Anales RANF

P.39 ADENOSINE-MEDIATED CONTROL OF SYNAPTIC AND BEHAVIOURAL ACTIONS OF CANNABINOIDS F.M. Mouro 1 , A Silva-Cruz A 1 , A Serpa 1,2 , A Köfalvi 3 , DM Rombo 1 , Y Baqi 4,5 , JF Cascalheira 2 , Carlstrom M 6 , CE Müller 4 , JA Ribeiro 1 , AM Sebastião 1 1 University of Lisbon, Portugal; 2 University of Beira Interior, Portugal; 3 Center for Neuroscience and Cell Biology of Coimbra, University of Coimbra, Portugal; 4 Pharma- Zentrum Bonn, University of Bonn, Germany; 5 Sultan Qaboos University, Oman, 6 Karolinska Institutet, Sweden. Cannabinoid use either for clinical or recreational purposes impacts in brain function and cognition. Therefore, it is of uttermost importance to understand in detail the synaptic and brain circuitry bases of the actions of cannabinoids as well as to discover strategies to mitigate the negative side-effects of cannabinoid-based therapies. The ubiquitous distribution of adenosine receptors in the brain, and the previous knowledge on the interaction between cannabinoid CB1 receptors and adenosine A 2A receptors (A 2A R) at the striatum (Fuxe et al., 2008; Ferré et al., 2009), inspired us to evaluate how adenosine receptors could affect synaptic and memory behavioural actions of cannabinoids. Prolonged intake of a cannabinoid receptor agonist affects brain metabolism and connectivity in brain areas relevant for memory processing (Mouro et al., 2018). A 1 R overexpression in the forebrain caused by chronic caffeine intake exacerbates memory deficits induced by a single administration of tetrahydrocannabinol (THC) to rats or mice (Sousa et al., 2011). The synaptic mechanisms underlying this interaction remain to be fully understood but may involve GABAergic interneurons since A 1 R activation attenuates the inhibitory action of the cannabinoid receptor agonist upon GABA release (Sousa et al., 2011) and selectively attenuates tonic inhibition of cannabinoid type 1 receptor positive (CB1R + ) hippocampal interneurons (Rombo et al., 2016). The inhibitory action of CB1Rs on synaptic transmission (Serpa et al., 2009), the dual influence of endocannabinoids upon synaptic plasticity (Silva-Cruz et al., 2017) or the inhibitory action of CB1Rs upon cyclic AMP accumulation (Serpa et al., 2015), do not seem to be influenced by A 1 R activity. Concerning A 2A R, we found out that they markedly influence cannabinoid actions in the forebrain. Thus, the inhibitory action of a CB1R agonist upon long-term potentiation (LTP), a synaptic correlate of memory processing, is attenuated by A 2A R blockade (Mouro et al., 2019). Accordingly, A 2A R antagonists are able to prevent memory consolidation deficits caused by both acute and chronic administration of a CB1R agonist (Mouro et al., 2017; 2019). The beneficial action of A 2A R antagonists to mitigate cannabinoid induced memory deficits are still evident upon prolonged agonist administration of the A 2A R antagonists (Mouro et al., 2019). Also, prolonged A 2A R antagonism does not cause significant alterations in A 2A R levels in the forebrain, as assessed by specific binding assays (Mouro et al., 2019). Taken together, our data highlights that selective A 2A R blockade, but not caffeine, is a promising strategy to mitigate cognitive side effects when therapeutic use of cannabinoids is desirable. Work supported by Fundação para a Ciência e Tecnologia, Portugal and European Union Ferré et al. (2009) Neuropharmacology. 56 Suppl 1:226-34; Fuxe et al. (2008) Brain Res Rev., 58:415-52; Mouro et al (2018) J Neurochem., 47:71-83; Mouro et al . (2017) Neuropharmacology, 117:316-327; Mouro et al . (2019). Neuropharmacology, 155:10-21; Rombo et al (2016) Cereb Cortex 26:1081-1095; Serpa et al (2009) Eur J Pharmacol. 623:41-46; Serpa et al . (2015) Biomed Res Int., ID 872684 eCollection; Silva-Cruz et al (2017) Front Pharmacol. 8:921.eCollection; Sousa et al . (2011) Neuropsychopharmacology, 36, 472-487.