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Projeto de investigação
Does context matter for drug action? Contextual dependency of the long-lasting neurobiological and antidepressant actions of psilocybin
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Publicações
A maestro role of adenosine A2A receptors in GABAergic synapses stabilization during postnatal neuronal maturation
Publication . Sebastião, Ana M
A recent work elegantly demonstrated a role of adenosine, through the high afnity Gs-coupled A2A receptors
(A2AR), on stabilization of GABAergic synapses during a critical post-natal period, which is discussed here within the context of the most recent advances on our understanding of the neurodevelopmental actions of adenosine. Neuronal activity requires a proper balance between excitatory and inhibitory inputs, GABA being the predominant inhibitory neurotransmitter in the brain. Dysfunction of GABAergic signalling, in particular in the maturation of GABAergic synapses, leads to severe neurodevelopmental diseases, which may express as drug-resistant forms of epilepsy, cognitive impairment and, often, mental retardation or even premature
death.
Adjusting the brakes to adjust neuronal activity: adenosinergic modulation of GABAergic transmission
Publication . Sebastião, Ana M; Ribeiro, Joaquim A.
About 50 years elapsed from the publication of the first full paper on the neuromodulatory action of adenosine at a 'simple' synapse model, the neuromuscular junction (Ginsborg and Hirst, 1972). In that study adenosine was used as a tool to increase cyclic AMP and for the great surprise, it decreased rather than increased neurotransmitter release, and for a further surprise, its action was prevented by theophylline, at the time only known as inhibitor of phosphodiesterases. These intriguing observations opened the curiosity for immediate studies relating the action of adenine nucleotides, known to be released together with neurotransmitters, to that of adenosine (Ribeiro and Walker, 1973, 1975). Our understanding on the ways adenosine uses to modulate synapses, circuits, and brain activity, vastly expanded since then. However, except for A2A receptors, whose actions upon GABAergic neurons of the striatum are well known, most of the attention given to the neuromodulatory action of adenosine has been focusing upon excitatory synapses. Evidence is growing that GABAergic transmission is also a target for adenosinergic neuromodulation through A1 and A2A receptors. Some o these actions have specific time windows during brain development, and others are selective for specific GABAergic neurons. Both tonic and phasic GABAergic transmission can be affected, and either neurons or astrocytes can be targeted. In some cases, those effects result from a concerted action with other neuromodulators. Implications of these actions in the control of neuronal function/dysfunction will be the focus of this review.
Unexpected short- and long-term effects of chronic adolescent HU-210 exposure on emotional behavior
Publication . Farinha Ferreira, Jorge Miguel; Rei, Nádia; Fonseca-Gomes, João; Miranda-Lourenço, Catarina; Serrão, Paula; Vaz, Sandra H.; Gomes, Joana I.; Martins, Valéria; Pereira, Beatriz de Alves; Sebastião, Ana M
Chronic adolescent cannabinoid receptor agonist exposure has been shown to lead to persistent increases in depressive-like behaviors. This has been a key obstacle to the development of cannabinoid-based therapeutics. However, most of the published work has been performed with only three compounds, namely Δ9-tetrahydrocannabinol, CP55,940 and WIN55,212-2. Hypothesizing that different compounds may lead to distinct outcomes, we herein used the highly potent CB1R/CB2R full agonist HU-210, and first aimed at replicating cannabinoid-induced long-lasting effects, by exposing adolescent female Sprague-Dawley rats to increasing doses of HU-210, for 11 days and testing them at adulthood, after a 30-day drug washout. Surprisingly, HU-210 did not significantly impact adult anxious- or depressive-like behaviors. We then tested whether chronic adolescent HU-210 treatment resulted in short-term (24h) alterations in depressive-like behavior. Remarkably, HU-210 treatment simultaneously induced marked antidepressant- and prodepressant-like responses, in the modified forced swim (mFST) and sucrose preference tests (SPT), respectively. Hypothesizing that mFST results were a misleading artifact of HU-210-induced behavioral hyperreactivity to stress, we assessed plasmatic noradrenaline and corticosterone levels, under basal conditions and following an acute swim-stress episode. Notably, we found that while HU-210 did not alter basal noradrenaline or corticosterone levels, it greatly augmented the stress-induced increase in both. Our results show that, contrary to previously studied cannabinoid receptor agonists, HU-210 does not induce persisting depressive-like alterations, despite inducing marked short-term increases in stress-induced reactivity. By showing that not all cannabinoid receptor agonists may induce long-term negative effects, these results hold significant relevance for the development of cannabinoid-based therapeutics.
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Entidade financiadora
Fundação para a Ciência e a Tecnologia
Programa de financiamento
3599-PPCDT
Número da atribuição
PTDC/MED-FAR/4834/2021