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Behavioral and molecular changes elicited by acute administration of SR141716 to Delta9-tetrahydrocannabinol-tolerant rats: an experimental model of cannabinoid abstinence.

Abstract

Whether chronic cannabinoid consumption produces a dependent state comparable to that occurring with other drugs (e.g. the appearance of withdrawal signs when consumption is interrupted), and whether chronic cannabinoid consumption increases the risk of consuming other drugs of greater addictive power, are probably the two questions relating to cannabinoid addiction that provoke the most controversy. The present study was designed to further explore these two questions in laboratory animals. Firstly, we examined the effects of an acute challenge with SR141716 (an antagonist for the cannabinoid CB(1) receptor) in Delta(9)-tetrahydrocannabinol (Delta(9)-THC)-tolerant rats. This antagonist has been reported to precipitate a cannabinoid withdrawal syndrome. Thus, the administration of SR141716 to Delta(9)-THC-tolerant rats reduced inactivity in the open-field test and enhanced responses as tremor, turning and retropulsion-these responses that were only slightly enhanced in control rats. The administration of SR141716 increased the plasma prolactin and the corticosterone concentration in controls, but these increases were much lesser in Delta(9)-THC-tolerant rats. In addition, CRF-mRNA levels in the paraventricular hypothalamic nucleus, while reduced in SR141716-treated controls, were significantly increased in Delta(9)-THC-tolerant rats. The analysis of endocannabinoids also revealed that the administration of SR141716, which was mostly inactive in control rats, was able to reverse the changes in anandamide or 2-arachidonoylglycerol concentrations found in Delta(9)-THC-tolerant rats, in the striatum, limbic forebrain, diencephalon, cerebellum and brainstem, but not in the midbrain and hippocampus. As a second objective, we evaluated whether Delta(9)-THC-tolerant rats were more vulnerable to morphine in a self-administration paradigm. The Delta(9)-THC-tolerant and control rats self-administered morphine to a similar extent, in concordance with the similar values of dopaminergic activity in limbic and motor regions. In summary, our data indicate that Delta(9)-THC-tolerant rats were not more vulnerable to the reinforcing properties of morphine. However, they responded to the blockade of CB(1) receptors by exhibiting slightly but possibly relevant differences in behavioral, endocrine and molecular parameters compared to the response in non-tolerant rats. This is indicative of the existence of a withdrawal syndrome in cannabinoid-tolerant rats that is mild compared with abstinence in opioid-dependent rats.

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  • Authors+Show Affiliations

    ,

    Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Universidad Complutense, 28040 Madrid, Spain.

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    Source

    Drug and alcohol dependence 74:2 2004 May 10 pg 159-70

    MeSH

    Animals
    Arachidonic Acids
    Behavior, Animal
    Brain
    Cannabinoid Receptor Antagonists
    Cannabinoid Receptor Modulators
    Corticosterone
    Dronabinol
    Drug Administration Schedule
    Drug Tolerance
    Endocannabinoids
    Glycerides
    Male
    Paraventricular Hypothalamic Nucleus
    Piperidines
    Polyunsaturated Alkamides
    Prolactin
    Pyrazoles
    RNA, Messenger
    Rats
    Rats, Wistar
    Receptors, Cannabinoid
    Receptors, Corticotropin-Releasing Hormone
    Rimonabant
    Substance Withdrawal Syndrome

    Pub Type(s)

