Effects of Delta9-tetrahydrocannabivarin on [35S]GTPgammaS Binding in Mouse Brain Cerebellum and Piriform Cortex Membranes

Overview

Journal Br J Pharmacol

Publisher Wiley

Specialty Pharmacology

Date 2008 May 22

PMID 18493244

Citations 16

Authors

I Dennis

B J Whalley

G J Stephens

Affiliations

Soon will be listed here.

Abstract

Background And Purpose: We have recently shown that the phytocannabinoid Delta9-tetrahydrocannabivarin (Delta9-THCV) and the CB1 receptor antagonist AM251 increase inhibitory neurotransmission in mouse cerebellum and also exhibit anticonvulsant activity in a rat piriform cortical (PC) model of epilepsy. Possible mechanisms underlying cannabinoid actions in the CNS include CB1 receptor antagonism (by displacing endocannabinergic tone) or inverse agonism at constitutively active CB1 receptors. Here, we investigate the mode of cannabinoid action in [35S]GTPgammaS binding assays.

Experimental Approach: Effects of Delta9-THCV and AM251 were tested either alone or against WIN55,212-2-induced increases in [35S]GTPgammaS binding in mouse cerebellar and PC membranes. Effects on non-CB receptor expressing CHO-D2 cell membranes were also investigated.

Key Results: Delta9-THCV and AM251 both acted as potent antagonists of WIN55,212-2-induced increases in [35S]GTPgammaS binding in cerebellar and PC membranes (Delta9-THCV: pA2=7.62 and 7.44 respectively; AM251: pA2=9.93 and 9.88 respectively). At micromolar concentrations, Delta9-THCV or AM251 alone caused significant decreases in [35S]GTPgammaS binding; Delta9-THCV caused larger decreases than AM251. When applied alone in CHO-D2 membranes, Delta9-THCV and AM251 also caused concentration-related decreases in G protein activity.

Conclusions And Implications: Delta9-THCV and AM251 act as CB1 receptors antagonists in the cerebellum and PC, with AM251 being more potent than Delta9-THCV in both brain regions. Individually, Delta9-THCV or AM251 exhibited similar potency at CB1 receptors in the cerebellum and the PC. At micromolar concentrations, Delta9-THCV and AM251 caused a non-CB receptor-mediated depression of basal [35S]GTPgammaS binding.

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References

Pertwee R . The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: delta9-tetrahydrocannabinol, cannabidiol and delta9-tetrahydrocannabivarin. Br J Pharmacol. 2007; 153(2):199-215. PMC: 2219532. DOI: 10.1038/sj.bjp.0707442. View

McLoughlin D, Strange P . Mechanisms of agonism and inverse agonism at serotonin 5-HT1A receptors. J Neurochem. 2000; 74(1):347-57. DOI: 10.1046/j.1471-4159.2000.0740347.x. View

Ma Y, Weston S, Whalley B, Stephens G . The phytocannabinoid Delta(9)-tetrahydrocannabivarin modulates inhibitory neurotransmission in the cerebellum. Br J Pharmacol. 2008; 154(1):204-15. PMC: 2438968. DOI: 10.1038/bjp.2008.57. View

Wilson J, Lin H, Fu D, Javitch J, Strange P . Mechanisms of inverse agonism of antipsychotic drugs at the D(2) dopamine receptor: use of a mutant D(2) dopamine receptor that adopts the activated conformation. J Neurochem. 2001; 77(2):493-504. DOI: 10.1046/j.1471-4159.2001.00233.x. View

Glass M, Dragunow M, Faull R . Cannabinoid receptors in the human brain: a detailed anatomical and quantitative autoradiographic study in the fetal, neonatal and adult human brain. Neuroscience. 1997; 77(2):299-318. DOI: 10.1016/s0306-4522(96)00428-9. View

Whalley B, Wilkinson J, Williamson E, Constanti A . A novel component of cannabis extract potentiates excitatory synaptic transmission in rat olfactory cortex in vitro. Neurosci Lett. 2004; 365(1):58-63. DOI: 10.1016/j.neulet.2004.04.044. View

