Article Figures & Data
Figures
- Figure 1.
Behavioral effects of tetrabenazine. A, Mean (±SEM) number of lever presses after treatment with vehicle and various doses of tetrabenazine (n = 8). B, Mean (±SEM) intake of laboratory chow (in grams) after treatment with vehicle and various doses of tetrabenazine. *p < 0.05, different from vehicle, planned comparison. C, Mean (±SEM) intake of Bio-serv pellets and laboratory chow (in grams) after treatment with vehicle and various doses of tetrabenazine (n = 8).
- Figure 2.
The effects of the adenosine A2A antagonist MSX-3 and the antidepressant bupropion on tetrabenazine-induced changes in performance on the concurrent lever pressing/chow-feeding procedure. A, B, Tetrabenazine and MSX-3. Rats (n = 8) received intraperitoneal injections of vehicle plus vehicle (Veh/Veh), 0.75 mg/kg tetrabenazine plus vehicle (TBZ/Veh), or tetrabenazine plus 0.25, 0.5, 1.0, or 2.0 mg/kg doses of MSX-3 (M). A, Mean (±SEM) number of lever presses (FR5 schedule) during the 30 min session. B, Mean (±SEM) gram quantity of chow intake. C, D, Tetrabenazine and bupropion. Rats (n = 11) received intraperitoneal injections of vehicle plus vehicle (Veh/Veh), 0.75 mg/kg tetrabenazine plus vehicle (TBZ/Veh), or tetrabenazine plus 5.0, 10.0, or 15.0 mg/kg doses of bupropion (BU). C, Mean (±SEM) number of lever presses (FR5 schedule) during the 30 min session. D, Mean (±SEM) gram quantity of chow intake. #p < 0.05, tetrabenazine plus vehicle significantly differed from vehicle/vehicle; *p < 0.05, significantly different from tetrabenazine plus vehicle.
- Figure 3.
Intracranial administration of tetrabenazine. A, Placements of cannulae in nucleus accumbens core (filled circles) and the dorsal control site (open circles) in rats that received the 20.0 μg dose of tetrabenazine. B, Mean (±SEM) number of lever presses after treatment with either vehicle (n = 7), 10.0 μg (n = 5), or 20.0 μg (n = 7) per side of tetrabenazine injected into nucleus accumbens core or 20.0 μg per side injected into the dorsal control site (n = 5). C, Mean (±SEM) intake of laboratory chow (in grams) after treatment with vehicle, 10.0 μg or 20.0 μg per side of tetrabenazine injected into nucleus accumbens core, or 20.0 μg per side injected into the dorsal control site. *p < 0.05, different from vehicle, planned comparison.
- Figure 4.
Neurochemical effects of tetrabenazine. A, Microdialysis data showing the effect of 0.75 mg/kg tetrabenaine on mean (±SEM) extracellular DA (expressed as percentage of baseline) in nucleus accumbens core. Samples (30 min) were collected during the baseline period (BL1 and BL2) and for the 7 samples after the injection of either tetrabenazine (n = 6) or vehicle (n = 5) (D1–D7). *p < 0.05, different from last baseline sample in the tetrabenazine group. B, Expression of c-Fos immunoreactivity in nucleus accumbens core. Mean (±SEM) number of c-Fos-positive cells in the accumbens and core after injection of vehicle plus vehicle (Veh/Veh; n = 8), 0.75 mg/kg tetrabenazine plus vehicle (TBZ/Veh; n = 8), or tetrabenazine plus the 2.0 mg/kg dose of MSX-3 (n = 8). #p < 0.05, tetrabenazine plus vehicle significantly differed from vehicle/vehicle; *p < 0.05, significantly different from tetrabenazine plus vehicle. C, Expression of pDARPP-32(Thr34) immunoreactivity in nucleus accumbens core and shell after injection of vehicle plus vehicle (Veh/Veh; n = 8), 0.75 mg/kg tetrabenazine plus vehicle (TBZ/Veh; n = 8), or tetrabenazine plus the 2.0 mg/kg dose of MSX-3 (n = 8). Left, Photomicrographs of individual animals. Right, Mean ± SEM number of pDARPP-32(Thr34)-positive cells. #p < 0.05, tetrabenazine plus vehicle significantly differed from vehicle/vehicle; *p < 0.05, significantly different from tetrabenazine plus vehicle; +TBZ plus MSX-3 in core significantly differed from TBZ plus MSX-3 in shell. D, Expression of pDARPP-32(Thr75) immunoreactivity in nucleus accumbens core and shell after injection of vehicle plus vehicle (Veh/Veh; n = 8), 0.75 mg/kg tetrabenazine plus vehicle (TBZ/Veh; n = 8), or tetrabenazine plus the 2.0 mg/kg dose of MSX-3 (n = 8). Left, Photomicrographs of individual animals. Right, Mean ± SEM number of pDARPP-32(Thr75) positive cells. #Tetrabenazine plus vehicle significantly differed from vehicle/vehicle across both core and shell.
- Figure 5.
A, Left, Diagram showing effect of DA on DARPP-32 phophorylation (for details, see Svenningsson et al., 2004; Bateup et al., 2008; Yger and Girault, 2011). D1 receptor stimulation increases c-AMP production and protein kinase A (PKA) activity, which phosphorylates DARPP-32 to yield pDARPP-32(Thr34). D2 receptor stimulation decreases c-AMP production and protein kinase A activity, which decreases the dephosphorylation of pDARPP-32(Thr75) by protein phosphatase 2A (PP-2A) and therefore increases pDARPP-32(Thr75) expression. Right, Tetrabenazine, which depletes DA, was hypothesized to have the opposite effect of DA, increasing pDARPP-32(Thr75) in substance-P-positive neurons and pDARPP-32(Thr34) in encephalin-positive neurons. B, C, Immunofluorescence double labeling of different forms of phosphorylated DARPP-32. B, pDARPP-32(Thr34) immunofluorescence is localized in encephalin-positive neurons (yellow/orange areas of cells in merged photo), whereas pDARPP-32(Thr75) immunofluorescence activity is colocalized with substance P (yellow/orange areas of cells in merged photo). C, pDARPP-32(Thr34) is not present in substance-P-positive neurons (separate green and red cells in merged photo) and pDARPP-32(Thr75) is not colocalized with enkephalin immunofluorescence activity (separate green and red cells in merged photo).
