RESUMO
The Transient Receptor Potential Vanilloid Type-1 (TRPV1) was first characterized in primary afferent fibers as a receptor for capsaicin (the pungent ingredient of chili peppers). Later on, this cation-permeable ion channel was also described in the central nervous system, where its main putative endogenous ligand is N-arachidonoyl ethanolamide (an endocannabinoid, also known as anandamide). Recent results employing genetic, pharmacological and histochemical techniques indicate that TRPV1 tonically modulate anxiety, fear and panic responses in brain regions related to defensive responses, such as the dorsal periaqueductal gray, the hippocampus and the medial prefrontal cortex. Genetic deletion or antagonism of this ion channel induces anxiolytic-like effects in several animal models. The main mechanism responsible for TRPV1-mediated effects on anxiety seems to involve facilitation of glutamatergic neurotransmission. In addition, there is evidence for interactions with other neurotransmitter systems, such as nitric oxide and endocannabinoids.
Assuntos
Encéfalo/metabolismo , Mecanismos de Defesa , Canais de Cátion TRPV/fisiologia , Animais , Ansiedade/tratamento farmacológico , Ansiedade/patologia , Modelos Animais de Doenças , Humanos , Modelos BiológicosRESUMO
The prelimbic medial prefrontal cortex (PL) is an important encephalic structure involved in the expression of emotional states. In a previous study, intra-PL injection of cannabidiol (CBD), a major non-psychotomimetic cannabinoid present in the Cannabis sativa plant, reduced the expression of fear conditioning response. Although its mechanism remains unclear, CBD can facilitate 5HT1A receptor-mediated neurotransmission when injected into several brain structures. This study was aimed at verifying if intra-PL CBD could also induce anxiolytic-like effect in a conceptually distinct animal model, the elevated plus maze (EPM). We also verified if CBD effects in the EPM and contextual fear conditioning test (CFC) depend on 5HT1A receptors and previous stressful experience. CBD induced opposite effects in the CFC and EPM, being anxiolytic and anxiogenic, respectively. Both responses were prevented by WAY100,635, a 5HT1A receptor antagonist. In animals that had been previously (24h) submitted to a stressful event (2h-restraint) CBD caused an anxiolytic, rather than anxiogenic, effect in the EPM. This anxiolytic response was abolished by previous injection of metyrapone, a glucocorticoid synthesis blocker. Moreover, restraint stress increased 5HT1A receptors expression in the dorsal raphe nucleus, an effect that was attenuated by injection of metyrapone before the restraint procedure. Taken together, these results suggest that CBD modulation of anxiety in the PL depend on 5HT1A-mediated neurotransmission and previous stressful experience.
Assuntos
Ansiolíticos/farmacologia , Ansiedade/tratamento farmacológico , Canabidiol/farmacologia , Córtex Pré-Frontal/efeitos dos fármacos , Receptor 5-HT1A de Serotonina/metabolismo , Estresse Psicológico/fisiopatologia , Animais , Ansiolíticos/administração & dosagem , Ansiedade/fisiopatologia , Canabidiol/administração & dosagem , Condicionamento Psicológico/efeitos dos fármacos , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/farmacologia , Comportamento Exploratório/efeitos dos fármacos , Medo/efeitos dos fármacos , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Metirapona/farmacologia , Piperazinas/farmacologia , Córtex Pré-Frontal/fisiopatologia , Piridinas/farmacologia , Núcleos da Rafe/efeitos dos fármacos , Núcleos da Rafe/fisiopatologia , Ratos Wistar , Restrição Física , Antagonistas do Receptor 5-HT1 de Serotonina/farmacologia , Fatores de TempoRESUMO
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.
Assuntos
Animais , Camundongos , Ratos , Ansiedade/fisiopatologia , Reação de Fuga/fisiologia , Neurotransmissores/fisiologia , Substância Cinzenta Periaquedutal/fisiologia , Transmissão Sináptica/fisiologia , Ansiedade/metabolismo , Ácidos Araquidônicos/farmacologia , Agonistas de Receptores de Canabinoides/farmacologia , Endocanabinoides/farmacologia , Endocanabinoides/fisiologia , Óxido Nítrico/fisiologia , Substância Cinzenta Periaquedutal/metabolismo , Alcamidas Poli-Insaturadas/farmacologia , Canais de Cátion TRPV/fisiologiaRESUMO
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.