CRF-5-HT interactions in the dorsal raphe nucleus and motivation for stress-induced opioid reinstatement

  • Psychopharmacology (Berl). 2021 Jan;238(1):29-40. doi: 10.1007/s00213-020-05652-3.
Chen Li  #  1 ,  Nicholas McCloskey  #  1 ,  Jared Phillips  1 ,  Steven J Simmons  2 ,  Lynn G Kirby  3
Affiliations
  • 1. Center for Substance Abuse Research and Department of Anatomy and Cell Biology, Lewis Katz School of Medicine at Temple University, 3500 N. Broad St., Philadelphia, PA, 19140, USA.
  • 2. Department of Anesthesia and Critical Care Medicine, The Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA.
  • 3. Center for Substance Abuse Research and Department of Anatomy and Cell Biology, Lewis Katz School of Medicine at Temple University, 3500 N. Broad St., Philadelphia, PA, 19140, USA. [email protected].
  • # Contributed equally.
PMID: 33231727 DOI: 10.1007/s00213-020-05652-3
Abstract

Rationale: The serotonin (5-hydroxytryptamine, 5-HT) system plays an important role in stress-related psychiatric disorders and substance abuse. Our previous data show that stressors can inhibit 5-HT neuronal activity and release by stimulating the release of the stress neurohormone corticotropin-releasing factor (CRF) within the serotonergic dorsal raphe nucleus (DRN). The inhibitory effects of CRF on 5-HT DRN neurons are indirect, mediated by CRF-R1 receptors located on GABAergic afferents.

Objectives: We tested the hypothesis that DRN CRF-R1 receptors contribute to stress-induced reinstatement of morphine-conditioned place preference (CPP). We also examined the role of this circuitry in stress-induced negative affective state with 22-kHz distress ultrasonic vocalizations (USVs), which are naturally emitted by rats in response to environmental challenges such as pain, stress, and drug withdrawal.

Methods: First, we tested if activation of CRF-R1 receptors in the DRN with the CRF-R1-preferring agonist ovine CRF (oCRF) would reinstate morphine CPP and then if blockade of CRF-R1 receptors in the DRN with the CRF-R1 antagonist NBI 35965 would attenuate swim stress-induced reinstatement of morphine CPP. Second, we tested if intra-DRN pretreatment with NBI 35965 would attenuate foot shock stress-induced 22-kHz USVs.

Results: Intra-DRN injection of oCRF reinstated morphine CPP, while intra-DRN injection of NBI 35965 attenuated swim stress-induced reinstatement. Moreover, intra-DRN pretreatment with NBI 35965 significantly reduced 22-kHz distress calls induced by foot shock.

Conclusions: These data provide evidence that stress-induced negative affective state is mediated by DRN CRF-R1 receptors and may contribute to reinstatement of morphine CPP.

Keywords
Addiction; Conditioned place preference; Corticotropin-releasing factor (CRF); Dorsal raphe; Foot shock; Morphine; Relapse; Stress-induced reinstatement; Stressor; Ultrasonic vocalizations.
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