Endogenous cannabis system and schizophrenia
Schizophrenia is a chronic brain disease, with a serious destructive, incidence rate of about 1%, mostly in late adolescence and early adulthood. The main manifestations of schizophrenia are abnormal psychological function and disordered behavior, which can be divided into three categories: (1) positive symptoms, mainly including hallucinations, delusions, memory disorders, movement disorders, etc; (2) Negative symptoms, mainly including social avoidance, decreased initiative, wrong judgment, problem-solving obstacles, etc; (3) Cognitive symptoms, which are the core symptoms of schizophrenia, mainly involve attention, learning, memory and executive dysfunction. Several hypotheses have been developed, such as the neurodevelopmental hypothesis, dopamine and NMDA neurotransmitters. The researchers proposed the research on endogenous cannabis in schizophrenia. The pathogenesis of schizophrenia is related to the endogenous cannabis system, especially the over activation of CB1 receptor.
Endogenous cannabis system.
The endogenous cannabis system is composed of cannabis receptors, endogenous cannabinoids and cannabinoid degrading enzymes, which regulate many important functions of the human body, such as cognition, emotion, sleep, pain, motivation and so on. In addition, it has effects on exercise control, cardiovascular regulation, endocrine activity, energy metabolism, immune response, etc. The endogenous cannabis system exists in the neural circuit of stress response. It is an endogenous neuroprotective system. It is activated under some neuropathological conditions and plays a role in homeostasis.
Cannabis receptors CB1 and CB2 belong to the G-protein coupled receptors (GPCRs) family. CB1 receptor is mainly distributed in the central system, with high concentration in sensory and motor control areas such as basal ganglia, hippocampus, globus pallidus, substantia nigra and cerebellum. It plays an important role in motivation and cognition. These regions are closely related to the pathogenesis of schizophrenia. CB1 receptors mainly exist in the presynaptic of central and peripheral neurons and inhibit the release of other neurotransmitters, which is also a major role of the endogenous cannabis system. The number of CB1 receptors in the brain increases gradually from birth to adulthood.
CB2 receptors are mainly distributed in peripheral immune cells. Studies have found that CB2 receptors also exist in the brain stem and cerebellum. CB2 receptors exist in the cerebral cortex, striatum, hippocampus, amygdala and hypothalamus. CB2 receptors play a role in emotional and cognitive functions.
Signal transduction of CB1 receptor
CB1 receptor is responsible for the signal transduction of endocannabinoids in the brain. AEA and 2-AG are released from the presynaptic cell membrane. CB1 receptor is activated by diffusion and binding with presynaptic CB1 receptor. The signal of CB1 receptor is mainly transmitted to the cell through its coupled k+ sensitive gi/o protein. The CB1 receptor activated by this protein inhibits the activity of adenylate cyclase, reduces the production of adenosine monophosphate, and weakens the activity of kinase A, Open k+ channel, increase k+ outflow, weaken neuronal discharge and pulse conduction, block ca2+ influx, and cut off the necessary channel for neurotransmitter release at presynaptic sites. CB1 receptor signal transduction regulated by endogenous cannabinoid affects the activities of a variety of neurotransmitters.
CB1 receptor and schizophrenia
Animal experiments have found that CB1 receptor plays an important role in schizophrenia. When mice use the N-methyl-D-aspartic acid receptor (NMDA) receptor antagonist phency clidine (PCP), they will produce schizophrenia like symptoms, such as increased exercise, stereotyped behavior, decreased social activities, etc. These symptoms were not observed in CB1 receptor gene knockout (cb1ko) mice. Experimental comparison showed that cb1ko mice had the symptoms of decreased movement and ataxia. CB1 receptor gene knockout changed the behavior caused by PCP, and CB1 receptor played an important role in the pathological mechanism of schizophrenia.
The density of PCP and CB1 receptors in amygdala and ventral dorsal tegmental area increased, which was reflected in brain areas closely related to schizophrenia. The density of CB1 receptors changed, CB1 receptors decreased in prefrontal cortex, hippocampus, basal ganglia and cerebellum, and increased in globus pallidus.
The pathology and mechanism of schizophrenia γ- Many neurotransmitters such as aminobutyric acid, dopamine, 5-hydroxytryptamine and glutamic acid have complex effects. CB1 receptor can directly or indirectly regulate many neurotransmitters. After CB1 receptor is activated, the channel is opened to stimulate dopamine outflow from the striatum, and dopamine is released from the midbrain margin, medial prefrontal cortex, midbrain region and substantia nigra. The positive symptoms of schizophrenia are related to the increased release of dopamine (especially dopamine released from the midbrain margin region).
