Cannabinoid receptors and dopamine neurons

Cannabinoid receptors and dopamine neurons

The endogenous cannabinoid system (ECS) consists of endogenous cannabinoids, cannabinoid receptors, cannabinoid ligands and several other enzymes and proteins that synthesize, transport and degrade them. At present, there are four kinds of endogenous cannabis substances found, including arachidonic acid ethanolamine (anandamide), 2-AG, nnoladin ether and virod- hamine.

Cannabinoid receptors include CB1 receptor and CB2 receptor; Cannabinoids exert various biological effects mainly through CB1 and CB2 pathways. It is found that cannabinoid receptors are involved in regulating the functional activities of dopamine neurons, and also play an important role in regulating the downstream signal pathway after dopamine receptor activation. Parkinson's disease (PD) is a common chronic neurodegenerative disease. The main pathological changes are the loss and death of dopaminergic neurons in the substantia nigra and striatum of the midbrain, and the presence of eosinophilic Lewy bodies in the cytoplasm of the remaining neurons. Cannabinoid CB1 and CB2 signal pathways in the central nervous system, the regulation of cannabinoid and its receptor on dopamine neuron function and the research on PD lesions can provide feasible ideas or strategies for drug design for cannabinoid receptor and the treatment of PD in the future.

Distribution of CB1 and CB2 receptors

Cannabinoid CB1 and CB2 are widely distributed in the central nervous system. CB1 mainly exists in the cortex, basal ganglia, hippocampus, cerebellum, striatum, amygdala, hypothalamus, periaqueductal gray of midbrain, spinal cord and other parts. In the study of cell localization, CB1 was observed in the globus pallidus of basal ganglia, the axon terminals and the anterior segment of axon terminals of putamen; The dorsal and ventral striatum contained medium-sized spinous neurons; The direct pathway axon from globus pallidus to substantia nigra. Parallel and ascending fibers in cerebellum, basket cells, motor neurons in anterior horn of spinal cord, sensory neurons in dorsal horn and microglia; CB1 was also found in glutamatergic neurons in the cortex and hippocampus.

CB2 is mainly distributed in the cerebral cortex, striatum, hippocampus, amygdala, brainstem, thalamus, substantia nigra, periaqueductal gray matter of midbrain, paratrochlear nucleus, lateral paralemma nucleus, red nucleus, pontine nucleus, medial vestibular nucleus, nucleus ambiguus, spinal trigeminal nucleus, etc. In the study of cell localization, CB2 was found in dopamine neurons in the ventral tegmental area of the midbrain, neurons in the dorsal motor nucleus of the vagus nerve, and microglia in the dorsal horn of the spinal cord. CB2 was found in cultured hippocampal pyramidal neurons, cerebral cortex microglia and astrocytes, and spinal dorsal horn microglia

Cannabinoid receptor and regulation of dopamine neurons

In the central nervous system, a variety of neurotransmitters and receptors often participate in the regulation of neuronal excitability and synaptic transmission efficiency through complex interactions. Dopamine is the most abundant catecholamine neurotransmitter in the brain. Cannabinoid acts on its receptor CB1 to affect dopamine neurons and the subsequent effects of dopamine receptor activation.

It can regulate the degradation of dopamine, synthesize tyrosine, and synthesize dopamine under the catalysis of tyrosine hydroxylase and dopa decarboxylase. Dopamine is degraded to dihydroxyphenylacetic acid by monoamine oxidase. Accelerated hydrolysis of dopamine; In PD mice with CB1 gene knockout, the contents of dopamine and dihydroxyphenylacetic acid in caudate nucleus decreased, and CB1 deletion promoted the hydrolysis of dopamine. Found in experiments with PD β- Caryophyllene can alleviate the loss of dopamine neuron fibers in substantia nigra and striatum. Cannabinoid CB1 and CB2 activation maintain the stability of dopamine content in substantia nigra, striatum and caudate nucleus, and play a certain protective role on dopamine neurons.

Endogenous cannabinoid system and Pd

Parkinson's disease (PD) is characterized by myotonia, tremor and bradykinesia, high-level cognitive dysfunction and fine language problems. It usually occurs due to the lack of dopamine formation caused by the apoptosis of dopaminergic neurons in the substantia nigra. Endogenous cannabinoid system plays an important role in the dopaminergic system, and they regulate each other. For example, CB1 receptors and d1/d2 like receptors in striatal neurons show complex interaction signals. The level of endogenous cannabinoid AEA in cerebrospinal fluid of patients with Parkinson's disease increased.

Changes of cannabinoid receptors and endogenous cannabinoids in Parkinson's disease model. It was found that in the primates treated with MPTP (1-methyl-4-phenyl-1,2,3,6-te-trahydropyridine, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, used to make animal Parkinson's disease models) and in the rats treated with 6-OHDA (6-hydroxy-dopamine, a hydroxylated derivative of catecholamine, used to induce animal Parkinson's disease), the binding of cannabinoid CB1 receptor and the level of CB1 mRNA increased.

ESC and Pd

Further studies found that ECs mainly existed in the indirect pathway in the basal ganglia loop. The AEA level was the highest in the reticular part of substantia nigra and the medial part of globus pallidus, and twice as high in the neostriatum and the lateral part of globus pallidus. The 2-AG level was evenly distributed in the whole basal ganglia region. These two main endogenous cannabinoids played different roles in the basal ganglia loop. PD experimental animals were treated with levodopa, and the ECS abnormality before treatment was reversed by levodopa.

Future and Outlook

CB1 and CB2 participate in the pathogenesis and progression of PD by regulating the functions of dopamine neurons and dopamine receptors. Their mechanism is to maintain the stability of dopamine content in neurons by regulating the degradation of dopamine; Regulate the release of dopamine, glutamate and GABA, interfere with the regulation of striatal efference and regulate the activity of dopamine neurons. Regulate cannabinoid receptors or design and develop drugs for CB1 and CB2 to provide an idea or strategy for the treatment of PD and neurology in the future.