ΔFosB enhances the rewarding effects of cocaine while reducing the pro-depressive effects of the kappa-opioid receptor agonist U50488

Abstract

Background: Elevated expression of the transcription factor ΔFosB accompanies repeated exposure to drugs of abuse, particularly in brain areas associated with reward and motivation (e.g., nucleus accumbens). The persistent effects of ΔFosB on target genes might play an important role in the development and expression of behavioral adaptations that characterize addiction. This study examines how ΔFosB influences the responsiveness of the brain reward system to rewarding and aversive drugs.

Methods: We used the intracranial self-stimulation paradigm to assess the effects of cocaine in transgenic mice with inducible overexpression of ΔFosB in striatal regions (including nucleus accumbens and dorsal striatum). Mice implanted with lateral hypothalamic stimulating electrodes were trained with the "rate-frequency" procedure for intracranial self-stimulation to determine the frequency at which stimulation becomes rewarding (threshold).

Results: A dose-effect analysis of cocaine effects revealed that mice overexpressing ΔFosB show increased sensitivity to the rewarding (threshold-lowering) effects of the drug, compared with littermate control subjects. Interestingly, mice overexpressing ΔFosB were also less sensitive to the pro-depressive (threshold-elevating) effects of U50488, a kappa-opioid agonist known to induce dysphoria and stress-like effects in rodents.

Conclusions: These data suggest that induction of ΔFosB in striatal regions has two important behavioral consequences-increased sensitivity to drug reward, and reduced sensitivity to aversion-producing a complex phenotype that shows signs of vulnerability to addiction as well as resilience to stress.

Figure 1

Representative micrographs from bitransgenic mice showing overexpression of ΔFosB. Nuclear labeling for FosB is lower in control mice maintained on doxycycline (left panel) than those not given doxycycline (right). ac = anterior commisure; NAc = nucleus accumbens. Scale bar = 200 µm.

Figure 2

Representative micrograph depicts stimulating electrode placement for ICSS (arrow). LHA = lateral hypothalamic area; fx = fornix. Scale bar = 250 µm.

Figure 3

Inducible ΔFosB overexpression has no effect on minimum current required to support ICSS. Scatterplot shows mean minimum current (bars) required to support robust ICSS behavior (60 ± 6 responses/min) in individual mice (filled circles) in the littermate control (on DOX, n = 11) or ΔFosB overexpression group (ΔFosB-ON, n = 13).

Figure 4

Inducible ΔFosB overexpression enhances sensitivity to the rewarding effects of cocaine. (A,B) Rate-frequency functions for individual representative mice in each group demonstrate leftward shifts in both groups that are larger in ΔFosB-ON mice following the 10 mg/kg dose of cocaine (COC 10). (C) Cocaine reduces mean (±SEM) ICSS thresholds for cocaine in both Control (n = 7) and ΔFosB-ON (n = 8), but this effect was apparent in off-DOX mice at lower doses. Inset: Cocaine (10 mg/kg; COC 10) causes equivalent reductions in mean ICSS thresholds in ON-DOX or OFF-DOX Control mice. Means are expressed as a percent of baseline ICSS threshold. (D) ΔFosB-ON mice show increased mean maximum rates of responding apparent at the highest doses of cocaine used. *p<0.05, **p<0.01 for within-group comparisons to saline vehicle treatment (VEH). Inset: Cocaine (10 mg/kg; COC 10) causes no elevation of mean maximum rates of responding in ON-DOX or OFF-DOX Control mice. Means are expressed as a percent of baseline maximum rate.

Figure 5

Inducible ΔFosB overexpression blocks anhedonic effects of U50488. (A,B) Rate-frequency functions for individual representative mice in each group demonstrate rightward shifts only in Control mice following the 5.5 mg/kg dose of U50488 (U50 5.5). (C) U50488 increases mean (±SEM) ICSS thresholds for Control mice (n = 4), while ΔFosB-ON (n = 8) mice are unaffected. (D) Mean maximum rates of responding in both groups were unaffected. **p<0.01 for within-group comparisons, ^^p<0.01 for between-group comparisons.