Striatal cell type-specific overexpression of DeltaFosB enhances incentive for cocaine

Abstract

The transcription factor DeltaFosB accumulates in substance P-dynorphin-containing striatal neurons with repeated cocaine use. Here, we show that inducible transgenic DeltaFosB overexpression in this same striatal cell type facilitates acquisition of cocaine self-administration at low-threshold doses, consistent with increased sensitivity to the pharmacological effects of the drug. Importantly, DeltaFosB also enhances the degree of effort mice will exert to maintain self-administration of higher doses on a progressive ratio schedule of reinforcement, whereas levels of cocaine intake are not altered on less demanding fixed-ratio schedules. Acquisition and extinction of behavior reinforced by food pellets is not altered in DeltaFosB-overexpressing mice, indicating that DeltaFosB does not alter the capacity to learn an instrumental response or cause response perseveration in the absence of reinforcement. These data suggest that accumulation of DeltaFosB contributes to drug addiction by increasing the incentive properties of cocaine, an effect that could increase the risk for relapse long after cocaine use ceases.

Fig. 1.

Striatal cell-specific overexpression of ΔFosB (n = 15; filled circles andbars) fails to alter acquisition and extinction of lever-press responding reinforced by food pellets compared with bigenic littermate controls maintained on doxycycline (n = 12; open circles and bars).A, The percentage of mice achieving acquisition criteria (for criteria, see Results) in daily 1 hr tests and the mean ± SEM number of test sessions to acquire self-administration of food pellets on an FR3 reinforcement schedule are shown. B, Spontaneous lever-press responding in naive mice before acquisition testing is similar between groups (left), and ΔFosB overexpression also fails to alter lever discrimination on the day acquisition criteria are met (middle) or the latency to consume 30 food pellets after 2 additional training days (right). C, The percentage of ΔFosB mice achieving extinction criteria (≤10 responses in 2 hr at both levers) and the number of test sessions to achieve extinction criteria in the absence of reinforcement are similar in ΔFosB and control mice.

Fig. 2.

Striatal cell-specific overexpression of ΔFosB (filled circles and bars) facilitates acquisition of cocaine self-administration (FR1) at a low-threshold dose of cocaine (125 μg/kg per injection) (A) but not at a higher suprathreshold dose (250 μg/kg per injection) (B) compared with littermate bigenic controls maintained on doxycycline (open circles and bars). The numbers of cocaine injections (solid lines) and inactive lever presses (dashed lines) are shown at left, and the number of test sessions (latency) to achieve criteria for acquisition of cocaine self-administration are shown at right (for criteria, see Results). Each dose is tested for 5 d, followed by a higher training dose (500 μg/kg per injection) for days 6–10 to demonstrate a capacity for acquisition in all mice used in the analysis. Asterisks indicate that ΔFosB mice (n = 11, 7) differ from littermate controls (n = 13, 10) for threshold–dose cocaine self-administration by tests for simple effects (p < 0.05).

Fig. 3.

Striatal cell-specific overexpression of ΔFosB increases sensitivity to a low threshold dose of cocaine after acquisition and stabilization of self-administration on an FR5 schedule (n = 16; filled circles) but does not alter self-administration rates at higher doses that are reinforcing in littermate controls (n = 17;open circles) (A) or overall cocaine intake across all doses (B). Black dots indicate that the 63 μg/kg per injection dose differs from saline by Dunnett's test (p < 0.001).

Fig. 4.

Striatal cell-specific overexpression of ΔFosB facilitates cocaine self-administration on a progressive ratio schedule of reinforcement. A, Cumulative active lever response records for representative mice show that ΔFosB increases the number of cocaine injections (arrows) earned relative to a bigenic littermate control (250 μg/kg per injection). dox, Doxycycline. B, ΔFosB mice (n = 11; filled circles) exert greater effort to maintain cocaine self-administration, as reflected by completing a higher ratio of responses per injection (distance between dotted lines in A) immediately before cessation of self-administration. Convergence of the final ratio completed at the highest injection dose indicates that littermate control mice (n = 17; open circles) are capable of performing at levels found in ΔFosB mice. Asteriskindicates main effect of group on ratio completed by ANOVA across the 250 and 500 μg/kg per injection dose (p< 0.05).