Tags

Type your tag names separated by a space and hit enter

Pharmacological evaluation of cannabinoid receptor ligands in a mouse model of anxiety: further evidence for an anxiolytic role for endogenous cannabinoid signaling.

Abstract

Extracts of Cannabis sativa have been used for their calming and sedative effects for centuries. Recent developments in drug discovery have suggested that modulation of neuronal endogenous cannabinoid signaling systems could represent a novel approach to the treatment of anxiety-related disorders while minimizing the adverse effects of direct acting cannabinoid receptor agonists. In this study, we evaluated the effects of direct cannabinoid receptor agonists and antagonists and endocannabinoid-modulating drugs on anxiety-like behavior in mice using the elevated-plus maze. We found that the direct CB1 receptor agonists (1R,3R,4R)-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-4-(3-hydroxypropyl)cyclohexan-1-ol (CP 55,940) (0.001-0.3 mg/kg) and 2,3-dihydro-5-methyl-3[(4-morpholinyl)methyl]pyrrolo [1,2,3-de]-1,4-benzoxazinyl]-(1-naphthalenyl)methanone mesylate) (WIN 55212-2) (0.3-10 mg/kg) increased time spent on the open arms (To) at low doses only. At the highest doses tested, both compounds altered overall locomotor activity. In contrast, Delta9-tetrahydrocannabinol (0.25-10 mg/kg) produced a dose-dependent reduction in To. The endocannabinoid uptake/catabolism inhibitor 4-hydroxyphenylarachidonylamide (AM404) (0.3-10 mg/kg) produced an increase in To at low doses and had no effect at the highest dose tested. The fatty acid amide hydrolase inhibitor cyclohexyl carbamic acid 3'-carbamoyl-biphenyl-3-yl ester (URB597) (0.03-0.3 mg/kg) produced a monophasic, dose-dependent increase in To. The CB1 receptor antagonists N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide HCl (SR141716) (1-10 mg/kg) and N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (AM251) (1-10 mg/kg) produced dose-related decreases in To. These data indicate that activation of CB1 cannabinoid receptors reduces anxiety-like behaviors in mice and further support an anxiolytic role for endogenous cannabinoid signaling. These results suggest that pharmacological modulation of this system could represent a new approach to the treatment of anxiety-related psychiatric disorders.

Links

  • FREE Publisher Full Text
  • Authors+Show Affiliations

    ,

    Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI 53226, USA.

    Source

    MeSH

    Animals
    Anti-Anxiety Agents
    Anxiety
    Cannabinoid Receptor Agonists
    Cannabinoid Receptor Antagonists
    Cannabinoid Receptor Modulators
    Disease Models, Animal
    Dose-Response Relationship, Drug
    Drug Evaluation, Preclinical
    Male
    Maze Learning
    Mice
    Mice, Inbred ICR
    Receptors, Cannabinoid

    Pub Type(s)

    Comparative Study
    Journal Article
    Research Support, N.I.H., Extramural

    Language

    eng

    PubMed ID

    16569753

    Citation

    Patel, Sachin, and Cecilia J. Hillard. "Pharmacological Evaluation of Cannabinoid Receptor Ligands in a Mouse Model of Anxiety: Further Evidence for an Anxiolytic Role for Endogenous Cannabinoid Signaling." The Journal of Pharmacology and Experimental Therapeutics, vol. 318, no. 1, 2006, pp. 304-11.
    Patel S, Hillard CJ. Pharmacological evaluation of cannabinoid receptor ligands in a mouse model of anxiety: further evidence for an anxiolytic role for endogenous cannabinoid signaling. J Pharmacol Exp Ther. 2006;318(1):304-11.
    Patel, S., & Hillard, C. J. (2006). Pharmacological evaluation of cannabinoid receptor ligands in a mouse model of anxiety: further evidence for an anxiolytic role for endogenous cannabinoid signaling. The Journal of Pharmacology and Experimental Therapeutics, 318(1), pp. 304-11.
    Patel S, Hillard CJ. Pharmacological Evaluation of Cannabinoid Receptor Ligands in a Mouse Model of Anxiety: Further Evidence for an Anxiolytic Role for Endogenous Cannabinoid Signaling. J Pharmacol Exp Ther. 2006;318(1):304-11. PubMed PMID: 16569753.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Pharmacological evaluation of cannabinoid receptor ligands in a mouse model of anxiety: further evidence for an anxiolytic role for endogenous cannabinoid signaling. AU - Patel,Sachin, AU - Hillard,Cecilia J, Y1 - 2006/03/28/ PY - 2006/3/30/pubmed PY - 2006/8/15/medline PY - 2006/3/30/entrez SP - 304 EP - 11 JF - The Journal of pharmacology and experimental therapeutics JO - J. Pharmacol. Exp. Ther. VL - 318 IS - 1 N2 - Extracts of Cannabis sativa have been used for their calming and sedative effects for centuries. Recent developments in drug discovery have suggested that modulation of neuronal endogenous cannabinoid signaling systems could represent a novel approach to the treatment of anxiety-related disorders while minimizing the adverse effects of direct acting cannabinoid receptor agonists. In this study, we evaluated the effects of direct cannabinoid receptor agonists and antagonists and endocannabinoid-modulating drugs on anxiety-like behavior in mice using the elevated-plus maze. We found that the direct CB1 receptor agonists (1R,3R,4R)-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-4-(3-hydroxypropyl)cyclohexan-1-ol (CP 55,940) (0.001-0.3 mg/kg) and 2,3-dihydro-5-methyl-3[(4-morpholinyl)methyl]pyrrolo [1,2,3-de]-1,4-benzoxazinyl]-(1-naphthalenyl)methanone mesylate) (WIN 55212-2) (0.3-10 mg/kg) increased time spent on the open arms (To) at low doses only. At the highest doses tested, both compounds altered overall locomotor activity. In contrast, Delta9-tetrahydrocannabinol (0.25-10 mg/kg) produced a dose-dependent reduction in To. The endocannabinoid uptake/catabolism inhibitor 4-hydroxyphenylarachidonylamide (AM404) (0.3-10 mg/kg) produced an increase in To at low doses and had no effect at the highest dose tested. The fatty acid amide hydrolase inhibitor cyclohexyl carbamic acid 3'-carbamoyl-biphenyl-3-yl ester (URB597) (0.03-0.3 mg/kg) produced a monophasic, dose-dependent increase in To. The CB1 receptor antagonists N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide HCl (SR141716) (1-10 mg/kg) and N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (AM251) (1-10 mg/kg) produced dose-related decreases in To. These data indicate that activation of CB1 cannabinoid receptors reduces anxiety-like behaviors in mice and further support an anxiolytic role for endogenous cannabinoid signaling. These results suggest that pharmacological modulation of this system could represent a new approach to the treatment of anxiety-related psychiatric disorders. SN - 0022-3565 UR - https://www.unboundmedicine.com/medline/citation/16569753/Pharmacological_evaluation_of_cannabinoid_receptor_ligands_in_a_mouse_model_of_anxiety:_further_evidence_for_an_anxiolytic_role_for_endogenous_cannabinoid_signaling_ L2 - http://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=16569753 DB - PRIME DP - Unbound Medicine ER -