Shapiro, R.M., Glick, S.D. and Hough, L.B., Striatal dopamine uptake asymmetries and rotational behavior in unlesioned rats: revising the model? Psychopharrnacology, 89 (1986) 25-30.
Brain Research 668 (1994) 239-242
Short communication
The effect of repeated amphetamine treatment on striatal D A transporter and rotation in rats Matti Mintz b,, Irit Gordon a
a
Netta Roz
a
Moshe Rehavi a
Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel b Psychobiology Research Unit, Department of Psychology, Tel-Aviv University, Tel-Aviv 69978, Israel
Accepted 4 October 1994
Abstract
The effect of repeated amphetamine treatment on the involvement of the striatal DA transporters in rotation behavior was tested in rats. Repeated amphetamine treatment had no effect on [3H]DA uptake or [3H]GBR-12935 binding density. However, unlike the naive rats who rotated away from the striatum with a lower density of DA transporters, rats sensitized to amphetamine rotated toward the striatum with a lower density of DA transporters. These findings imply that repeated amphetamine augments the subcortical involvement in behavioral output. Keywords: Rotation; Repeated amphetamine; Sensitization; Striatum; DA; DA transporter; DA uptake
Recent studies have shown that female rats challenged with amphetamine rotate toward the striatum with a higher extracellular D A level [7] and a higher density of D A transporters [8]. Given that excess of DA transporters contribute to increase in extracellular D A level in response to amphetamine, the above findings imply that asymmetry in the density of DA transporters may be causally related to rotation asymmetry. The present study attempts to further assess the relationship between the asymmetries of striatal D A transporter and rotation. Repeated amphetamine treatment has been shown to change rotation asymmetry [6,16] but has no effect on the density of striatal D A transporters [1,12]. We, therefore, predicted that repeated amphetamine treatment would change the relationship between the asymmetry in striatal D A transporters and the asymmetry in rotation. Expt. 1: Female Wistar rats were treated with either D-amphetamine (3 m g / k g i.p.) or saline for 5 days. Rotation [8] was recorded only in response to the first injection (presensitization). Amphetamine stimulated only a moderate level of rotation, due to interference by stereotypy (Fig. 1A). Nevertheless, it caused a clear
* Corresponding author. Fax: (972) (21) 931-7810. 0006-8993/94/$07.00 © 1994 Elsevier Science B.V. All rights reserved SSDI 0006-8993(94)01180-X
side preference in comparison to the effect of saline (group by side interaction; Fl,10 = 12.9, P < 0.005). Rats were sacrificed after 2 days of withdrawal from the repeated injections (Fig. 3A,C). The specific binding of [3H]GBR-12935 [8,10] to striatal membranes (2 nM) was similar in both amphetamine-treated and control rats (group effect P = 0.23; Fig. 1B). In five out of six rats in each group, binding was lower in the striatum contralateral to the preferred side of full circle rotations (hemisphere effect; F],10 --- 2.9, P < 0.12). The rate of [3H]DA uptake 3 (5 × 10 -7) into striatal synaptosomes was similar in both amphetamine-treated and control rats (group effect; P = 0.20; Fig. 1C). In five out of six rats in each group, D A uptake was lower in the striatum contralateral to the preferred side of rotation (hemisphere effect; F~,10 = 8.7, P < 0.014). Expt. 2: Rats were treated with either amphetamine (3 m g / k g i.p.) or saline for 5 days. Presensitization rotation was tested in response to either amphetamine (1.5 m g / k g ) or saline, respectively. Rotation to amphetamine (1.5 m g / k g ) was retested both 2 and 14 days after withdrawal from the repeated amphetamine regime (postsensitization). Amphetamine-treated rats were sacrificed 2 days later, i.e., 16 days after withdrawal from repeated amphetamine (Fig. 3E). Saline-
M. Mintz et al. / Brain Research 668 (1994) 239-242
240 AMPHETAMINE GROUP
"~ ,o o
~0
E
20
~]
nonpreferred
i~pref . . . . d
SALINE
]
2
"6
~0
pre
"2". ~
6, E -G E
13-
8 6
B
pre
SESSION
Iz i El
HEMISPHERE contralateral ipsilaterol
1 ] J
2
v ¢'n
0
c
E
• o O,. O'}
40
E -G E
2o
&
C Hemisphere effect p
30
~o
o!