Cannabinoid decreased the release of acetylcholine in the medial prefrontal cortex, hippocampus and striatum, while CB1 receptor antagonist increased the concentration of acetylcholine in these areas. The activities of norepinephrine in hippocampus, cerebellum, hypothalamus and cerebral cortex were inhibited as CB1 receptor agonists, CB1 receptor antagonists attenuated the inhibition, and cannabinoid inhibited the activities of norepinephrine in hypothalamus and striatum. Endocannabinoids act on CB1 receptors at the axonal terminals of GABAergic and glutamatergic neurons, activating the downstream of gi/o protein intramolecular signals, resulting in the short-term or long-term inhibition of the release of neurotransmitters in the vesicles. This method has an effect in the brain stem, midbrain, striatum, hippocampus, cerebellum, amygdala and other parts.
Study on different genes of CB1 receptor. The polymorphism of CB1 receptor gene has a certain relationship with schizophrenia. The variation of this gene leads to different phenotypes of schizophrenia. In the study of AAT repeat polymorphism of CB1 receptor gene, it was found that the AAT repeat polymorphism of CB1 receptor gene was significantly associated with schizophrenia. Other studies on CB1 receptor genotyping did not find such an important link. It is found that drug sensitive patients have lower levels of allele g than insensitive patients, and CB1 receptor genotyping has nothing to do with susceptibility to disease, which provides a new direction for research.
CB2 receptors mainly act in the peripheral nervous system, but the central system has no significant function. More and more studies on CB2 have found that CB2 receptors are widely distributed in the central system and play a role in the neurobiological mechanism of schizophrenia. By comparing the levels of AEA in the blood of schizophrenic patients and healthy volunteers, it was found that the remission of schizophrenic symptoms was accompanied by the decrease of the mRNA level encoding CB2 receptor in peripheral blood monocytes, and CB2 receptor played a role in mental diseases.
Endocannabinoids and schizophrenia
Cannabis receptor is related to schizophrenia, and the level of endogenous cannabinoid in schizophrenic patients has significant changes. The study found that the AEA level in the blood of schizophrenic patients was higher than that of healthy people, and the remission of their clinical symptoms was accompanied by a significant decline in the AEA level, which showed that in severe schizophrenia, the AEA endogenous cannabinoid signal changed in the central system and in the blood.
The study found that AEA increased in the cerebrospinal fluid of patients with acute schizophrenia, and increased in the cerebrospinal fluid of early patients without drug treatment. The change of AEA level in cerebrospinal fluid was negatively correlated with symptoms. The increase of AEA level was due to the self-regulation of the central system and played a role of self-protection. Studies have found that cannabidiol (CBD), a cannabidiol receptor antagonist, inhibits the degradation of AEA, and the improvement of patients' clinical condition is related to the increase of serum AEA level. It is further found that AEA plays a protective role in the pathological mechanism of schizophrenia.
CB1 receptor antagonists and schizophrenia
In the process of optimizing small molecule antihistamines, researchers synthesized clozapine to become a representative atypical drug. Clozapine can better control emotions and reduce extravertebral reactions. There are many deficiencies in clozapine, such as the improvement of cognitive impairment is still unsatisfactory, and it can not produce sufficient treatment effect for many patients. The side effects of existing drugs damage the health of patients and reduce the quality of life, We need to find new drugs or combination drugs.
Studies have found that CB1 receptor antagonists have become a hot topic, and CB1 receptor has become a new anti schizophrenia drug. CBD is one of the main components of cannabis plant. CBD is an antagonist of CB1 receptor, which inhibits the reabsorption and degradation of AEA, and has neuroprotective and antioxidant effects.
Studies have found that CBD plays a role in combating schizophrenia. In the experiments of dopamine and glutamate basic schizophrenia animal models, CBD has a significant role in combating schizophrenia. CBD alleviates the excitatory movement induced by NMDA receptor antagonist ketamine in rats using D-2 receptor agonists, reverses the pre pulse inhibition induced by NMDA receptor antagonist MK-801, and CBD antagonizes Δ 9-THC induced psychotic effects, reducing psychotic symptoms in patients with ketamine or Parkinson's disease.
Cannabis receptor CB1 and CB2 receptors play an important role in the pathological mechanism of schizophrenia and become a new treatment direction for the treatment of schizophrenia. Endogenous cannabinoids play a protective role in the pathological mechanism of schizophrenia. The exact role of endogenous cannabis system in the pathophysiology of schizophrenia is still unknown, and more research is needed. Cannabis receptors are widely distributed in the human body. It is a new way and direction for the development of cannabis drugs to activate or antagonize cannabis receptors for therapeutic purposes
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