A single intra-PFC infusion of BDNF prevents cocaine-induced alterations in extracellular glutamate within the nucleus accumbens

Abstract

The glutamatergic pathway arising in the dorsomedial prefrontal cortex (dmPFC) and projecting to the nucleus accumbens (NAc) core is a critical component of the reward circuitry that underlies reinstatement to cocaine-seeking behavior. Brain-derived neurotrophic factor (BDNF) is expressed by and modulates PFC-NAc neurons. BDNF infusion into the dmPFC attenuates reinstatement to cocaine-seeking behavior, as well as some cocaine-induced molecular adaptations within the NAc. In the present study, it is demonstrated that a single intra-dmPFC infusion of BDNF prevents cocaine self-administration-induced reduction in basal extracellular glutamate, as well as cocaine prime-induced increases in extracellular glutamate levels within the NAc. These data suggest that intra-PFC BDNF attenuates reinstatement to cocaine-seeking behavior by normalizing cocaine-induced neuroadaptations that alter glutamate neurotransmission within the NAc.

Figure 1.

Cannula placements. A schematic representation of the active length of dialysis membranes within the NAc (left) and the tip of the infusion cannulae within the dmPFC (right).

Figure 2.

Intra-dmPFC BDNF suppressed cocaine-primed reinstatement. Left, The average number of lever presses during the last 3 d of self-administration (before BDNF infusion) was not different between groups (N = 9–10 per group). Intra-PFC BDNF infusion at the end of self-administration suppressed active lever presses on the first day of extinction (left, middle) but did not affect the remainder of extinction training (right, middle). Intra-dmPFC BDNF suppressed cocaine prime-induced reinstatement (right, N = 6–8 rats per group; only rats with complete microdialysis data were included). *p < 0.05.

Figure 3.

Effect of intra-dmPFC BDNF on extracellular glutamate levels in NAc before and after a single cocaine challenge (10 mg/kg, i.p.) in rats with a cocaine self-administration history. Microdialysis timeline at 10 min intervals before and after a cocaine challenge. Rats that received intra-PFC infusions of BDNF exhibited a suppression of the cocaine-induced increase in glutamate observed in rats that received intra-dmPFC vehicle infusions (VEH, N = 6; BDNF, N = 8). *p < 0.05, AUC of extracellular glutamate levels in BDNF-treated group after a cocaine prime versus AUC of extracellular glutamate levels in the vehicle-treated group after a cocaine prime; ^#p < 0.05, AUC of baseline extracellular glutamate levels in the vehicle-treated group versus extracellular glutamate levels in vehicle-treated group after a cocaine prime. Inset, Average AUC values before and after a cocaine challenge in rats with a cocaine history. VEH–Base, Average baseline AUC value for rats that received an intra-dmPFC vehicle infusion; VEH–COC, average AUC value after the cocaine challenge for rats that received a vehicle infusion; BDNF–Base, average baseline AUC value for rats that received an intra-dmPFC BDNF infusion; BDNF–COC, average AUC value after the cocaine challenge for rats that received an intra-dmPFC BDNF infusion. *p < 0.05 versus BDNF–COC; ^#p < 0.05 versus VEH–Base.

Figure 4.

No-net flux procedure reveals that BDNF normalizes basal NAc glutamate levels in rats with a cocaine self-administration history. A, The mean ± (SEM) gain or loss of dialysate glutamate concentrations to and from the brain as a function of the perfusate glutamate concentration. A positive number on the y-axis indicates a net diffusion of glutamate into the brain, and a negative number indicates a net diffusion from the brain into the perfusate. The zero point on the y-axis indicates the steady state at which there is no-net flux of glutamate across the dialysis membrane and provides a measure of the basal extracellular glutamate concentration in each group. B, BDNF normalizes basal extracellular glutamate levels in the NAc of rats with a cocaine self-administration history. Intra-dmPFC BDNF treatment significantly increased the point of no-net flux, indicating an increase in the basal extracellular glutamate concentrations in the rats compared with those that received intra-dmPFC vehicle infusions. *p < 0.05 (N = 4–7 per group).