IGF-1 Microinjection in the Prefrontal Cortex Attenuates Fentanyl-Seeking Behavior in Mice

Abstract

Background Opioid use disorder (OUD) is a chronic relapsing psychiatric disorder with an enormous socioeconomic burden. Opioid overdose deaths have reached an epidemic level, especially for fentanyl. One of the biggest challenges to treat OUD is the relapse to drug seeking after prolonged abstinence. Abnormalities in insulin-like growth factor-1 (IGF-1) have been reported in various neurological and psychiatric disorders, including OUD. However, whether IGF-1 and its downstream signaling pathways are associated with relapse to fentanyl seeking remains unclear. Methods Mice were subjected to daily 2-h fentanyl (10 μg/ml, 27μl/infusion) oral self-administration training for 14 days, followed by 14-day fentanyl cessation. Expression levels of IGF-1/IGF-1 receptor (IGF-1R) and downstream signaling pathways in the dorsomedial prefrontal cortex (dmPFC) were detected. Then, IGF-1 was bilaterally microinjected into the dmPFC from fentanyl cessation day 9 to day 13. Fentanyl-seeking behavior and excitatory synaptic transmission of pyramidal neurons in PFC were evaluated. Results We found that 14-daycessation from fentanyl oral self-administration caused significant downregulation of IGF-1 and IGF-1R phosphorylation in the dmPFC. These changes were accompanied by inhibition of downstream Aktand S6 signaling pathway. In addition, local administration of IGF-1 in the dmPFC attenuated context-induced fentanyl-seeking behavior. Furthermore, electrophysiology and immunohistochemistry analyses showed that IGF-1 blocked fentanyl-induced reduction of a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-D-aspartate (NMDA) receptors-mediated excitatory synaptic transmission as well as synaptic expression of AMPAR and NMDAR subunits. Conclusions These results suggest that IGF-1 in the PFC plays a pivotal role in regulating fentanyl seeking after prolonged cessation from fentanyl oral self-administration.

Transcriptional signatures of fentanyl use in the mouse ventral tegmental area

“…Of the differentially expressed genes in these categories, decreased expression of Igf1 (insulin-like growth factor 1) is a standout, as recent work in the prefrontal cortex showed decreased IGF1 protein in mice that self-administered oral fentanyl, and IGF1 replacement in the PFC attenuated fentanyl seeking behaviour. 36 Decreased expression of Calcr (calcitonin receptor) is another intriguing target, as…”

“…In dopamine neurons, we found mostly upregulation of genes associated with calcium signalling, mostly downregulation of genes associated with growth hormones, and both up‐ and down‐regulation of genes involved in tyrosine kinase receptor signalling. Of the differentially expressed genes in these categories, decreased expression of Igf1 (insulin‐like growth factor 1) is a standout, as recent work in the prefrontal cortex showed decreased IGF1 protein in mice that self‐administered oral fentanyl, and IGF1 replacement in the PFC attenuated fentanyl seeking behaviour 36 . Decreased expression of Calcr (calcitonin receptor) is another intriguing target, as Calcr expression has bidirectional effects on opioid self‐administration in nucleus accumbens neuron subtypes 37 .…”

“…Of the differentially expressed genes in these categories, decreased expression of Igf1 (insulin‐like growth factor 1) is a standout, as recent work in the prefrontal cortex showed decreased IGF1 protein in mice that self‐administered oral fentanyl, and IGF1 replacement in the PFC attenuated fentanyl seeking behaviour. 36 Decreased expression of Calcr (calcitonin receptor) is another intriguing target, as Calcr expression has bidirectional effects on opioid self‐administration in nucleus accumbens neuron subtypes. 37 The top upregulated genes in dopamine neurons was the extracellular matrix protein Ecel1 , and the actin polymerization regulator Diaph3 , both of which are implicated in synaptic function and structural remodelling.…”

Transcriptional signatures of fentanyl use in the mouse ventral tegmental area

“…In dopamine neurons, we found mostly upregulation of genes associated with calcium signaling, mostly downregulation of genes associated with growth hormones, and both up– and down-regulation of genes involved in tyrosine kinase receptor signaling. Of the differentially expressed genes in these categories, decreased expression of Igf1 (insulin-like growth factor 1) is a standout, as recent work in the prefrontal cortex showed decreased IGF1 protein in mice that self-administered oral fentanyl, and IGF-1 replacement in the PFC attenuated fentanyl seeking behavior 37 . Decreased expression of Calcr (calcitonin receptor) is another intriguing target, as Calcr expression has bidirectional effects on opioid self-administration in nucleus accumbens neuron subtypes 37 .…”

“…Of the differentially expressed genes in these categories, decreased expression of Igf1 (insulin-like growth factor 1) is a standout, as recent work in the prefrontal cortex showed decreased IGF1 protein in mice that self-administered oral fentanyl, and IGF-1 replacement in the PFC attenuated fentanyl seeking behavior 37 . Decreased expression of Calcr (calcitonin receptor) is another intriguing target, as Calcr expression has bidirectional effects on opioid self-administration in nucleus accumbens neuron subtypes 37 . The top upregulated genes in dopamine neurons was the extracellular matrix protein Ecel1 , and the actin polymerization regulator Diaph3 , both of which are implicated in synaptic function and structural remodeling.…”