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

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.

Role of oestrous cycle and orbitofrontal cortex in oxycodone seeking after 15-day abstinence in female rats.

Relapse to oxycodone seeking progressively increases after abstinence in rats, a phenomenon termed incubation of oxycodone craving. We have previously shown that the orbitofrontal cortex (OFC) plays a critical role in incubation of oxycodone craving in male rats. Here, we examined the effect of oestrous cycle on incubated oxycodone seeking in female rats, and whether the critical role of OFC in incubated oxycodone seeking generalizes to female rats. We first assessed oxycodone self-administration and incubated oxycodone seeking on abstinence day 15 across the oestrous cycle. Next, we determined the effect of chemogenetic inactivation of OFC by JHU37160 (J60), a novel agonist for Designer Receptors Exclusively Activated by Designer Drugs (DREADDs), on incubated oxycodone seeking on abstinence day 15. Finally, we determined the effect of J60 alone on incubated oxycodone seeking on abstinence day 15. We found no difference in oxycodone intake across oestrus, pro-oestrus, and metoestrus stages during oxycodone self-administration training. Incubated oxycodone seeking was also similar between nonoestrus and oestrus female rats. Moreover, chemogenetic inactivation of OFC by J60 decreased incubated oxycodone seeking on abstinence day 15, while J60 alone had no effect on incubated oxycodone seeking in no-DREADD control rats. Taken together, results here show that the oestrous cycle has no effect on oxycodone intake and incubated oxycodone seeking in female rats under our experimental conditions. Furthermore, consistent with our previous findings in male rats, results here show that OFC also plays a critical role in incubated oxycodone seeking in female rats.

Operant social seeking to a novel peer after social isolation is associated with activation of nucleus accumbens shell in rats.

RATIONALE AND OBJECTIVE: Deprivation of social interaction promotes social reward seeking in rodents, assessed primarily by the conditioned place preference procedure. Here, we used an operant social procedure in rats and examined the effect of the housing condition (pair-housing vs. single-housing) during or after social self-administration on social reward seeking. METHODS: We first trained paired-housed or single-housed rats to gain access to an age- and sex-matched novel peer. On post-training day 1 (PTD1), we tested both groups for social seeking without the presence of the novel peer. Next, we divided each group into pair-housing or single-housing conditions and tested all four groups (pair-pair, pair-single, single-pair, and single-single) for social seeking on post-training day 12 (PTD12). Finally, we analyzed Fos expression in the striatum associated with social seeking on PTD12. RESULT: Single-housed rats earned more social rewards during social self-administration than pair-housed rats. Social isolation during social self-administration also promoted social seeking on PTD1 and PTD12, regardless of their housing conditions after social self-administration training. Additionally, in pair-housed rats, social isolation during the post-training period led to a time-dependent increase of social seeking on PTD12 compared with PTD1. Finally, the Fos analyses revealed an increase of Fos expression in NAc shell of single-single rats after social seeking test on PTD12 compared with pair-pair rats. CONCLUSION: Our data suggest that social isolation promotes operant social self-administration and social seeking. In addition, neuronal activation of NAc shell is associated with social seeking after social isolation.