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Thanks For The Memories: Cocaine Cue Reactivity and the 5‐HT 2A receptor (5‐HT 2A R) System
Author(s) -
Holliday Erica,
Sholler Dennis J,
Fox Robert G,
Stutz Sonja J,
Dineley Kelly T,
Anastasio Noelle C,
Cunningham Kathryn A.
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.lb593
Subject(s) - cue reactivity , small hairpin rna , psychology , prefrontal cortex , 5 ht receptor , self administration , neuroscience , serotonin , receptor , chemistry , pharmacology , medicine , craving , apoptosis , addiction , cognition , biochemistry , gene knockdown
Success in recovery from cocaine use disorder (CUD) is challenged by vulnerability to relapse, propelled in part by exposure to cocaine‐linked cues (‘cue reactivity’; Anastasio et al., Neuropharmacol 76 Pt B:460 , 2014). The memory for the association between environmental cues (e.g., drug paraphernalia, people, places) and cocaine‐taking engages the serotonin (5‐HT) 5‐HT 2A receptor (5‐HT 2A R) system in the medial prefrontal cortex (mPFC) (Penkowski et al., Psychopharmacol 213 :307, 2011), a region importantly involved in associative learning processes (Harvey, Learn Mem 10 :355, 2003). In the present experiment, we hypothesized that an engineered loss of the 5‐HT 2A R in the mPFC would alter cocaine cue reactivity as well as cued fear learning. A short hairpin RNA (shRNA) that efficiently knocks down over 90% of 5‐HT 2A R mRNA in vitro was designed, validated, and packaged into an adeno‐associated viral (AAV) vector; the non‐silencing control (NSC) hairpin had no effect on 5‐HT 2A R mRNA expression. Rats acquired cocaine self‐administration (0.75 mg/kg/inf) to stability prior to bilateral microinfusion of 5‐HT 2A R‐shRNA‐eGFP AAV or NSC‐eGFP‐AAV into the mPFC (AP: +3.0 mm; ML: +1.4 mm; DV: −5.1, −4.1, −3.1 mm; relative to Bregma) (n=10–12/group). One month after microinfusions, rats were returned to the chambers and cue reactivity was assessed as lever presses for drug‐associated cues. In a second cohort, microinfusion of 5‐HT 2A R‐shRNA‐eGFP AAV or NSC‐eGFP‐AAV into the mPFC occurred one month prior to the acquisition of trace fear conditioning (n=5–7/group). Acquisition consisted of two presentations of a conditioned stimulus (white noise; 85dB) and a 500 ms trace interval before presentation of the unconditioned stimulus (foot shock; 0.75 mA). Freezing in the context or upon presentation of the auditory cue served as measures of hippocampal and mPFC involvement, respectively. Western blot analysis indicated that 5‐HT 2A R protein expression was significantly reduced following 5‐HT 2A R shRNA vs. NSC ( p <0.05). The knockdown of the 5‐HT 2A R in the mPFC significantly augmented cue reactivity ( p <0.05 vs. NSC) and increased freezing upon exposure to the auditory cue ( p <0.05 vs. NSC), with no difference in acquisition or freezing to the context. These data suggest that loss of tone in the 5‐HT 2A R system in the mPFC results in dysregulation of cue‐associated behavior in two distinct paradigms of associative learning. Future studies will explore the molecular mechanisms through which decrements in 5‐HT 2A R mPFC signaling affect cue‐mediated behavior. Support or Funding Information T32DA07287 (EDH, DJS), P50DA033935 (KAC/NCA), K05DA020087 (KAC)