Striatal CB1 and D2 receptors regulate expression of each other, CRIP1A and delta opioid systems

Authors

  • Lawrence C. Blume,

    1. Department of Physiology and Pharmacology, Wake Forest University Health Sciences, Winston-Salem, North Carolina, USA
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  • Caroline E. Bass,

    1. Department of Physiology and Pharmacology, Wake Forest University Health Sciences, Winston-Salem, North Carolina, USA
    Current affiliation:
    1. CEB: Department of Pharmacology and Toxicology, University at Buffalo, Buffalo, NY, USA
    2. JMR: College of Pharmacy and Health Sciences, Campbell University, Buies Creek, NC, USA
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  • Steven R. Childers,

    1. Department of Physiology and Pharmacology, Wake Forest University Health Sciences, Winston-Salem, North Carolina, USA
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  • George D. Dalton,

    1. Department of Physiology and Pharmacology, Wake Forest University Health Sciences, Winston-Salem, North Carolina, USA
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  • David C. S. Roberts,

    1. Department of Physiology and Pharmacology, Wake Forest University Health Sciences, Winston-Salem, North Carolina, USA
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  • Jasmine M. Richardson,

    1. Department of Physiology and Pharmacology, Wake Forest University Health Sciences, Winston-Salem, North Carolina, USA
    Current affiliation:
    1. CEB: Department of Pharmacology and Toxicology, University at Buffalo, Buffalo, NY, USA
    2. JMR: College of Pharmacy and Health Sciences, Campbell University, Buies Creek, NC, USA
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  • Ruoyu Xiao,

    1. Department of Physiology and Pharmacology, Wake Forest University Health Sciences, Winston-Salem, North Carolina, USA
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  • Dana E. Selley,

    1. Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, Virginia, USA
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  • Allyn C. Howlett

    Corresponding author
    • Department of Physiology and Pharmacology, Wake Forest University Health Sciences, Winston-Salem, North Carolina, USA
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Address correspondence and reprint requests to Allyn C. Howlett, Department of Physiology and Pharmacology, Wake Forest University Health Sciences, One Medical Center Blvd., Winston-Salem, NC 27157 USA. E-mail: ahowlett@wakehealth.edu

Abstract

Although biochemical and physiological evidence suggests a strong interaction between striatal CB1 cannabinoid (CB1R) and D2 dopamine (D2R) receptors, the mechanisms are poorly understood. We targeted medium spiny neurons of the indirect pathway using shRNA to knockdown either CB1R or D2R. Chronic reduction in either receptor resulted in deficits in gene and protein expression for the alternative receptor and concomitantly increased expression of the cannabinoid receptor interacting protein 1a (CRIP1a), suggesting a novel role for CRIP1a in dopaminergic systems. Both CB1R and D2R knockdown reduced striatal dopaminergic-stimulated [35S]GTPγS binding, and D2R knockdown reduced pallidal WIN55212-2-stimulated [35S]GTPγS binding. Decreased D2R and CB1R activity was associated with decreased striatal phosphoERK. A decrease in mRNA for opioid peptide precursors pDYN and pENK accompanied knockdown of CB1Rs or D2Rs, and over-expression of CRIP1a. Down-regulation in opioid peptide mRNAs was followed in time by increased DOR1 but not MOR1 expression, leading to increased [D-Pen2, D-Pen5]-enkephalin-stimulated [35S]GTPγS binding in the striatum. We conclude that mechanisms intrinsic to striatal medium spiny neurons or extrinsic via the indirect pathway adjust for changes in CB1R or D2R levels by modifying the expression and signaling capabilities of the alternative receptor as well as CRIP1a and the DELTA opioid system.

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