    Journal Article
    Research Support, Non-U.S. Gov't

    Language

    eng

    PubMed ID

    15099659

    Citation

    González, Sara, et al. "Behavioral and Molecular Changes Elicited By Acute Administration of SR141716 to Delta9-tetrahydrocannabinol-tolerant Rats: an Experimental Model of Cannabinoid Abstinence." Drug and Alcohol Dependence, vol. 74, no. 2, 2004, pp. 159-70.
    González S, Fernández-Ruiz J, Di Marzo V, et al. Behavioral and molecular changes elicited by acute administration of SR141716 to Delta9-tetrahydrocannabinol-tolerant rats: an experimental model of cannabinoid abstinence. Drug Alcohol Depend. 2004;74(2):159-70.
    González, S., Fernández-Ruiz, J., Di Marzo, V., Hernández, M., Arévalo, C., Nicanor, C., ... Ramos, J. A. (2004). Behavioral and molecular changes elicited by acute administration of SR141716 to Delta9-tetrahydrocannabinol-tolerant rats: an experimental model of cannabinoid abstinence. Drug and Alcohol Dependence, 74(2), pp. 159-70.
    González S, et al. Behavioral and Molecular Changes Elicited By Acute Administration of SR141716 to Delta9-tetrahydrocannabinol-tolerant Rats: an Experimental Model of Cannabinoid Abstinence. Drug Alcohol Depend. 2004 May 10;74(2):159-70. PubMed PMID: 15099659.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Behavioral and molecular changes elicited by acute administration of SR141716 to Delta9-tetrahydrocannabinol-tolerant rats: an experimental model of cannabinoid abstinence. AU - González,Sara, AU - Fernández-Ruiz,Javier, AU - Di Marzo,Vincenzo, AU - Hernández,Mariluz, AU - Arévalo,Cristina, AU - Nicanor,Cristina, AU - Cascio,Maria Grazia, AU - Ambrosio,Emilio, AU - Ramos,José A, PY - 2003/07/11/received PY - 2003/11/27/revised PY - 2003/12/02/accepted PY - 2004/4/22/pubmed PY - 2004/9/24/medline PY - 2004/4/22/entrez SP - 159 EP - 70 JF - Drug and alcohol dependence JO - Drug Alcohol Depend VL - 74 IS - 2 N2 - Whether chronic cannabinoid consumption produces a dependent state comparable to that occurring with other drugs (e.g. the appearance of withdrawal signs when consumption is interrupted), and whether chronic cannabinoid consumption increases the risk of consuming other drugs of greater addictive power, are probably the two questions relating to cannabinoid addiction that provoke the most controversy. The present study was designed to further explore these two questions in laboratory animals. Firstly, we examined the effects of an acute challenge with SR141716 (an antagonist for the cannabinoid CB(1) receptor) in Delta(9)-tetrahydrocannabinol (Delta(9)-THC)-tolerant rats. This antagonist has been reported to precipitate a cannabinoid withdrawal syndrome. Thus, the administration of SR141716 to Delta(9)-THC-tolerant rats reduced inactivity in the open-field test and enhanced responses as tremor, turning and retropulsion-these responses that were only slightly enhanced in control rats. The administration of SR141716 increased the plasma prolactin and the corticosterone concentration in controls, but these increases were much lesser in Delta(9)-THC-tolerant rats. In addition, CRF-mRNA levels in the paraventricular hypothalamic nucleus, while reduced in SR141716-treated controls, were significantly increased in Delta(9)-THC-tolerant rats. The analysis of endocannabinoids also revealed that the administration of SR141716, which was mostly inactive in control rats, was able to reverse the changes in anandamide or 2-arachidonoylglycerol concentrations found in Delta(9)-THC-tolerant rats, in the striatum, limbic forebrain, diencephalon, cerebellum and brainstem, but not in the midbrain and hippocampus. As a second objective, we evaluated whether Delta(9)-THC-tolerant rats were more vulnerable to morphine in a self-administration paradigm. The Delta(9)-THC-tolerant and control rats self-administered morphine to a similar extent, in concordance with the similar values of dopaminergic activity in limbic and motor regions. In summary, our data indicate that Delta(9)-THC-tolerant rats were not more vulnerable to the reinforcing properties of morphine. However, they responded to the blockade of CB(1) receptors by exhibiting slightly but possibly relevant differences in behavioral, endocrine and molecular parameters compared to the response in non-tolerant rats. This is indicative of the existence of a withdrawal syndrome in cannabinoid-tolerant rats that is mild compared with abstinence in opioid-dependent rats. SN - 0376-8716 UR - https://www.unboundmedicine.com/medline/citation/15099659/Behavioral_and_molecular_changes_elicited_by_acute_administration_of_SR141716_to_Delta9_tetrahydrocannabinol_tolerant_rats:_an_experimental_model_of_cannabinoid_abstinence_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0376871604000055 DB - PRIME DP - Unbound Medicine ER -