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

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.

Unconventional neurotransmitters, neurodegeneration and neuroprotection

Neurotransmitters are also involved in functions other than conventional signal transfer between nerve cells, such as development, plasticity, neurodegeneration, and neuroprotection. For example, there is a considerable amount of data indicating developmental roles for the glutamatergic, cholinergic, dopaminergic, GABA-ergic, and ATP/adenosine systems. In this review, we discuss the existing literature on these "new" functions of neurotransmitters in relation to some unconventional neurotransmitters, such as the endocannabinoids and nitric oxide. Data indicating both transcriptional and post-transcriptional modulation of endocannabinoid and nitrinergic systems after neural lesions are discussed in relation to the non-conventional roles of these neurotransmitters. Knowledge of the roles of neurotransmitters in brain functions other than information transfer is critical for a more complete understanding of the functional organization of the brain and to provide more opportunities for the development of therapeutical tools aimed at minimizing neuronal death.

Fine-tuning of defensive behaviors in the dorsal periaqueductal gray by atypical neurotransmitters

This paper presents an up-to-date review of the evidence indicating that atypical neurotransmitters such as nitric oxide (NO) and endocannabinoids (eCBs) play an important role in the regulation of aversive responses in the periaqueductal gray (PAG). Among the results supporting this role, several studies have shown that inhibitors of neuronal NO synthase or cannabinoid receptor type 1 (CB1) receptor agonists cause clear anxiolytic responses when injected into this region. The nitrergic and eCB systems can regulate the activity of classical neurotransmitters such as glutamate and γ-aminobutyric acid (GABA) that control PAG activity. We propose that they exert a ‘fine-tuning’ regulatory control of defensive responses in this area. This control, however, is probably complex, which may explain the usually bell-shaped dose-response curves observed with drugs that act on NO- or CB1-mediated neurotransmission. Even if the mechanisms responsible for this complex interaction are still poorly understood, they are beginning to be recognized. For example, activation of transient receptor potential vanilloid type-1 channel (TRPV1) receptors by anandamide seems to counteract the anxiolytic effects induced by CB1 receptor activation caused by this compound. Further studies, however, are needed to identify other mechanisms responsible for this fine-tuning effect.

Mapping and signaling of neural pathways involved in the regulation of hydromineral homeostasis

Several forebrain and brainstem neurochemical circuitries interact with peripheral neural and humoral signals to collaboratively maintain both the volume and osmolality of extracellular fluids. Although much progress has been made over the past decades in the understanding of complex mechanisms underlying neuroendocrine control of hydromineral homeostasis, several issues still remain to be clarified. The use of techniques such as molecular biology, neuronal tracing, electrophysiology, immunohistochemistry, and microinfusions has significantly improved our ability to identify neuronal phenotypes and their signals, including those related to neuron-glia interactions. Accordingly, neurons have been shown to produce and release a large number of chemical mediators (neurotransmitters, neurohormones and neuromodulators) into the interstitial space, which include not only classic neurotransmitters, such as acetylcholine, amines (noradrenaline, serotonin) and amino acids (glutamate, GABA), but also gaseous (nitric oxide, carbon monoxide and hydrogen sulfide) and lipid-derived (endocannabinoids) mediators. This efferent response, initiated within the neuronal environment, recruits several peripheral effectors, such as hormones (glucocorticoids, angiotensin II, estrogen), which in turn modulate central nervous system responsiveness to systemic challenges. Therefore, in this review, we shall evaluate in an integrated manner the physiological control of body fluid homeostasis from the molecular aspects to the systemic and integrated responses.