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OBJECTIVES: Given the challenges arising from the poor effectiveness of therapies for Cannabis-related disorders, the most commonly used illicit drug in the world, this paper aims to review the present knowledge about the neuroanatomic, biomolecular and cellular substrate of the endocannabinoid system, describing the mechanisms of cannabinoid-dependent neuronal plasticity and relating them with the neurobiology of Cannabis-related disorders (abuse and dependence). METHODS: Medline, Scopus and ISI Web of Knowledge were searched for the keywords Cannabis, neurobiology, endocannabinoid system, endocannabinoids, receptors, cannabinoid, neuronal plasticity, long-term synaptic depression, long-term potentiation, marijuana abuse and tetrahydrocannabinol. Eighty studies were included in this review. DISCUSSION: The neuroanatomical, cellular and biomolecular characterization of the endocannabinoid system serves perfectly its neuromodulatory neuroplastic and metaplastic functions, particularly in pathways related to substance-related disorders. Exogenous cannabinoids disrupt these functions. CONCLUSION: The endocannabinoid system contributes to the definition of setpoints in several neuronal pathways, including pathways critical for the development of substance-related disorders; with Cannabis use these setpoints become more permissive, facilitating Cannabis-related disorders. The advances in understanding the neurobiology of Cannabis open a window of opportunities for new therapeutic strategies in Cannabis-related disorders.OBJETIVOS: Diante das lacunas na efetividade das terapêuticas para transtornos por uso de Cannabis, a droga ilícita mais consumida no mundo, este trabalho propõe-se a rever os conhecimentos sobre o substrato neuroanatômico, biomolecular e celular do sistema endocanabinoide, descrever os mecanismos de neuroplasticidade dependente dos canabinoides e relacioná-los com a neurobiologia dos transtornos por uso de Cannabis (abuso e dependência). MÉTODOS: Recorreu-se às bases de dados Medline, Scopus e ISI Web of Knowledge; as palavras-chave pesquisadas foram Cannabis, neurobiology, endocannabinoid system, endocannabinoids, receptors, cannabinoid, neuronal plasticity, long-term synaptic depression, long-term potentiation, marijuana abuse e tetrahydrocannabinol. Foram incluídos 80 trabalhos nesta revisão. DISCUSSÃO: A distribuição neuroanatômica, celular e biomolecular do sistema endocanabinoide adequa-se perfeitamente às suas funções de neuromodulação (via neuroplasticidade e metaplasticidade), nomeadamente em vias relacionadas aos transtornos por uso de substâncias. Os canabinoides exógenos perturbam essas funções. CONCLUSÃO: O sistema endocanabinoide contribui para a definição de setpoints em diversas vias neuronais, incluindo vias cruciais na instalação de transtornos por uso de substâncias; com o uso de Cannabis, esses setpoints tornar-se-ão mais permissivos, facilitando os transtornos por uso de Cannabis. Os avanços no entendimento da neurobiologia da Cannabis abrem uma janela de oportunidades para novas estratégias terapêuticas nos transtornos por uso de Cannabis

Neurobiologia da Cannabis: do sistema endocanabinoide aos transtornos por uso de Cannabis