Fig. 1. A: presensitization rotation (mean_+ S.E.M.) to 3.0 m g / k g of d - a m p h e t a m i n e (n = 6) or saline (n = 6). B: [3HlGBR-12935 (2 nM) binding. C: [3H]DA ( 5 × 10 -7 M) uptake in striati either contra- or ipsilateral to the preferred direction of presensitization rotation to a m p h e t a m i n e or saline. Rats were decapitated after 2 days of withdrawal from repeated a m p h e t a m i n e treatment.
treated rats were sacrificed 2 days after their last saline injection (Fig. 3A). Repeated amphetamine treatment increased the rats' activity (total count of an eights of a circle in the rotometer) in response to the challenge dose of amphetamine (1528 + 298 vs. 1930 + 275 and 1938 + 135; in presensitization vs. 2 and 14 days postsensitization sessions, respectively; session effect, Fz,10= 5.6, P < 0.03). During the presensitization session, amphetamine stimulated a robust and highly asymmetrical rotation (Fig. 2A; group by side interaction; F I A 4 = 23.2, P < 0.001). Sensitization reversed the preferred side of rotation in four out of eight rats. Membranes of the bilateral striati were assessed for a saturable binding of [3H]GBR-12935 (0.5-8.0 nM final concentration) using the Scatchard plot analysis. The K~ values of [3H]GBR-12935 binding were higher in rats treated repeatedly with amphetamine (Fla 4 = 6.0, P < 0.03) but Bm~ values were similar in both groups ( P = 0.10). Bilateral values of Bmax and K~ were similar in both groups when the striati were designated according to the preferred side of rotation to amphetamine in the presensitization session (0.99 >
P > 0.79; Fig. 2B). However, when the striati were defined according to the preferred side of rotation in the postsensitization session, higher Brnax value was found in the striatum contralateral to the preferred side of rotation ( t 6 = 3.4, P < 0.02, two-tailed). Among control rats 75% of those with reliable asymmetry in [3H]GBR-12935 binding rotated spontaneously away from the striatum with a lower density of DA transporters. Repeated amphetamine treatment sensitized the rats' activity response to amphetamine challenge and in half of the animals reversed the preferred side of rotation to amphetamine. In line with others, the behavioral sensitization to amphetamine was not associated with change in DA transporters density or DA uptake [1,12]. Unlike Shapiro et al. [18], we have shown that [3H]DA uptake or [3H]GBR-12935 binding [8] is lower in the striatum contralateral to either the spontaneous or amphetamine-stimulated rotation in female rats (Fig. 3A,B). In the present study, these findings were replicated in spontaneously rotating naive females. Furthermore, 2 days after the withdrawal from the repeated amphetamine treatment, the transporters density was still lower contralaterally to the presensitization preferred side of rotation (Fig. 3C). The emergence of the permanent effects of sensitization may require, however, longer withdrawal periods [11]. Indeed, after 16 days of withdrawal, the asymmetry of DA transporters was no longer associated with a specific pattern of presensitization side preference (Fig. 3D). Loosening A
18,0
SALINE
AMPHETAMINE
150
I
SiDE
|~
nonpreferred pref . . . . d
L. ~
120
I
90 60
o
pre
B o
o.
pre
14 days post
Hemisphere effect
SESSION
HE~,SdHERE [ ~ ] contralateral
8
E -6 E x fib
0
Fig. 2. A: presensitization rotation (mean + S.E.M.) to saline (n = 8) and pre- and postsensitization rotation to 1.5 m g / k g of d-amphetamine (n = 8). B: [3H]GBR-12935 maximal binding capacity to striatal m e m b r a n e s classified as either contra- or ipsilateral to the preferred side of rotation at each test represented in A.
