Orbitofrontal cortex to dorsal striatum circuit is critical for incubation of oxycodone craving after forced abstinence

Abstract

Relapse is a major challenge in treating opioid addiction, including oxycodone. During abstinence, oxycodone seeking progressively increases, a phenomenon termed incubation of oxycodone craving. We previously demonstrated a causal role of orbitofrontal cortex (OFC) in this incubation. Here, we studied the interaction between glutamatergic projections from OFC and dopamine 1-family receptor (D1R) signaling in dorsal striatum (DS) in this incubation in male rats. We first examined the causal role of D1R signalling in DS in incubated oxycodone seeking. Next, we combined fluorescence-conjugated cholera toxin subunit B (CTb-555, a retrograde tracer) with Fos (a neuronal activity marker) to assess whether the activation of OFC→DS projections was associated with incubated oxycodone seeking. We then used a pharmacological asymmetrical disconnection procedure to examine the role of the interaction between projections from OFC and D1R signalling in DS in incubated oxycodone seeking. We also tested the effect of unilateral pharmacological inactivation of OFC or unilateral D1R blockade of DS on incubated oxycodone seeking. Finally, we assessed whether contralateral disconnection of OFC→DS projections impacted non-incubated oxycodone seeking on abstinence day 1. We found that D1R blockade in DS decreased incubated oxycodone seeking and OFC→DS projections were activated during incubated oxycodone seeking. Moreover, anatomical disconnection of OFC→DS projections, but not unilateral inactivation of OFC or unilateral D1R blockade in DS, decreased incubated oxycodone seeking. Lastly, contralateral disconnection of OFC→DS projections had no effect on oxycodone seeking on abstinence day 1. Together, these results demonstrated a causal role of OFC→DS projections in incubation of oxycodone craving.

Keywords: craving; dorsal striatum; orbitofrontal cortex; oxycodone; retrograde tracing; self‐administration.

FIGURE 1

Bilateral SCH23390 injections into dorsal striatum (DS) decreased oxycodone seeking on abstinence day 15 (Experiment 1). (A) Timeline of the experiment. (B) Oxycodone self‐administration. Data are mean $\pm$ SEM number of oxycodone (0.1 mg/kg/infusion) infusions or lever presses during the ten 6‐h daily self‐administration sessions (total n = 10). (C) Seeking test. Data are mean $\pm$ SEM of lever presses on the previously active lever and on the inactive lever during the seeking‐test sessions. *Different from Vehicle, p < 0.05, Vehicle: n = 5, SCH23390: n = 5. (D) Approximate placement (mm from Bregma ⁵² ) of injection tips (vehicle: open circles; SCH23390: closed circles), and a representative image of cannula placements.

FIGURE 2

Incubated oxycodone seeking is associated with the activation of orbitofrontal cortex (OFC)→dorsal striatum (DS) projections (Experiment 2). (A) Timeline of the experiment. (B) Representative plots of the spread of CTb‐555 injections in No‐test and Seeking‐test groups. (C) Oxycodone self‐administration. Data are mean $\pm$ SEM number of oxycodone (0.1 mg/kg/infusion) infusions or lever presses during the ten 6‐h daily self‐administration sessions (total n = 11). (D) Seeking tests on abstinence days 1 and 15. Data are mean $\pm$ SEM of lever presses on the previously active lever and on the inactive lever during the seeking‐test sessions. *Different from Vehicle, p < 0.05, No test: n = 4, Test: n = 7. (E–G) Data are the mean ± SEM of CTb/mm², CTb + Fos/mm² and CTb + Fos% in OFC after the seeking test on abstinence day 15. *Different from No test, p < 0.05, No test: n = 4, Test: n = 7. (H) Representative images of CTb and Fos labelling in OFC.

FIGURE 3

Contralateral and ipsilateral disconnection of orbitofrontal cortex (OFC) and dorsal striatum (DS) decreased oxycodone seeking on abstinence day 15 (Experiment 3). (A) Timeline of the experiment. (B–C) Oxycodone self‐administration. Data are mean $\pm$ SEM number of oxycodone (0.1 mg/kg/infusion) infusions or lever presses during the ten 6‐h daily self‐administration sessions (contralateral: total n = 18; ipsilateral: total n = 13). (D–E) Seeking tests. Data are mean $\pm$ SEM of lever presses on the previously active lever and on the inactive lever during the seeking test sessions. *Different from Vehicle, p < 0.05, Contralateral: Vehicle, n = 10; Contralateral, n = 8. Ipsilateral: Vehicle, n = 7; Ipsilateral, n = 6. (F–G) Approximate placement (mm from Bregma ⁵² ) of injection tips (vehicle: open circles; muscimol + baclofen or SCH23390: closed circles), and representative images of cannula placements.

FIGURE 4

Unilateral inactivation of orbitofrontal cortex (OFC) or dorsal striatum (DS) had no effect on oxycodone seeking on abstinence day 15 (Experiment 4). (A) Timeline of the experiment. (B–C) Oxycodone self‐administration. Data are mean $\pm$ SEM number of oxycodone (0.1 mg/kg/infusion) infusions or lever presses during the ten 6‐h daily self‐administration sessions (OFC: total n = 15; DS: total n = 16). (D–E) Seeking tests. Data are mean $\pm$ SEM of lever presses on the previously active lever and on the inactive lever during the seeking test sessions. OFC: Vehicle, n = 7; Mus + Bac, n = 8. DS: Vehicle, n = 7; SCH23390, n = 9. (F–G) Approximate placement (mm from Bregma ⁵² ) of injection tips (vehicle: open circles; muscimol + baclofen or SCH23390: closed circles), and representative images of cannula placements.

FIGURE 5

Contralateral disconnection of orbitofrontal cortex (OFC) or dorsal striatum (DS) had no effect on oxycodone seeking on abstinence day 1 (Experiment 5). (A) Timeline of the experiment. (B) Oxycodone self‐administration. Data are mean $\pm$ SEM number of oxycodone (0.1 mg/kg/infusion) infusions or lever presses during the ten 6‐h daily self‐administration sessions (total n = 15). (C) Seeking test. Data are mean $\pm$ SEM of lever presses on the previously active lever and on the inactive lever during the seeking test sessions. Vehicle, n = 8; Contralateral, n = 7. (D) Approximate placement (mm from Bregma ⁵² ) of injection tips (vehicle: open circles; muscimol + baclofen or SCH23390: closed circles), and representative images of cannula placements.

FIGURE 6

Contralateral or ipsilateral disconnection of orbitofrontal cortex (OFC) or dorsal striatum (DS) had no effect on ongoing food self‐administration. (A) Contralateral disconnection. Data are mean $\pm$ SEM number of food pellets or active lever presses during the 1‐h food self‐administration sessions. n = 5. (B) Ipsilateral disconnection. Data are mean $\pm$ SEM number of food pellets or active lever presses during the 1‐h food self‐administration sessions. n = 5.