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Molecular Pharmacology

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Research ArticleArticle

Prolonged Recovery Rate of CB1 Receptor Adaptation after Cessation of Long-Term Cannabinoid Administration

Laura J. Sim-Selley, Nicole S. Schechter, W. Kirk Rorrer, George D. Dalton, Jerry Hernandez, Billy R. Martin and Dana E. Selley
Molecular Pharmacology September 2006, 70 (3) 986-996; DOI: https://doi.org/10.1124/mol.105.019612
Laura J. Sim-Selley
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Nicole S. Schechter
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W. Kirk Rorrer
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George D. Dalton
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Jerry Hernandez
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Billy R. Martin
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Dana E. Selley
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Abstract

Long-term cannabinoid administration produces region-dependent CB1 receptor desensitization and down-regulation. This study examined the time course for normalization of CB1 receptors and G-protein activation using 3H-labeled N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboximide hydrochloride (SR141716A) and guanosine 5′-O-(3-[35S]thio)triphosphate ([35S]GTPγS binding), respectively, in hippocampus and striatum/globus pallidus (GP). Mice were treated with escalating doses of Δ9-tetrahydrocannabinol (Δ9-THC) or R(+)-[2,3-dihydro-5-methyl-3-[(morpholinyl)methyl]pyrrolo-[1,2,3-de]-1,4-benzoxazinyl]-(1-naphthalenyl)methanone mesylate (WIN55,212-2) for 15 days, and tissue was collected 1, 3, 7, or 14 days after final injection. [3H]SR141716A and WIN55,212-2-stimulated [35S]GTPγS binding were decreased in both regions 1 day after treatment. WIN55,212-2-stimulated G-protein activation in striatum/GP returned to control level at 3 days after cessation of treatment with either drug but did not return to control level in hippocampus until 14 days. CB1 receptor binding did not recover to control levels until day 7 or 14 after treatment in striatum/GP and hippocampus, respectively. The mechanism of CB1 binding site down-regulation was investigated after long-term Δ9-THC treatment. Analysis of CB1 receptor mRNA in hippocampus and striatum/GP showed that transcriptional regulation could not explain prolonged recovery rates from CB1 receptor down-regulation. In contrast, CB1 receptor protein, as determined by immunoblot analysis, matched the down-regulation and recovery rates of CB1 receptor binding sites relatively closely. These data demonstrate that cannabinoid-induced decreases in CB1 receptor function persist for relatively long time periods after cessation of long-term drug treatment and that CB1 receptor signaling recovers more quickly in striatum/GP than hippocampus. Moreover, down-regulation of CB1 receptor binding sites does not seem to result mainly from transcriptional regulation, suggesting that adaptive regulation of CB1 receptors in brain primarily occurs at the protein level.

Footnotes

  • This work was supported by National Institute on Drug Abuse grants DA14277 (to L.J.S.-S.), DA05274 (to D.E.S.), and DA03672 (to B.R.M.), and antibody development was supported by grant DA11322 (to K.M.).

  • Portions of this work were presented previously in abstract form.

  • ABBREVIATIONS: BSA, bovine serum albumin; CHO, Chinese hamster ovary; O.D., optical density; GP, globus pallidus; ECL, enhanced chemiluminescence; SSPE, sodium chloride/sodium phosphate/EDTA; TBST, Tris-buffered saline/Tween 20; CB1-ir, CB1 receptor immunoreactivity; THC, Δ9-tetrahydrocannabinol; [35S]GTPγS, guanosine 5′-O-(3-[35S]thio)triphosphate; SR141716A, N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboximide hydrochloride; WIN55,212-2, R(+)-[2,3-dihydro-5-methyl-3-[(morpholinyl)methyl]pyrrolo-[1,2,3-de]-1,4-benzoxazinyl]-(1-naphthalenyl)methanone mesylate.

    • Received October 7, 2005.
    • Accepted May 31, 2006.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 70 (3)
Molecular Pharmacology
Vol. 70, Issue 3
1 Sep 2006
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Research ArticleArticle

Prolonged Recovery Rate of CB1 Receptor Adaptation after Cessation of Long-Term Cannabinoid Administration

Laura J. Sim-Selley, Nicole S. Schechter, W. Kirk Rorrer, George D. Dalton, Jerry Hernandez, Billy R. Martin and Dana E. Selley
Molecular Pharmacology September 1, 2006, 70 (3) 986-996; DOI: https://doi.org/10.1124/mol.105.019612

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Research ArticleArticle

Prolonged Recovery Rate of CB1 Receptor Adaptation after Cessation of Long-Term Cannabinoid Administration

Laura J. Sim-Selley, Nicole S. Schechter, W. Kirk Rorrer, George D. Dalton, Jerry Hernandez, Billy R. Martin and Dana E. Selley
Molecular Pharmacology September 1, 2006, 70 (3) 986-996; DOI: https://doi.org/10.1124/mol.105.019612
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