Article Figures & Data
Figures
- Figure 1.
Cocaine reexposure transiently decreases withdrawal-induced enhancements in NAc AMPAR sensitivity but enhances expression of cocaine sensitization. A, Experiment outline testing the effects of cocaine reexposure on AMPAR sensitivity. B, Left, AMPAR-induced locomotor responses are increased 1 d after an acute cocaine treatment (15 mg/kg, i.p.) in cocaine-naive animals. Enhanced AMPAR sensitivity in cocaine withdrawal is reversed 1 d after cocaine reexposure that is prevented by intra-NAc CNQX (0.1 nm/side) during cocaine reexposure. The dotted line represents the combined mean of vehicle-treated animals after either repeated saline or cocaine treatments (470.83 ± 81.7 and 457.66 ± 49.3, respectively). Middle, Time course for AMPA-induced locomotor activity in cocaine-sensitized animals. Right, Reduction in AMPAR sensitivity recovers 6 d after cocaine reexposure. C, Repeated cocaine treatments and a cocaine challenge (15 mg/kg, i.p.) during withdrawal enhances the expression of cocaine sensitization 1 d after reexposure. D, Histological plates illustrating NAc core infusion sites for all experiments. Data are expressed as mean (±SEM) beam breaks/2 h (n = 6–12/group). The solid line differs from repeated saline/saline challenge controls and (†) differs from repeated saline/Veh-cocaine challenged group (p < 0.05, t test). *Post hoc comparison with respective Veh-saline or saline-challenged animals (p < 0.05, Fisher's LSD test or t test, respectively). Rep., Repeated; Veh, vehicle.
- Figure 2.
Stimulation of NAc AMPARs, but not GluR1 upregulation, is sufficient to reverse AMPA-induced locomotion. A, Experiment outline testing the effects of GluR1 overexpression on AMPAR sensitivity. B, Photomicrographs illustrating injector tracts and immunohistochemical labeling of GluR1 protein localized in the NAc core 2 d after HSV-GluR1 infusion (right) compared with HSV-LacZ infusion (left). ac, Anterior commissure. C, Both groups show equivalent cocaine-induced locomotion (left). GluR1 upregulation increases AMPA-induced locomotion in saline-challenged animals and is unaltered by a cocaine challenge the previous day (right). D, Experiment outline testing the sufficiency of NAc AMPAR stimulation to reduce enhanced AMPAR responses. Enhanced AMPAR sensitivity is reduced 1 d after intra-NAc AMPA, and normalized within 6 d after initial AMPAR stimulation (bottom left). Locomotor time courses are shown in bottom right panel. Data are expressed as mean (±SEM) beam breaks/2 h (n = 8–16/group). *Post hoc comparison from LacZ or vehicle-challenged animals (p < 0.05, Fisher's LSD test).
- Figure 3.
Dopamine D1 receptor stimulation reduces enhanced AMPAR responses through NAc AMPAR stimulation. A, Experiment outline testing the effects of D1/D2 receptor stimulation on enhanced AMPAR sensitivity. SKF 81297 (3 mg/kg, s.c.) and quinpirole (3 mg/kg, s.c.) treatments increase AMPAR-induced locomotion in cocaine-naive animals after 1 d, but D1 receptor stimulation reverses enhanced AMPAR responses in cocaine-treated animals. B, Experiment outline testing the necessity of NAc D1 receptor stimulation for cocaine-induced reversal enhanced AMPAR sensitivity. Intra-NAc infusion with SCH 23390 (0.1 μg/side) blocks cocaine-induced locomotion during challenge treatment (bottom left) but has no effect on subsequent cocaine-induced reversal of AMPAR sensitivity (bottom right). C, Experiment outline testing the necessity of NAc AMPAR stimulation for D1-induced reversal of enhanced AMPAR sensitivity. D1-induced reversal of AMPAR sensitivity is prevented by intra-NAc CNQX. Data are expressed as mean (±SEM) beam breaks/2 h (n = 6–12/group). The solid line differs from repeated saline/saline challenge controls and (†) differs from repeated saline/SKF 81297 challenged group (p < 0.05, t test). *Post hoc comparison from respective Veh-saline or Veh-SKF 81297 challenged animals (p < 0.05, Fisher's LSD test).
