Behavioral Methods in Cannabinoid Research

Fride, Ester; Perchuk, Alex; Hall, F. Scott; Uhl, George R.; Onaivi, Emmanuel S.

doi:10.1385/1-59259-999-0:269

Cited by 19 publications

(18 citation statements)

References 64 publications

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“…The neuroanatomical distribution of the CB1 receptor is also consistent with the behavioral effects produced by alcohol that include decreased motor activity, hypothermia, memory consolidation and catalepsy [7,36,37].…”

Section: Alcoholism and Endocannabinoid Systemsupporting

confidence: 62%

Role of the Endocannabinoid System in Alcohol-Related Behaviors

Hungund¹

2011

tonj

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Alcoholism is a psychiatric disorder characterized by impaired control over drinking, leading to tolerance, physical dependence, uncontrollable craving and relapse. The mechanism/s underlying this disorder is poorly understood at present. Ethanol (alcohol) effects are mediated through several signal transduction pathways involving many neurotransmitters and ion channels in various brain regions. There is a growing body of evidence now suggesting a critical role for the endocannabinoid (EC) system in alcohol-related behaviors. The EC system is comprised of endogenous cannabimimetic substances (endocannabinoids) and their receptors [cannabinoid (CB)] and the enzymes involved in the synthesis and degradation of the ECs. Recent studies have demonstrated that both the genetic and pharmacological manipulation of the EC system modulate the development of tolerance to and dependence on alcohol. The present article provides a review of the existing literature on the role of the EC system, and possible mechanisms and the therapeutic potential of the drugs targeted against this system in preventing alcohol addiction.

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Section: Alcoholism and Endocannabinoid Systemsupporting

confidence: 62%

Role of the Endocannabinoid System in Alcohol-Related Behaviors

Hungund¹

2011

tonj

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“…CB 1 R cannabinoid agonists produce characteristic dose-dependent effects in a set of four biobehavioral endpoints when administered in rodents [ e.g. , hypothermia, antinociception, decreased locomotor activity, and increased catalepsy], referred to as the cannabinoid tetrad (55). Similar to previous reports (34, 56) in this study NIH-Swiss mice were injected intraperitoneally (i.p.)…”

Section: 0 Resultsmentioning

confidence: 99%

Characterization of structurally novel G protein biased CB 1 agonists: Implications for drug development

Ford

Franks

Tai

et al. 2017

Pharmacological Research

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The human cannabinoid subtype 1 receptor (hCB1R) is highly expressed in the CNS and serves as a therapeutic target for endogenous ligands as well as plant-derived and synthetic cannabinoids. Unfortunately, acute use of hCB1R agonists produces unwanted psychotropic effects and chronic administration results in development of tolerance and dependence, limiting the potential clinical use of these ligands. Studies in β-arrestin knockout mice suggest that interaction of certain GPCRs, including μ-, δ-, κ-opioid and hCB1Rs, with β-arrestins might be responsible for several adverse effects produced by agonists acting at these receptors. Indeed, agonists that bias opioid receptor activation toward G-protein, relative to β-arrestin signaling, produce less severe adverse effects. These observations indicate that therapeutic utility of agonists acting at hCB1Rs might be improved by development of G-protein biased hCB1R agonists. Our laboratory recently reported a novel class of indole quinulidinone (IQD) compounds that bind cannabinoid receptors with relatively high affinity and act with varying efficacy. The purpose of this study was to determine whether agonists in this novel cannabinoid class exhibit ligand bias at hCB1 receptors. Our studies found that a novel IQD-derived hCB1 receptor agonist PNR-4-20 elicits robust G protein-dependent signaling, with transduction ratios similar to the non-biased hCB1R agonist CP-55,940. In marked contrast to CP-55,940, PNR-4-20 produces little to no β-arrestin 2 recruitment. Quantitative calculation of bias factors indicates that PNR-4-20 exhibits from 5.4-fold to 29.5-fold bias for G protein, relative to β-arrestin 2 signaling (when compared to G protein activation or inhibition of forskolin-stimulated cAMP accumulation, respectively). Importantly, as expected due to reduced β-arrestin 2 recruitment, chronic exposure of cells to PNR-4-20 results in significantly less desensitization and down-regulation of hCB1Rs compared to similar treatment with CP-55,940. PNR-4-20 (i.p.) is active in the cannabinoid tetrad in mice and chronic treatment results in development of less persistent tolerance and no significant withdrawal signs when compared to animals repeatedly exposed to the non-biased full agoinst JWH-018 or Δ9-THC. Finally, studies of a structurally similar analog PNR-4-02 show that it is also a G protein biased hCB1R agonist. It is predicted that cannabinoid agonists that bias hCB1R activation toward G protein, relative to β-arrestin 2 signaling, will produce fewer and less severe adverse effects both acutely and chronically.

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“…Single i.p. injections of CP-55,940 within this dosage range have previously been shown to evoke the characteristic tetrad of cannabinoid-induced behaviors (hypolocomotion, antinociception, decrease in rectal temperature, and catalepsy) in mice (Fride et al, 2006; Hamamoto et al, 2007). The cannabinoid tetrad is considered one of the most widely used assays for characterizing overt cannabinoid-induced behaviors in animals, and results are thought to closely model physiological responses to cannabinoid receptor activation in humans (Tai and Fantegrossi, 2014).…”

Section: Methodsmentioning

confidence: 93%