Thomas A, Baillie G, Phillips A, Razdan R, Ross R, Pertwee R . Cannabidiol displays unexpectedly high potency as an antagonist of CB1 and CB2 receptor agonists in vitro. Br J Pharmacol. 2007; 150(5):613-23. PMC: 2189767. DOI: 10.1038/sj.bjp.0707133. View

Howlett A, Barth F, Bonner T, Cabral G, Casellas P, Devane W . International Union of Pharmacology. XXVII. Classification of cannabinoid receptors. Pharmacol Rev. 2002; 54(2):161-202. DOI: 10.1124/pr.54.2.161. View

Landsman R, Burkey T, Consroe P, Roeske W, Yamamura H . SR141716A is an inverse agonist at the human cannabinoid CB1 receptor. Eur J Pharmacol. 1997; 334(1):R1-2. DOI: 10.1016/s0014-2999(97)01160-6. View

10.

Herkenham M, Groen B, Lynn A, De Costa B, Richfield E . Neuronal localization of cannabinoid receptors and second messengers in mutant mouse cerebellum. Brain Res. 1991; 552(2):301-10. DOI: 10.1016/0006-8993(91)90096-e. View

11.

Smith A, Dar M . Behavioral cross-tolerance between repeated intracerebellar nicotine and acute Delta(9)-tetrahydrocannabinol-induced cerebellar ataxia: role of cerebellar nitric oxide. J Pharmacol Exp Ther. 2007; 322(1):243-53. DOI: 10.1124/jpet.107.120634. View

12.

Breivogel C, Selley D, Childers S . Cannabinoid receptor agonist efficacy for stimulating [35S]GTPgammaS binding to rat cerebellar membranes correlates with agonist-induced decreases in GDP affinity. J Biol Chem. 1998; 273(27):16865-73. DOI: 10.1074/jbc.273.27.16865. View

13.

LOWRY O, ROSEBROUGH N, FARR A, RANDALL R . Protein measurement with the Folin phenol reagent. J Biol Chem. 1951; 193(1):265-75. View

14.

Howlett A, Scott D, Wilken G . Regulation of adenylate cyclase by cannabinoid drugs. Insights based on thermodynamic studies. Biochem Pharmacol. 1989; 38(19):3297-304. DOI: 10.1016/0006-2952(89)90628-x. View

15.

Price M, Baillie G, Thomas A, Stevenson L, Easson M, Goodwin R . Allosteric modulation of the cannabinoid CB1 receptor. Mol Pharmacol. 2005; 68(5):1484-95. DOI: 10.1124/mol.105.016162. View

16.

Lawrence D, GILL E . The effects of delta1-tetrahydrocannabinol and other cannabinoids on spin-labeled liposomes and their relationship to mechanisms of general anesthesia. Mol Pharmacol. 1975; 11(5):595-602. View

17.

Ashton J, Friberg D, Darlington C, Smith P . Expression of the cannabinoid CB2 receptor in the rat cerebellum: an immunohistochemical study. Neurosci Lett. 2005; 396(2):113-6. DOI: 10.1016/j.neulet.2005.11.038. View

18.

Breivogel C, Sim L, Childers S . Regional differences in cannabinoid receptor/G-protein coupling in rat brain. J Pharmacol Exp Ther. 1997; 282(3):1632-42. View

19.

TSOU K, Brown S, Mackie K, Walker J . Immunohistochemical distribution of cannabinoid CB1 receptors in the rat central nervous system. Neuroscience. 1998; 83(2):393-411. DOI: 10.1016/s0306-4522(97)00436-3. View

20.

Savinainen J, Saario S, Niemi R, Jarvinen T, Laitinen J . An optimized approach to study endocannabinoid signaling: evidence against constitutive activity of rat brain adenosine A1 and cannabinoid CB1 receptors. Br J Pharmacol. 2003; 140(8):1451-9. PMC: 1574161. DOI: 10.1038/sj.bjp.0705577. View