241
M. Mintz et aL / Brain Research 668 (1994) 239-242
of the above association was caused by a change in the preferred side of rotation in a half of the sample and possibly by a change in the asymmetry of the D A transporter's density in other rats. As a result of these changes, rats retested for rotation after 14 days of withdrawal preferred to rotate away from the striatum with a higher, rather than lower, density of D A transporters (Fig. 3E). In line with Glick et al. [6], these results support the hypothesis of asymmetric sensitization of rotation behavior. The following is a working hypothesis concerning the site of the sensitizing effect. The endogenous asymmetry of D A transporters may contribute to a bilateral imbalance in extracellular D A levels, causing spontaneous rotation away from the striatum with lower DA uptake and higher levels of extracellular DA [7] (Fig. 3A). In the context of amphetamine challenge, a lower density of DA transporters implies lower intraterminal uptake of amphetamine [5,17] and less effective D A release [14]. It seems, therefore, that amphetamine interacting with an asymmetric DA uptake systems, generates asymmetric increase in extracellular D A levels. The direction of this asymmetry is reversed in comparison to that observed during spontaneous conditions. Thus, rotation
to amphetamine directed away from the striatum with lower density of DA transporters [8] corresponds to amphetamine-stimulated rotation directed away from the striatum with lower extracellular D A levels [7] (Fig. 3B). Based on the same reasoning, rotation to amphetamine of rats previously treated repeatedly with amphetamine is directed away from the striatum with higher D A uptake and higher extracellular DA levels (Fig. 3E). According to the above reasoning, rotation away from the striatum with higher D A activity characterizes the spontaneous conditions (Fig. 3A); however, in response to amphetamine, it prevails only in sensitized (Fig. 3E) and not in naive rats (Fig. 3B). We assume that the spontaneous rotation is determined preferentially by the nigrostriatal D A asymmetry. Amphetamine challenge to naive rats expands the extrastriatal involvement in rotation. Indeed, acute amphetamine activates preferentially the mesocortical vs. the nigrostriatal DA terminals. This may be inferred from the findings that amphetamine increases extracellular DA in the accumbens more than in the caudate [4] although it increases the extracellular DA in the accumbens and medial prefrontal cortex to the same
REPEATED AMPH 14 DAYS OFF ROTATION
SALINE
AMPH
AMPH
AMPH
REPEATED AMPH
REPEATED AMPH
2 DAYS OFF
16 DAYS OFF
AMPH
2 DAYS OFF
. . . .
Fig. 3. A schematic representation of the striatal DA terminals involvement in rotation. Arrows represent the preferred side of rotation stimulated by i.p. saline (A) or amphetamine (B-E). Rotation test was followed (C,D) or preceded (E) by repeated amphetamine treatment. Pump symbols represent the density of the striatal DA transporter. Dots represent the quantity of the extracellular DA.
