Neurodegenerative diseases such as Alzheimer’s and Parkinson’s diseases are among the leading causes of physical and cognitive disability across the globe. Fifty million people worldwide suffer these diseases, and that number is expected to rise as the population ages. Ictus is another pathology that also courses with neurodegeneration and is a leading cause of mortality and long-term disability in developed countries. Schizophrenia is not as common as other mental disorders, affecting approximately 24 million people worldwide. All these disorders have in common that still there is not an effective pharmacological treatment to cure them. The N-methyl-D-aspartate (NMDA) receptor (NMDAR) has attracted attention as a potential therapeutic target due to its important role in learning and memory and also due to its implication in excitotoxicity processes. Some drugs targeting NMDARs are already being used to treat symptoms of disorders affecting the central nervous system (CNS). Here, we aim to review the implications of NMDAR in these CNS pathologies, its role as a potential therapeutic target, and the future perspectives for developing new treatments focused on these receptors.

According to the World Drug Report, there are nearly 300 million drug users globally. Drug addiction is a chronic, relapsing brain disease that leads to medical, psychological, and social complications. This neuropsychiatric disorder is characterized by a compulsive drug-seeking behavior, continued use despite harmful consequence, and long-lasting changes in the brain. The reward system, which involves dopaminergic circuits, plays a key role in addiction. Dopamine levels have been described to fluctuate throughout the day, in a circadian fashion, and the effects of drugs have been shown to depend on the time when they are used. Hence, due to its important role in the control of circadian rhythms, the orexinergic system seems to have a role in the regulation of addiction. This system is composed by the orexin receptors 1 and 2 (OX₁R and OX₂R), the ligands orexin A (OXA) and orexin B (OXB) and their respective enzymes for degradation or synthesis. Here, we explore how orexin receptors and orexin peptides are involved in addiction. For instance, OX₁R has been shown to be strongly involved in specific behaviors such as drug-seeking for stimulants, alcohol and other addiction problems, whereas OX₂R appears to be linked with arousal and stress responses. We also investigate how the orexinergic system may regulate drug-seeking behavior by interaction with other brain systems such as the dopaminergic, cannabinoid or opioid systems. Finally, the potential of receptor complexes as new therapeutic targets to treat drug addiction is explored.

Parkinson’s disease (PD) is a progressive neurological disorder that affects movement, causing symptoms such as tremors, stiffness, slowness, and balance problems due to the degeneration of dopamine-producing neurons in the brain. Nowadays there is no cure for PD. Alpha synuclein (α-syn) aggregates, which are a hallmark of PD, are known to induce microglial activation, specifically the detrimental M1 microglial phenotype, which contributes to neuroinflammation and disease progression. Cannabinoid receptor 2 (CB₂R) activation has been shown to counteract neuroinflammation. CB₂R is able to interact with N-methyl-D-aspartate (NMDA) receptors (NMDAR), which has also attracted attention in PD research due to its role in excitotoxicity. Here we aimed to study the interaction between CB₂R and NMDAR in a PD context in rat tissue. We observed that α-syn fibrils alter CB₂R activation and CB₂R-NMDAR heteromerization in a heterologous expression system. Furthermore, activation of CB₂R counteracted NMDAR signaling. In microglia, α-syn fibrils decreased CB₂R-NMDAR heteromer expression while increasing CB₂R signaling. Importantly, CB₂R activation counteracted the α-syn fibrils-induced increase in M1-activated microglia, while it favored the polarization of microglia to the beneficial M2 phenotype. These results reinforce the idea of using cannabinoids for treating PD, as they provide not only the anti-inflammatory effects of cannabinoids but also counteract the detrimental increase in NMDAR signaling present in this disease.

Parkinson’s disease (PD) is a progressive neurological disorder that affects movement, causing symptoms such as tremors, stiffness, slowness, and balance problems due to the degeneration of dopamine-producing neurons in the brain. Nowadays there is no cure for PD. Alpha synuclein (α-syn) aggregates, which are a hallmark of PD, are known to induce microglial activation, specifically the detrimental M1 microglial phenotype, which contributes to neuroinflammation and disease progression. Cannabinoid receptor 2 (CB ₂ R) activation has been shown to counteract neuroinflammation. CB2R is able to interact with NMDA receptors (NMDAR), which has also attracted attention in PD research due to its role in excitotoxicity. Here we aimed to study the interaction between CB ₂ R and NMDAR in a PD context. We observed that α-syn fibrils alter CB2R activation and CB ₂ R-NMDAR heteromerization in a heterologous expression system. Furthermore, activation of CB2R counteracted NMDAR signaling. In neurons α-syn fibrils decreased CB2R-NMDAR heteromer expression, while increasing CB ₂ R signaling. Importantly, CB ₂ R activation counteracted the α-syn fibrils-induced increase in M1 activated microglia, while it favored the polarization of microglia to the beneficial M2 phenotype. These results reinforce the idea of using cannabinoids for treating PD, as they provide not only the anti-inflammatory effects of cannabinoids but also counteract the detrimental increase in NMDAR signaling present in this disease.