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

• Published in: Journal of neurochemistry 2013-03, Vol.124 (6), p.808-820
• Main Authors: Blume, Lawrence C., Bass, Caroline E., Childers, Steven R., Dalton, George D., Roberts, David C. S., Richardson, Jasmine M., Xiao, Ruoyu, Selley, Dana E., Howlett, Allyn C.
• Format: Article
• Language: English
• Subjects: Animals; basal ganglia; cannabinoid receptor; Carrier Proteins - biosynthesis; Carrier Proteins - genetics; Carrier Proteins - physiology; Corpus Striatum - metabolism; Dopamine; Dopamine D2 Receptor Antagonists; enkephalin; gene expression; Gene Expression Regulation; Gene Knockdown Techniques - methods; Male; medium spiny neurons; mesolimbic dopamine pathway; Mice; Neurochemistry; Neurons; Peptides; Proteins; Rats; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB1 - antagonists & inhibitors; Receptor, Cannabinoid, CB1 - physiology; Receptors, Dopamine D2 - physiology; Receptors, Opioid, delta - biosynthesis; Receptors, Opioid, delta - genetics
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1111/jnc.12139

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. Schematic representation of changes in striatal proteins following knockdown of CB1R or D2R. Striatal knockdown of either CB1R or D2R decreased expression of the alternative receptor, and reduced [35S]GTPγS binding, phosphoERK, pDYN and pENK expression, but increased DOR1. CB1R or D2R knockdown increased CRIP1a, which evoked similar responses. These studies identify a functional interaction between these receptor systems in vivo.