The endocannabinoid system is a modulatory system, with endocannabinoids as retrograde neurotransmitters. Neuropharmacology of cannabinoid ligands in the brain can therefore be understood in terms of their modulatory actions through other neurotransmitter systems. An overview of the neuropharmacology of several cannabinoid receptor ligands, including endocannabinoids, herbal cannabis, and synthetic cannabinoid receptor ligands is given in this review. Their mechanism of action at the endocannabinoid system is described and effects of cannabinoid ligands on other neurotransmitter systems will be described.

Here, we used selective pharmacological compounds during operant training to determine the impact of increased anandamide (and other FAAH substrates) or 2-AG levels on the formation of habitual behaviors in mice using a food-reinforced contingency degradation procedure. We found, contrary to our hypothesis, that FAAH and MAGL inhibition disrupted the formation of habits.

Reactivation of glutamatergic and GABAergic CB1 receptor populations unbalances exploratory drive beyond wild-type and complete CB1-KO behaviour, respectively. Our study confirms the opposing effects of glutamatergic and GABAergic CB1 receptor population signalling.

Both endocannabinoid (eCB) and noradrenergic (NA) signalling are linked to PTSD and fear extinction, but interactions between these systems in relation to fear extinction are largely unexplored. CB1 receptor activation facilitates fear extinction and increases prefrontal NA transmission, which is also associated with augmented fear extinction. Interactions between the eCB and NA systems may contribute to the regulation of fear extinction, which may have implications for PTSD treatment.

Plasticity of the neocortex during childhood and adolescence shapes the adult excitability of the cortex. Key components of this plasticity are astrocytes, somatostatin (SOM) interneurons, parvalbumin basket cells (bPV), GABA and Glutamate (Glu) release and thus the Excitation/Inhibition (E/I) balance. They are regulated by the endocannabinoid system through the CB1 receptor. The same components happen to be dysregulated in schizophrenia, a condition characterized by unbalanced E/I.

Growth cones exposed to CB1R agonist had fewer filopodial protrusions, whereas those exposed to CB1R inverse agonist had more filopodial protrusions than controls. A β-catenin mutant induced the same effects as CBR agonist, while an inhibitor of Myosin II phenocopied the inverse agonist on growth cone filopodia. These results imply that the activation of CB1R results in negative regulation of β-catenin and positive regulation of Myosin II, which both ultimately leads to fewer filopodia protrusions. By oppositely modulating β-catenin and Myosin II, CB1R regulates growth cone filopodia and the balance of destabilization/stabilization of the filopodia results in proper axonal defasciculation in the tract.

Olfactory processing is at the center of an activated endocannabinoid system and as a bridge to olfactory deficits and dysfunction. Physiological and environmental stimuli activate the endocannabinoid system, whereas neurodegenerative, neuropsychiatric and communication disorders can manifest themselves as olfactory deficits.

Nitroglycerin induces degranulation of dural mast cells, and increases CGRP release from peripheral terminals of trigeminal sensory nerves in meninges and the central terminals in the brainstem, and also cell bodies of trigeminal ganglion neurons, respectively. Methanandamide alleviates nitroglycerin-induced these changes in the CGRP release through CB1 receptors, and in mast cell degranulation through CB2 receptors. NTG: nitroglycerin, mAEA: methanandamide, MC: mast cell, R: receptor, CB1: cannabinoid receptor-1, CB2: cannabinoid receptor-2, CGRP: calcitonin gene-related peptide, TRPV1: transient receptor potential vanilloid-1. While straight red arrows depict the activation, black arrows with dashed line delineate the inhibition.

Burning mouth syndrome (BMS) is a neuropathic pain disorder associated with a burning sensation on oral mucosal surfaces. Although still poorly understood, it is believed to be a multifactorial disease with four underlying pathophysiological mechanisms: neuropathic, immunological, hormonal and psychological. Due to its complexity, there is no cure and current treatments lack efficacy. In this context, cannabis-based therapeutics may present a potential therapeutic alternative for BMS.

2-AG is the principal endocannabinoid molecule. 2-AG signaling is altered in many brain diseases, thus, targeting the key 2-AG turnover enzymes, DAGLα and MAGL is an emerging therapeutic strategy. We optimized a technique for ex vivo brain homogenates, using the surrogate chromogenic DAGLα and MAGL substrate, 4-NPB. We observed increased DAGL and MAGL activity in the cerebral cortex of a rat model of sporadic AD. This assay also can facilitate the discovery of novel DAGLα and MAGL inhibitors.

Genetic Absence Epilepsy Rats from Strasbourg (GAERS) spontaneously produce spike-and-slow wave discharges (SWDs). In the first experiments assessing cannabinoids in GAERS, injected tetrahydrocannabinol (Δ⁹-THC) dose-dependently increased SWDs, whereas injected cannabidiol (CBD) reduced these events. Furthermore, smoke exposure from high-Δ⁹-THC cannabis increased SWDs, but high-CBD cannabis had no effect. These experiments show dissociable effects using two different exposure paradigms.

Cannabidiol and Omega-3 fatty acids may act as activators of nuclear PPAR receptors. This review summarizes recent evidence for potential synergy between these pathways in the mesocorticolimbic circuitry and their potential therapeutic properties for various neuropsychiatric conditions.