Tables
Day 1 Day 7 Challenge Experiment 1: Effects of cocaine challenge on AMPAR sensitization Repeated saline-Veh/saline 439.5 ± 92.7 462.4 ± 69.7 470.8 ± 81.7 Repeated saline-CNQX/saline 493.6 ± 68.6 363.4 ± 31.9 224.6 ± 34.7 Repeated saline-Veh/cocaine 493.3 ± 81.2 340.7 ± 46.7 1186.7 ± 175.1* Repeated saline-CNQX/cocaine 476.3 ± 82.1 390.5 ± 55.6 1089.2 ± 149.5* Repeated cocaine-Veh/saline 1896.5 ± 315.1 2860.5 ± 562.1 457.6 ± 49.3 Repeated cocaine-CNQX/saline 1829.7 ± 298.6 2930.0 ± 312.3 388.3 ± 50.0 Repeated cocaine-Veh/cocaine 1843.6 ± 331.5 2812.5 ± 384.9 2217.0 ± 240.5* Repeated cocaine-CNQX/cocaine 1806.9 ± 351.0 2997.9 ± 461.5 1561.4 ± 269.9*^ Experiment 2a: Effects of increasing GluR1 on AMPAR sensitization Repeated saline-HSV-LacZ/saline 409.5 ± 98.7 462.3 ± 59.7 362.8 ± 51.7 Repeated saline-HSV-LacZ/cocaine 352.8 ± 115.1 422.0 ± 77.4 1972.5 ± 322.6* Repeated saline-HSV-GluR1/saline 407.5 ± 72.0 479.3 ± 99.9 327.17 ± 82.86 Repeated saline-HSV-GluR1/cocaine 420.0 ± 117.6 513.2 ± 117.8 2305.17 ± 452.5* Experiment 2b: Effects of AMPA stimulation on AMPAR sensitization Repeated cocaine-Veh/AMPA/AMPA 1263.5 ± 262.0 2703.4 ± 392.5 506.8 ± 41.7 Repeated cocaine-AMPA/AMPA/AMPA 1293.2 ± 327.4 2662.2 ± 326.4 1859.1 ± 156.1* Experiment 3a: Effects of dopamine agonist challenge on AMPAR sensitization Repeated saline-saline 379.6 ± 94.7 465.3 ± 64.6 435.83 ± 61.7 Repeated saline-SKF 81297 382.8 ± 101.4 412.0 ± 67.2 1015.3 ± 226.8* Repeated saline-quinpirole 397.5 ± 71.0 449.3 ± 89.9 579.0 ± 96.8 Repeated cocaine-saline 1841.0 ± 420.2 2767.2 ± 397.5 435.8 ± 165.9 Repeated cocaine-SKF 81297 1822.7 ± 373.2 2763.3 ± 342.3 1229.3 ± 305.0* Repeated cocaine-quinpirole 1799.9 ± 421.2 2703.0 ± 371.7 459.9 ± 92.5 Experiment 3b: Effects of NAc D1 receptor blockade during cocaine challenge Repeated cocaine-Veh/saline 1259.4 ± 285.6 2480.8 ± 546.5 398.3 ± 75.65 Repeated cocaine-Veh/cocaine 1241.8 ± 282.2 2170.0 ± 192.7 1926.0 ± 285.7* Repeated cocaine-SCH 23390/cocaine 1237.0 ± 234.6 2104.9 ± 145.1 553.4 ± 172.2^ Experiment 3c: Effects of NAc AMPAR blockade during D1 agonist treatment Repeated cocaine-Veh/SKF 81297 1578.3 ± 284.8 2653.0 ± 214.3 892.0 ± 447.1 Repeated cocaine-CNQX/ SKF 81297 1621.1 ± 321.1 2727.8 ± 293.5 924.8 ± 432.8 -
↵*Post hoc comparison with respective saline or vehicle (Veh)-challenged animals. ^Post hoc comparison with respective Veh/cocaine-challenged animals (p < 0.05, Fisher's LSD test).
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