Cannabinoids (marijuana…) Are Known To Inhibit Calcium Channels- Glutamate Release In Schizophrenia

I read with the interest article “What Is The Best Approach To Treating Schizophrenia In Developing Countries?” (19 Jun 2007). There I read; “how best to improve the care of the 25 million people living with schizophrenia in low and middle income countries…?”. I think that there can be also a “marijuana problem”, because it seems that cannabis use can precipitate schizophrenia in “vulnerable individuals”, especially.

It is generally accepted that the influx of Ca2+ as a result of excessive activation of the NMDA receptor underlies the toxic actions of glutamate in many systems. During periods of ischemia and in many neurodegenerative diseases, excessive stimulation of glutamate receptors is thought to occur. These neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease…, are caused by different mechanisms but may share a final common pathway to neuronal injury due to the overstimulation of glutamate receptors, especially of the NMDA subtype. On the other hand , recently, a hypofunction of glutamatergic neurons has been hypothesized to caused schizophrenia. Functional diversity of NMDA receptors may be expected from the assembly of different subunit combinations, and there is very important „Ca2+-dependent manner” which permits activation of NMDA receptors. So, also dietary calcium deficiency can be important about „NMDA hypofunction“ in schizophrenia…

However, there can be another example about hypoglutamatergic condition; cannabinoids are known to inhibit Ca2+ channels- glutamate release in schizophrenia. Cannabinoids are a group of terpenophenolic compounds present in Cannabis sativa L. Natural cannabinoids are only known to occur naturally in the cannabis plant. The chemical tetrahydrocannabinol (THC) found in marijuana is a cannabinoid, though different from the endogenous cannabinoids naturally produced in the bodies of animals. The broader definition of cannabinoids refer to a group of substances that are structurally related to THC or that bind to cannabinoid receptors. THC is the primary psychoactive component of the plant ,medically, it appears to ease moderate pain and to be neuroprotective. Endocannabinoids serve as intercellular 'lipid messengers', signaling molecules that are released from one cell and activate the cannabinoid receptors present on other nearby cells. So, cannabinoids are naturally occurring compounds in vertebrates, and are known to play an important role in intercellular signaling. In 1992, the first such compound was identified as arachidonoyl ethanolamide and named anandamide. It has a pharmacology similar to THC, although its chemical structure is different.

THC mediates the majority of its activities through stimulation of cannabinoid receptors (CB). Two cannabinoid receptors, CB1 and CB2, were discovered only the last ten years. CB1 exists primarily in the central nervous system, while CB2 is found primarily in the peripheral nervous system. Also, endogenous anandamide binds to both the central (CB1) and peripheral (CB2) cannabinoid receptors, and is found in nearly all tissues in a wide range of animals, it is about as potent as THC. Activation of CB1 receptor inhibits neurotransmitter release in many brain regions. CB1 receptors are essentially absent in the medulla oblongata, the part of the brain stem that is responsible for respiratory and cardiovascular functions. Thus, there is not a risk of respiratory or cardiovascular failure as there is with many other drugs. CB1 receptors appear to be responsible for the euphoric and anticonvulsive effects of cannabis.

Some studies suggest that cannabis is neither a sufficient nor necessary factor in developing schizophrenia, but that cannabis may significantly increase the risk of developing schizophrenia and may be, among other things, a significant causal factor. Nevertheless, some previous research in this area has been criticised as it has often not been clear whether cannabis use is a cause or effect of schizophrenia. The goal of this article is to show that cannabis use can be a cause of schizophrenia; characterize two effects on NMDA hypofunction, related to schizophrenia-associated neurodegenerative impairment. See also website http://www.bse-expert.cz , chapter; Hyperfunction (Alzheimer’s disease and Parkinson disease) and hypofunction (schizophrenia) of glutamatergic neurons;

1. Cannabinoids activity about NMDA glutamate receptor hypofunction; as a ´ schizophreniform effect;

In expression systems and cell bodies, CB1 receptor couples to activation of K+ channels or inhibition of neuronal Ca2+ channels, or both. Either of these mechanisms can reduce Ca2+ influx at nerve terminals and thereby inhibit transmitter release. Activation of K+ channels may change the presynaptic action potential and thus indirectly modulate Ca2+ channel activity. So, communication between the cells requires the release of a glutamate neurotransmitter, triggered by calcium currents passing through a specific Ca2+ channel. Cannabinoids are known to inhibit Ca2+ channels. If we shut down the channel, we shut down the release of glutamate, and profoundly alter the cell's ability to signal.
2. Cannabinoids can regulate NMDA glutamate receptor by reducing intracellular Ca2+ release ; as a neuroprotective effect;
There is evidence that cannabinoids can regulate glutamate release, oxidant free radicals and calcium influxes, which, in excess, can cause neuronal death. Cannabinoids can tonically regulate NMDA glutamate receptor activity in vitro and support the in vivo observation that CB1 regulates NMDA-induced and ischaemic excitotoxicity. Exogenously administered cannabinoids are neuroprotective in several different cellular and animal models. Cannabinoids produce neuroprotection by reducing intracellular Ca2+ release. Emerging evidence indicates that cannabinoids may play a role in slowing the progression of certain neurodegenerative diseases, such as Multiple Sclerosis, Parkinson's disease, Alzheimer's, and Amyotrophic Lateral Sclerosis.

Read the news article that this opinion was posted about:
The Best Approach For Treating Schizophrenia In Developing Countries

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