PMC

Effects of TrkB deletion in NAc neurons on sucrose and CSA. (A,B) Localized TrkB knockdown in NAc neurons (AAV-CreGFP) has no effect on the rate of acquisition of lever-press behavior for sucrose pellets (FR5) or CSA (FR1; 500 μg/kg/injection) compared with control mice (AAV-GFP). (C) However, after acquisition, localized TrkB knockdown in NAc neurons produces a downward shift in the inverted U-shaped dose-response curve for CSA (FR5) compared with control mice [group effect, F(1,70) = 5.44, p < .001]. (D) Conversion of dose-response data into dose intake (# of injections × unit dose/injection, cocaine only) shows an overall reduction in cocaine intake [group effect, F(1,70) = 11.64, p < .01]. Data are expressed as (A) a percentage meeting acquisition criteria or (B–D) mean ± SEM reinforcements/hour (n = 6−7 mice/group). AAV, adeno-associated virus; CreGFP, green fluorescent protein fused to Cre recombinase; CSA, cocaine self-administration; FR1, fixed-ratio 1; FR5, fixed-ratio 5; GFP, green fluorescent protein; NAc, nucleus accumbens; TrkB, tropomyosin-related kinase B.

Effects of BDNF and TrkB deletion in VTA and NAc neurons on cocaine reward. (A) Representative GFP immunofluorescence depicting localized AAV-mediated GFP-Cre expression in medial NAc and VTA neurons. Immunoblots from VTA tissue infected with AAV-CreGFP show a 25% reduction in full-length TrkB protein levels compared with AAV-GFP infected control animals (n = 3 mice/group). (B) Localized BDNF knockdown in either VTA neurons [t(28) = 2.244, p < .05] or NAc neurons [t(24) = 2.067, p < .05] reduces cocaine place conditioning (10 mg/kg). (C) In contrast, only localized TrkB knockdown in NAc neurons [t(17) = 2.180, p < .05], but not VTA neurons, reduces cocaine place conditioning. Data are expressed as mean ± SEM difference scores for time spent in drug- and saline-paired sides. Asterisk indicates p < .05 compared with AAV-GFP control animals by unpaired t test (n = 8−17 mice/group). AAV, adeno-associated virus; BDNF, brain-derived neurotrophic factor; Cre, Cre recombinase; CreGFP, green fluorescent protein fused to Cre recombinase; GFP, green fluorescent protein; NAc, nucleus accumbens; TrkB, tropomyosin-related kinase B; VTA, ventral tegmental area.

Volitional and passive cocaine administration differentially regulates TrkB in the NAc shell and VTA. (A) Schematic figure depicting timelines and treatment groups for self-administering and yoked rats used for TrkB protein and mRNA determinations. Rats self-administered cocaine (500 μg/kg/50 μL injection) or saline in daily 4-hour sessions over 18 days (6 days/week), and tissue was collected immediately after the final session or after 1-day withdrawal (WD). Self-administering rats were paired with yoked rats that received the same amount and temporal pattern of passive cocaine injections throughout training (chronic yoked). Another group received yoked saline injections on all but the final session, when they received cocaine injections for the first time (acute yoked). (B) Representative blots depicting TrkB protein changes in the NAc shell or VTA with acute yoke (AY), chronic yoke (CY), and chronic cocaine SA (CSA) compared with untreated home cage control rats (HC). (C) TrkB protein levels increase in the NAc shell immediately after 4 hours of CSA (SA) but not in yoked animals [F(3,156) = 6.47, p < .001] and returns to basal levels 24 hours later. (D) In contrast, in the VTA, TrkB protein levels increase in cocaine yoke (acute and chronic) but not in cocaine self-administering animals immediately after the session [F(3, 116) = 11.31, p < .001]. These data indicate that the context of cocaine reinforcement is important for TrkB regulation in the NAc shell, while the stressful effects of unanticipated cocaine injections in yoked animals potentially contribute to regulation of TrkB in the VTA. Animals self-administering saline throughout show no statistically significant difference in TrkB levels compared with untreated HC control animals. Data are expressed as mean ± SEM percent change from HC control animals. Asterisk indicates p < .05 compared with pooled HC and saline SA control animals (cocaine-exposed: n = 6−9, untreated and saline SA control animals: n = 8−24). AY, acute yoke; CY, chronic yoke; CSA, cocaine self-administration; HC, home cage control rats; mRNA, messenger RNA; NAc, nucleus accumbens; SA, self-administering; TrkB, tropomyosin-related kinase B; VTA, ventral tegmental area; WD, withdrawal.