Cannabinoid withdrawal is dependent upon PKA activation in the cerebellum

Cannabinoid withdrawal is dependent upon PKA activation in the cerebellum Region‐specific up‐regulation of the cyclic AMP pathway is considered an important molecular mechanism in the origin of the somatic manifestations of the withdrawal syndrome to known drugs of abuse. Nevertheless, the existence of a withdrawal syndrome after prolonged cannabinoid administration has long been a controversial issue. Recent studies, in different species, have shown that withdrawal to prolonged cannabinoid exposure precipitated by the cannabinoid antagonist SR141716A is characterized by physical signs underlying impairment of motor coordination. Interestingly, cannabinoid withdrawal is accompanied by an increase of adenylyl cyclase activity in the cerebellum. Here, we investigate the functional role of the cyclic AMP pathway in the cerebellum in the establishment of cannabinoid withdrawal. We show that after SR141716A precipitation of cannabinoid withdrawal, basal and calcium‐calmodulin‐stimulated adenylyl cyclase activities as well as active PKA in the cerebellum increase in a transient manner with a temporal profile which matches that of the somatic expression of abstinence. Selectively blocking the up‐regulation of the cyclic AMP pathway in the cerebellum, by microinfusing the cyclic AMP blocker Rp‐8Br‐cAMPS in this region, markedly reduced both PKA activation and the somatic expression of cannabinoid withdrawal. Our results (i) directly link the behavioural manifestations of cannabinoid withdrawal with the up‐regulation of the cyclic AMP pathway in the cerebellum, pointing towards common molecular adaptive mechanisms for dependence and withdrawal to most drugs of abuse; (ii) suggest a particular role for the cerebellum as a major neurobiological substrate for cannabinoid withdrawal. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png European Journal of Neuroscience Wiley

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Publisher
Wiley
Copyright
Copyright © 2000 Wiley Subscription Services, Inc., A Wiley Company
ISSN
0953-816X
eISSN
1460-9568
D.O.I.
10.1046/j.1460-9568.2000.00971.x
Publisher site
See Article on Publisher Site

Abstract

Region‐specific up‐regulation of the cyclic AMP pathway is considered an important molecular mechanism in the origin of the somatic manifestations of the withdrawal syndrome to known drugs of abuse. Nevertheless, the existence of a withdrawal syndrome after prolonged cannabinoid administration has long been a controversial issue. Recent studies, in different species, have shown that withdrawal to prolonged cannabinoid exposure precipitated by the cannabinoid antagonist SR141716A is characterized by physical signs underlying impairment of motor coordination. Interestingly, cannabinoid withdrawal is accompanied by an increase of adenylyl cyclase activity in the cerebellum. Here, we investigate the functional role of the cyclic AMP pathway in the cerebellum in the establishment of cannabinoid withdrawal. We show that after SR141716A precipitation of cannabinoid withdrawal, basal and calcium‐calmodulin‐stimulated adenylyl cyclase activities as well as active PKA in the cerebellum increase in a transient manner with a temporal profile which matches that of the somatic expression of abstinence. Selectively blocking the up‐regulation of the cyclic AMP pathway in the cerebellum, by microinfusing the cyclic AMP blocker Rp‐8Br‐cAMPS in this region, markedly reduced both PKA activation and the somatic expression of cannabinoid withdrawal. Our results (i) directly link the behavioural manifestations of cannabinoid withdrawal with the up‐regulation of the cyclic AMP pathway in the cerebellum, pointing towards common molecular adaptive mechanisms for dependence and withdrawal to most drugs of abuse; (ii) suggest a particular role for the cerebellum as a major neurobiological substrate for cannabinoid withdrawal.

Journal

European Journal of NeuroscienceWiley

Published: Mar 1, 2000

References

  • Cannabis: pharmacology and toxicology in animals and humans
    Adams, Adams; Martin, Martin
  • A role for the cerebellum in the control of limb movement velocity
    Ebner, Ebner
  • The cerebellum and motor learning
    Glickstein, Glickstein
  • Cannabinoids decrease excitatory synaptic transmission and impair long‐term depression in rat cerebellar Purkinje cells
    Levenes, Levenes; Daniel, Daniel; Soubrie, Soubrie; Crepel, Crepel
  • Effects of SR 141716A after acute or chronic cannabinoid administration in dogs
    Lichtman, Lichtman; Wiley, Wiley; LaVecchia, LaVecchia; Neviaser, Neviaser; Arthur, Arthur; Wilson, Wilson; Martin, Martin
  • Discrete expression of Ca 2+ /calmodulin‐sensitive and Ca 2+ ‐insensitive adenylyl cyclases in the rat brain
    Mons, Mons; Yoshimura, Yoshimura; Cooper, Cooper
  • Calmodulin‐regulated adenylyl cyclases and neuromodulation
    Xia, Xia; Storm, Storm

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