These receptors increase calcium influx, facilitating a rapid depolarization of the neuronal cells (Casarotto, de Bortoli & Zangrossi Jr, 2012; Moreira et al., 2012). observed that the local administration of ACEA (a CB1 agonist) into the prelimbic region of prefrontal cortex (PL-PFC) was sufficient to reduce the burying behavior, while capsaicin or BDNF exerted the opposite effect, increasing the number of buried marbles. In addition, both ACEA and capsaicin effects were blocked by previous administration of k252a (an antagonist of TRK receptors) into PL-PFC. The effect of systemically injected CB1 agonist WIN55,212-2 was blocked by previous administration of k252a. We also observed a partial colocalization of CB1/TRPV1/TRKB in the PL-PFC, and the localization of TRPV1 in CaMK2+ cells. Conclusion Taken together, our data indicate that anandamide engages a coordinated activation of TRKB, via CB1 and TRPV1. Thus, acting upon CB1 and TRPV1, AEA could regulate the TRKB-dependent plasticity in both pre- and postsynaptic compartments. (while the indirect pathway engages a more complex set of relay structures, involving the and subthalamic nucleus (for review see Canales & Graybiel, 2000; Canales & Graybiel, 2000). The resultant activity between these two pathways regulates the output of the basal ganglia in favor of one of the two possible effects: increase in the repetitive movements (favored by the direct pathway activity) or inhibition of such programs, a consequence of activation of the indirect pathway. Although highly simplified, this model of the CSTC circuit provides a useful framework for understanding circuit physiology and putative dysfunctions (Casarotto, Gomes & Guimar?es, 2015). Multiple neurotransmitters/neuromodulators systems act in coordination to regulate the balance in the CSTC circuitry. Among them, endocannabinoids play a central role regulating not only glutamatergic, but also GABAergic, serotonergic, and dopaminergic transmission (for review see (Lpez-Moreno et al., 2008; Lpez-Moreno et al., 2008). Briefly, the activation of CB1 receptors by AEA (N-arachidonoylethanolamine) or 2AG (2-arachidonoylglycerol), produced as on-demand retrograde messengers, usually decreases the activity of presynaptic neurons via Gi/0 and modulation of calcium and potassium channels (for review see (Chevaleyre, Takahashi & Castillo, 2006; Chevaleyre, Takahashi & Castillo, 2006)). Due to these effects, endocannabinoids are putatively able to regulate excessive neurotransmission in the CSTC system. Otherwise, endocannabinoids are also described to trigger Gq downstream signaling at astrocytes to increase calcium intracellular levels, and others endocannabinoids such as N-arachidonoyl-dopamine are even potent agonists to TRPV1 (Hashimotodani et al., 2007; Castillo et al., 2012). Besides, the synthesis and release of endocannabinoids usually is triggered by depolarization-induced calcium influx, as well as by MAP2K2 Z-YVAD-FMK activated phospholipase-C-beta following activation of Gq-protein coupled receptors (Hashimotodani et al., 2007; Castillo et al., 2012). Endocannabinoids can also act on TRPV1 receptors. These receptors increase calcium influx, facilitating a rapid depolarization of the neuronal cells (Casarotto, de Bortoli & Zangrossi Jr, 2012; Moreira et al., 2012). In preclinical anxiety models, high doses of AEA are usually ineffective or cause anxiogenic rather than anxiolytic effects. This Z-YVAD-FMK bell-shaped doseCeffect curve has been associated with TRPV1 activation and is reversed by pretreatment with antagonists of these receptors (Casarotto, de Bortoli & Zangrossi Jr, 2012; and for review see Moreira & Wotjak, 2010; Aguiar et al., 2014). Accordingly, the anxiolytic effect of capsaicin, an agonist of TRPV1 receptors, observed after intracerebral administration was attributed to a desensitization of the channels (Terzian et al., 2009). CB1 receptors are highly expressed in the anterior cingulate cortex, Z-YVAD-FMK striatum and (Harkany et al., 2007; Daz-Alonso, Guzmn & Galve-Roperh, 2012), major hubs of CSTC circuitry. TRPV1 has a less broad expression when compared to CB1 (Tth et al., 2005; Menigoz & Boudes, 2011). However, these two receptors are colocalized in the periaqueductal grey matter (PAG) and prefrontal cortex playing opposite functional roles (Casarotto, de Bortoli &.