242
M. Mintz et al. / Brain Research 668 (1994) 239-242
extent [15]. Therefore, rotation to amphetamine is modulated by a discordant asymmetry of nigrostriatal [7] and mesocortical [13] DA release, with the latter overriding the effect of the former. As a result, the rats not necessarily rotate away from the striatum with a higher extracellular DA level (Fig. 3B). The critical impact of the nigrostriatal DA asymmetry on rotation is most probably restored in the process of sensitization to amphetamine.. Sensitization is characterized by a selective increase in the reactivity of the nigrostriatal but not the mesocortical DA terminals to amphetamine challenge [2,9]. Thus, in sensitized rats, the rotation to amphetamine is affected by the nigrostriatal rather than the mesocortical DA asymmetry. These considerations suggest that a moderate dose of acute amphetamine suppresses the striatal involvement in rotation and that its involvement may be regained in a process of repeated amphetamine treatment. [1] Allard, P., Eriksson, K., Ross, S.B. and Marcusson, J.O., Unaltered [3H]GBR-12935 binding after chronic treatment with dopamine active drugs, Psychopharmacology, 102 (1990) 291294. [2] Camp, D.M. and Robinson, T.E., Susceptibility to sensitization. I. Sex differences in the enduring effects of chronic Damphetamine treatment on locomotion, stereotyped behavior and brain monoamines, Behav. Brain Res., 30 (1988) 55-68. [3] Coyle, J.T. and Snyder, S.H., Catecholamine uptake by synaptosomes in homogenates of rat brain, J. Pharmacol. Exp. Ther., 170 (1969) 221-231. [4] Di Chiara, G. and Imperato, A., Drugs abused by humans preferentially increase synaptic dopamine concentrations in the mesolimbic system of freely moving rats, Proc. Natl. Acad. Sci. USA, 85 (1988) 5274-5278. [5] Fischer, J.F. and Cho, A.K., Chemical release of dopamine from striatal homogenates: evidence for an exchange diffusion model, J. Pharmacol. Exp. Ther., 208 (1979) 203-209. [6] Glick, S.D., Shapiro, R.M., Drew, K.L., Hinds, P.A. and Carlson, J.N., Differences in spontaneous and amphetamine-in-
[7]
[8]
[9]
[10]
[11]
[12]
[13]
[14] [15]
[16]
[17]
[18]
duced rotational behavior, and in sensitization to amphetamine, among Sprague-Dawley derived rats from different sources, Physiol. Behav., 38 (1986) 67-70. Glick, S.D., Carlson, J.N., Baird, J.L., Maisonneuve, I.M. and Bullock, A.E., Basal and amphetamine-induced asymmetries in striatal dopamine releases and metabolism: bilateral in vivo microdialysis in normal rats, Brain Res., 473 (1988) 161-164. Gordon, I., Rehavi, M. and Mintz, M., Bilateral imbalance in striatal DA-uptake controls rotation behavior, Brain Res., 646 (1994) 207-210. Hamamura, T. and Fibiger, H.C., Enhanced stress-induced dopamine release in the prefrontal cortex of amphetaminesensitized rats, Eur. J. Pharmacol., 237 (1993) 65-71. Janowsky, A., Berger, P., Vocci, F., Labarca, R., Skolnick, P. and Paul, S.M., Characterization of sodium-dependent [3H]GBR-12935 binding in brain: a radioligand for selective labeling of the Dopamine transport complex, J. Neurochem., 46 (1986) 1272-1276. Kalivas, P.W. and Stewart, J., Dopamine transmission in the initiation and expression of drug- and stress-induced sensitization of motor activity, Brain Res. Rev., 16 (1991) 223-244. Kula, N.S. and Baldessarini, R.J., Lack of increase in dopamine transporter binding or function in rat brain tissue after treatment with blockers of neuronal uptake of dopamine, Neuropharmacology, 30 (1991) 89-92. Maisonneuve, I.M., Keller, R.W. and Glick, S.D., Similar effects of d-amphetamine and cocaine on extracellular DA levels in medial prefrontal cortex of rats, Brain Res., 535 (1990) 221-226. McMillen, B.A., CNS stimulants: two distinct mechanisms of action for amphetamine-like drugs, TIPS, (1983) 429-432. Moghaddam, B. and Bunney, B.S., Differential effect of cocaine on extracellular dopamine levels in rat medial prefrontal cortex and nucleus accumbens: comparison to amphetamine, Synapse, 4 (1989)156-161. Robinson, T.E., Becker, J.B. and Presty, S.K., Long-term facilitation of amphetamine-induced rotational behavior and striatal dopamine release produced by a single exposure to amphetamine: sex differences, Brain Res., 253 (1982) 231-241. Seiden, L.S., Sabol, K.E. and Ricaurte, G.A., Amphetamine: effects on catecholamine systems and behavior, Annu. Rev. Pharmacol. Toxicol., 32 (1993) 639-677. Shapiro, R.M., Glick, S.D. and Hough, L.B., Striatal dopamine uptake asymmetries and rotational behavior in unlesioned rats: revising the model? Psychopharrnacology, 89 (1986) 25-30.