Department of Psychology, University of Maryland College Park, College Park, Maryland, USA.
Program in Neuroscience and Cognitive Science, University of Maryland College Park, College Park, Maryland, USA.
Addict Biol. 2024 Oct;29(10):e13440. doi: 10.1111/adb.13440.
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.
复吸是治疗阿片类药物成瘾（包括羟考酮）的主要挑战。在戒断期间，羟考酮的寻求逐渐增加，这种现象被称为羟考酮渴求的潜伏期。我们之前证明了眶额皮层（OFC）在这种潜伏期中起因果作用。在这里，我们研究了雄性大鼠中，OFC 谷氨酸能投射与背侧纹状体（DS）中多巴胺 1 家族受体（D1R）信号之间的相互作用在这种潜伏期中对羟考酮渴求的影响。我们首先研究了 DS 中 D1R 信号在潜伏期中对羟考酮寻求的因果作用。接下来，我们将荧光偶联霍乱毒素亚单位 B（CTb-555，逆行示踪剂）与 Fos（神经元活性标记物）结合，以评估 OFC→DS 投射的激活是否与潜伏期中羟考酮的寻求有关。然后，我们使用药理学不对称分离程序来研究 OFC 与 DS 中 D1R 信号之间的相互作用在潜伏期中对羟考酮寻求的作用。我们还测试了单侧 OFC 药理学失活或单侧 DS 中 D1R 阻断对潜伏期中羟考酮寻求的影响。最后，我们评估了 OFC→DS 投射的对侧分离是否对戒断第 1 天的非潜伏期羟考酮寻求产生影响。我们发现，DS 中的 D1R 阻断降低了潜伏期中羟考酮的寻求，并且在潜伏期中羟考酮寻求时，OFC→DS 投射被激活。此外，OFC→DS 投射的解剖学分离，而不是单侧 OFC 失活或单侧 DS 中 D1R 阻断，降低了潜伏期中羟考酮的寻求。最后，OFC→DS 投射的对侧分离对戒断第 1 天的羟考酮寻求没有影响。总之，这些结果表明 OFC→DS 投射在羟考酮渴求的潜伏期中起因果作用。
