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. 1998 Nov 15;18(22):9547-55.
doi: 10.1523/JNEUROSCI.18-22-09547.1998.

Long-lasting induction of astrocytic basic fibroblast growth factor by repeated injections of amphetamine: blockade by concurrent treatment with a glutamate antagonist

C Flores  1 , D Rodaros, J Stewart
Affiliations

Long-lasting induction of astrocytic basic fibroblast growth factor by repeated injections of amphetamine: blockade by concurrent treatment with a glutamate antagonist

C Flores et al. J Neurosci. .

Abstract

Repeated administration of stimulant drugs leads to lasting changes in their behavioral and neurochemical effects. These changes are initiated by drug actions in the somatodendritic regions of midbrain dopaminergic neurons in the ventral tegmental area (VTA) and substantia nigra pars compacta (SNc) and continue to develop for a period of time after termination of drug treatment. Here we show that repeated administration of amphetamine (3.0 mg/kg, i.p.; three injections, once every other day) results in sustained increases in basic fibroblast growth factor immunoreactivity (bFGF-IR) in both VTA and SNc, 200-500% over that seen in saline-treated animals. Increases were observed 24 hr, 72 hr, 1 week and 1 month after the last drug injection. Because glutamate participates in the development of sensitization to stimulant drugs, we assessed the effect of the glutamate antagonist, kynurenic acid (KYN), on amphetamine-induced bFGF-IR. Coadministration of KYN prevented the increases in bFGF-IR in both VTA and SNc assessed 1 week after the amphetamine treatment. No changes in bFGF-IR were observed in the nucleus accumbens or dorsal striatum. bFGF-IR was found to be associated with astrocytes and not with dopaminergic neurons. These findings suggest that sustained enhancement of astrocytic bFGF expression in DA somatodendritic regions is a mechanism whereby stimulant drugs exert enduring effects on midbrain DA function. We hypothesize that increased glutamatergic activity elicited by amphetamine and other stimulant drugs places excessive demands on the functioning of DA neurons recruiting regulatory and neuroprotective processes that lead to enduring changes in DA neuron functioning and connectivity.

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Figures

Fig. 1.
Fig. 1.
Diagram outlining the timing of the treatment and experimental manipulations in experiments 1 and 2.
Fig. 2.
Fig. 2.
Time course. Mean (± SEM) percent of saline control (bFGF-immunoreactive cells per square millimeter) in the VTA and SNc in groups (n = 5 per group) of amphetamine-treated animals (3.0 mg/kg, i.p., on three occasions, once every other day) killed 24 hr, 72 hr, 1 week, and 1 month after the last injection. One hundred percent (100) represents the mean (solid line) and SEM (dashed lines) counts from saline-treated animals that were killed at each of the time intervals after the last injection (n = 15). ANOVAs performed on the actual counts showed a significant effect of drug treatment (VTA, F(4,30) = 11.61; p = 0.0001; SNc,F(4,30) = 16.85; p < 0.0001). Asterisks indicate significant differences from the saline group, p < 0.01; daggersindicate significant differences from the peak, p< 0.05.
Fig. 3.
Fig. 3.
Digitized images showing darkly labeled bFGF-immunoreactive cells in tissue lightly counterstained with cresyl violet (revealing both glia and larger neurons). Images were taken from representative animals that were injected, intraperitoneally, with either saline or amphetamine (3.0 mg/kg), on three occasions, once every other day, and killed 1 week later. Images A(saline) and B (amphetamine) were taken from theVTA, and images C (saline) andD (amphetamine) were taken from the SNc. Scale bar, 50 μm. Cell counts included only darkly labeled profiles that were in the same plane of focus.
Fig. 4.
Fig. 4.
Role of glutamate in DA somatodendritic regions. Mean (± SEM) percent of vehicle–saline control (bFGF-immunoreactive cells per square millimeter) in the VTA and SNc in groups of animals treated daily with kynurenic acid (n = 4 per group) or vehicle (VTA,n = 8; SNc, n = 7), given three injections of saline or amphetamine (3.0 mg/kg), and killed 1 week after the last injection of saline or amphetamine;100% represents the mean (solid line) and SEM (dashed lines) counts from vehicle–saline-treated animals (n = 8). See Materials and Methods for details. ANOVAs performed on the actual counts showed significant group difference in each area (VTA, F(3,20) = 3.77;p < 0.05; SNc,F(3,19) = 4.11; p < 0.05). Asterisks indicate that the vehicle-amphetamine group was significantly different from all other groups (p < 0.05).
Fig. 5.
Fig. 5.
Role of glutamate in DA terminal regions. Mean (± SEM) percent of vehicle–saline control (bFGF-immunoreactive cells per square millimeter) in the NAcc shell and core and in the dorsal region of the STR in groups (n = 4 per group) of animals treated daily with kynurenic acid or vehicle (n = 8 per group), given three injections of saline or amphetamine (3.0 mg/kg), and killed 1 week after the last injection of saline or amphetamine; 100% represents the mean (solid line) and SEM (dashed lines) counts from vehicle–saline-treated animals (NAcc Core andSTR, n = 7; NAcc Shell, n = 8). See Materials and Methods for details. ANOVAs performed on the actual counts showed no significant group differences in any of the areas (NAcc Shell, F(3,20) = 0.89; NAcc Core, F(3,19) = 1.52;STR, F(3,19) = 0.21).
Fig. 6.
Fig. 6.
Digitized images of VTA sections from an animal treated with amphetamine as in experiment 1 and killed 1 week after the last injection. The large black blobs indicate bFGF immunoreactivity. A, Section labeled with both TH and bFGF. bFGF-IR (indicated by the white arrow) was not found within the large TH-positive cells (see black arrow). B, Section labeled with both GFAP and bFGF. Arrows point to three GFAP-IR astrocytes. Thewhite arrow points to an astrocyte that was not labeled for bFGF. The black arrows point to two astrocytes that were labeled with both bFGF and GFAP. (Oil immersion: Scale bar, 25 μm).
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