Cannabinoid withdrawal is dependent upon PKA activation in the cerebellum

Autor:	Nicole Defer, Rafael Maldonado, Magdalena Mas, Cedric Firmo, Jacques Hanoune, Françoise Beslot, Bernard P. Roques, Eleni T. Tzavara, Emmanuel Valjent
Rok vydání:	2000
Předmět:	medicine.medical_specialty Cerebellum Chemistry Kindling General Neuroscience medicine.medical_treatment Antagonist Motor coordination Adenylyl cyclase chemistry.chemical_compound Endocrinology medicine.anatomical_structure Internal medicine medicine Cannabinoid receptor type 2 Cannabinoid Protein kinase A
Zdroj:	European Journal of Neuroscience. 12:1038-1046
ISSN:	0953-816X
DOI:	10.1046/j.1460-9568.2000.00971.x
Popis:	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.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_________::c4d7bf562c3999ef99a260040555ed52 https://doi.org/10.1046/j.1460-9568.2000.00971.x Zobrazit plný text záznamu Plný text ve formátu PDF Plný text ve formátu HTML
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