Amphetamine-induced time-dependent sensitization of dopamine neurotransmission in the dorsal and ventral striatum: a microdialysis study in behaving rats

Abstract

The purpose of this study was to compare the effects of amphetamine exposure on subsequent amphetamine-induced changes in behavior and dopamine (DA) release in the dorsal and ventral striatum, as a function of time following the discontinuation of repeated amphetamine treatment. Rats were pretreated with either saline or an escalating-dose amphetamine regimen, and then received a 0.5 mg/kg amphetamine "challenge" after either 3, 7, or 28 days of withdrawal. Animals tested after 28 days of withdrawal were hypersensitive (sensitized) to the locomotor-activating effects of amphetamine, and relative to control animals showed a significant enhancement in amphetamine-stimulated DA release in both the dorsal and ventral striatum, as revealed by in vivo microdialysis. Animals tested after only 3 or 7 days of withdrawal showed neither behavioral sensitization nor enhanced amphetamine-stimulated DA release. These results establish that time-dependent changes in behavioral sensitization to amphetamine are associated with time-dependent changes in amphetamine-stimulated DA release, and support the hypothesis that persistent sensitization-related changes in striatal DA neurotransmission contribute to the expression of behavioral sensitization.

Fig. 1

Schematic drawings of coronal sections of the rat brain adapted from the atlas of Paxinos and Watson (1986), showing the location of the dialysis surface of probes in either the nucleus accumbens (ventral striatum; a) or dorsolateral caudate nucleus (dorsal striatum; b). Probe locations in control (saline-pretreated) animals are shown on the left-hand side of each section and those in amphetamine-pretreated animals on the right-hand side of each section.

Fig. 2

The mean (± S.E.M.) number of 90° movements per 5 min interval in control animals (○, open circles; N = 42) and animals tested after 3 days (□, open squares; N = 20), 7 days (△, open triangles; N = 18), or 28 days (◆, closed diamonds; N = 20) of withdrawal from escalating-dose amphetamine treatment. The first eight intervals represent basal activity. The animals received an injection of saline at the time indicated by the first arrow and then were left undisturbed for 12 intervals (1 h), at which time they received an injection of 0.5 mg/kg of amphetamine (second arrow). There were significant group differences in the response to amphetamine (two-way ANOVA with repeated measures on one factor, effect of treatment group, F = 5.47, P < 0.002; effect of time, F = 74.8, P < 0.0001; group by time interaction, F = 2.11, P < 0,0001). Subsequent factorial one-way ANOVAs (followed by Fisher’s PLSD tests if significant) at each point in time after amphetamine administration revealed that the group tested after 28 days of withdrawal differed from the other three groups at the times indicated by asterisks. The control, 3 day, and 7 day withdrawal groups did not differ from one another at any point in time. * 28 days differs from control, 3 day, and 7 day groups, P < 0.05, † 28 days differs from control and 3 day groups.

Fig. 3

The mean (+S.E.M.) basal concentrations of DA (A,B), dihydroxyphenylacetic acid (DOPAC; C,D), homovanillic acid (HVA; E,F), and 5-hydroxyindoleacetic acid (5-HIAA; G,H) in the nucleus accumbens (accumbens) and dorsolateral caudate nucleus (caudate) of control animals (C) and animals tested after 3, 7, or 28 days of withdrawal. The data were analyzed by one-way ANOVAs, and if significant, followed by Fisher’s PLSD tests. There was no effect of amphetamine withdrawal on the basal concentration of DA in the accumbens (F = 0.62), DOPAC in the accumbens (F = 0.52), DOPAC in the caudate (F = 0.861, HVA in the caudate (F = 1.29), 5-HIAA in the accumbens (F = 0.92), or 5-HIAA in the caudate (F = 1.79). There was a significant effect of amphetamine withdrawal on DA in the caudate (F = 4.62, P < 0.01) and HVA in the accumbens (F = 4.16, P = 0.012). The asterisk in panel B indicates that there was a significant (P < 0.05) decrease in basal DA in animals tested after 3 days of withdrawal relative to all other groups (which did not differ from one another). The asterisk in panel E indicates there was a significant (P < 0.05) increase in basal HVA in animals tested after 28 days of withdrawal, relative to all other groups (which did not differ from one another). Group Ns: accumbens control, N = 18-20; caudate control, N = 15-17; accumbens 3 day, N = 8-11; 7 day, N = 9-10; 28 day, N = 4-7; caudate 3 day, N = 6-7; 7 day, N = 8; 28 day, N = 9. Group Ns vary because both DA and metabolite data were not available for every animal.

Fig. 4

The mean (± S.E.M.) concentration (pg/μl) of DA in 20 min dialysate samples obtained from the nucleus accumbens or dorsolatera1 caudate nucleus in control animals (open circles) and animals tested 3 (open squares), 7 (open triangles), or 28 (closed diamonds) days after the discontinuation of amphetamine pretreatment. The first three samples represent the basal concentration of DA, and the animals were given an injection of saline at the time indicated by the first arrowhead. After 1 h the animals received an injection of 0.5 mg/kg of amphetamine (where indicated by the second arrowhead) and an additional nine samples collected. There was a significant effect of amphetamine withdrawal on the response to an amphetamine challenge in both the nucleus accumbens and caudate nucleus, as indicated by two-way ANOVAs with repeated measures on one factor: Accumbens (A) effect of treatment group, F = 10.4, P < 0.0001, effect of time, F = 98.7, P < 0.0001, group by time interaction, F = 9.3, P < 0,0001. Caudate (B) group, F = 11.15, P < 0.0001, time, F = 140.4, P < 0.0001, interaction, F = 5.85, P < 0.0001. Subsequent one-way ANOVAs (followed by Fisher’s PLSD tests if significant) for each interval after amphetamine administration revealed that the group tested after 28 days of withdrawal differed significantly from all other groups, at all points in time after amphetamine (Ps range from 0.03 to <0.0001), in both structures, but the control, 3 day, and 7 day groups did not differ from each other at any point in time after amphetamine administration. Group Ns: accumbens control, N = 18; caudate control, N = 15; accumbens 3 day, N = 8; accumbens 7 day, N = 9; accumbens 28 day, N = 7; caudate 3 day, N = 6; caudate 7 day, N = 8; caudate 28 day, N = 9.