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Line of research could advance schizophrenia Tx.

NEW YORK -- Overexpression of cannabinoid receptors and hyperactivity of the brain's endogenous endocannabinoid system may be responsible for the delusions and aberrant associations characteristic of schizophrenia, Steven Laviolette, Ph.D., said at the annual meeting of the National Alliance for Research on Schizophrenia and Depression.

The endocannabinoid system, which is acted upon by use of marijuana (Cannabis sativa), is a naturally occurring receptor system within the brain that has become the subject of considerable research in recent years. It is responsible for the processing of the emotional salience connected with direct sensory perceptions. In other words, it is the brain system responsible for assigning and evaluating the emotional significance of what we perceive.

Current research indicates that people with schizophrenia show significant differences in the expression and activity of the endocannabinoid system, said Dr. Laviolette, of the department of anatomy and cell biology, Schulich School of Medicine, University of Western Ontario, London.

"The delusions, psychotic ideation, and distorted associations of schizophrenia are related to aberrant emotional processing of sensory inputs," he said. "Our evidence suggests that a dysregulated cannabinoid system may be involved in the emotional processing disturbances observed in schizophrenia. Increased cannabinoid levels in schizophrenia may pathologically amplify the emotional significance of sensory stimuli, similar to the effect of heavy marijuana exposure."

Emotional salience is the province of the prefrontal cortex, the amygdala, and in particular, the cingulate gyrus. All of these brain regions are normally rich in endocannabinoid receptors. But people with schizophrenia show markedly increased expression of these receptors in the cingulate gyrus, compared with controls who do not have schizophrenia.

The available data suggest that a hyperactive cannabinoid system may be one of the core neurologic abnormalities underlying schizophrenia. Endocannabinoid hyperactivity causes the person to perceive intense emotional significance from an ordinary external signal that would carry no such meaning for an individual with normal endocannabinoid expression.

Thus, an individual with schizophrenia may believe that an ordinary television news broadcast is a message from a demon directed personally at him, said Dr. Laviolette by way of example.

This line of research is interesting, given what is known about the impact of marijuana use on individuals at risk for schizophrenia and schizotypal disorders. "Abuse of marijuana early on in life is associated with higher rates of schizophrenia in males, and it is also linked to increased numbers of psychotic episodes in patients with schizophrenia."

Dr. Laviolette stressed that these findings should not be misconstrued to mean that cannabis smoking causes schizophrenia; the link may not, in fact, be causal. But the data do suggest that for someone with an already overactive endocannabinoid system and a predisposition for developing schizophrenia, abuse of the drug only adds fuel to the fire and may be a triggering factor for frank psychosis.

Research into endocannabinoid function is also opening up new possibilities for treatment of schizophrenia using agents that block cannabinoid signaling. Work in this direction is still at the earliest stages, but it represents an entirely new direction in drug development.

Dr. Laviolette and his colleagues are experimenting with two drugs, one known as WIN-55, which is a cannabinoid receptor activator, and the other called AM-251, which blocks cannabinoid signals. Using rodent models and newly developed techniques for placing microelectrodes on single endocannabinoid neurons to monitor their activity, they have been able to track the intensity with which the animals respond to mild foot shocks paired with olfactory cues.

The experiment involves a basic Pavlovian conditioning process, in which the animals are pretrained to expect a foot shock when they smell mint oil. The investigators also use control scents, not paired with the shocks. The implanted microelectrodes allow the researchers to track neural responses to the olfactory cues in the absence of any shock.

When treated with WIN-55, the cannabinoid receptor activator, the rats show a dramatic potentiation and amplification of cannabinoid neuronal activity when they are exposed to the mint oil. In contrast, treatment with AM-251 markedly downregulated the animals' response to the external olfactory cue.

This is obviously a far cry from a clinical trial in human subjects, but the findings do suggest that various substances like these two experimental drugs can significantly amplify or attenuate emotional responsiveness at the neuronal level.

"This really gives us another neurobiological system to target our treatment, in the hope of helping to deal with the emotional processing problems of schizophrenia," said Dr. Jeffrey Lieberman, chairman of psychiatry, Columbia University, New York, commenting on Dr. Laviolette's presentation. "We've heard a lot about the cognitive problems in schizophrenia. Now we can look at emotional perception and emotional salience, which is relevant for social cognition. And this is related to endocannabinoid neurosignaling."

The closest thing to a clinical trial in this context was a preliminary experiment with rimonabant (Acomplia), a synthetic cannabinoid drug recently introduced for modulation of appetite and treatment of obesity. When given to people with schizophrenia, it had no effect on psychotic symptom profiles, but this should not give cause for abandoning this general line of investigation; many different substances can interact with the endocannabinoid system.

The widespread distribution of endocannabinoid receptors throughout the brain begs the question of what, if not marijuana, is supposed to bind to them. Dr. Laviolette explained that there are several naturally occurring endocannabinoids, the most common being a substance called anandamide. "It is interesting that we can measure increased levels of anandamide in first-episode, nontreated schizophrenia patients." Researchers are only at the beginning stages of learning about anandamide and other related substances. In addition to mediating emotional salience, the endocannabinoid system is also involved in regulating memory.

The subject of endocannabinoid neurobiology has generated much excitement worldwide but less in the United States. Dr. Laviolette attributes this to the "reefer madness mentality" that is still prevalent among policy makers and researchers in this country. "It becomes a morality issue, rather than a scientific one. Cannabinoid research is, unfortunately, still quite controversial in the U.S."


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Title Annotation:Adult Psychiatry
Author:Goldman, Erik L.
Publication:Clinical Psychiatry News
Geographic Code:1USA
Date:Feb 1, 2007
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