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Cannabinoids and Schizophrenia: A Compensation Issue?

13 August 2008. Epidemiological studies suggest cannabis use is both a risk factor for developing schizophrenia and is associated with worse symptoms and cognitive impairment in people with the disease, but the exact nature of the link between cannabis use and schizophrenia is not known (see SRF related news story). A new paper from Stephen Eggan, Takanori Hashimoto, and David Lewis at the University of Pittsburgh in Pennsylvania presents evidence for a biochemical link, showing that people with schizophrenia have lower levels of a major receptor for cannabinoids. The data, published in the July issue of the Archives of General Psychiatry, suggests that downregulation of the cannabinoid pathway could be a compensatory response to changes in GABAergic neurotransmission in the prefrontal cortex in schizophrenia. These same GABAergic aberrations may underlie the cognitive deficits seen in schizophrenia. Thus, the results could help shed light on the links between cannabis use and schizophrenia, and at the same time offer new targets for drug development aimed specifically at the cognitive aspects of the disease.

Though a cause-and-effect relationship has not been established between cannabis use and schizophrenia, it is known that long-term cannabis use in otherwise healthy people can affect working memory in a way that resembles the deficits seen in schizophrenia. In schizophrenia, Lewis and colleagues have suggested that these defects may be associated with reductions in GABA neurotransmission in the dorsolateral prefrontal cortex (for recent review, see Lewis and Gonzalez-Burgos, 2008). In that region, the cannabinoid receptor CB1R is found in a subpopulation of GABAergic, cholecystokinin-positive interneurons (distinct from the more well-known parvalbumin-containing GABA cells that Lewis's group also studies; see interview with Lewis), and functions to suppress GABA release. From this, Lewis and colleagues hypothesized that the CB1R in the prefrontal cortex might be altered in schizophrenia.

To test that idea, the investigators used in situ hybridization, and immunohistochemistry to look at CB1R mRNA and protein levels in postmortem brain tissue from 23 people with schizophrenia and 23 age-matched controls. They found that in the tissue from people with schizophrenia, both CB1R mRNA and protein showed a normal laminar distribution, but amounts were reduced. CB1R mRNA was down by 15 percent; protein was reduced by 12 percent, and both reductions were statistically significant. The CB1R protein was mainly detected in axons and synaptic terminals, and in subjects with schizophrenia, the density of CB1R-containing axons was reduced.

The reduction in CB1R correlated with reduction in markers of GABAergic neurotransmission in the same region. The subjects showed a significant within-pair correlation between differences in CB1R and the mRNA for GABA-synthesizing enzyme glutamic acid decarboxylase (GAD-67), and cholecystokinin, a neuropeptide that among its other actions appears to regulate the synthesis of endogenous cannabinoids. Because CB1R stimulation inhibits GABA release from CB1R and CCK-containing neurons, the authors suggest that the downregulation of CB1R could be a compensatory response to impaired GABA neurotransmission in the region.

Could the changes in CB1R stem from the use of antipsychotic medications, or even cannabis? Apparently not, the data suggest, as the results did not differ when adjusted for sex, diagnosis, or use of various medications. To directly test that idea that medications might affect CB1R levels, the investigators treated macaque monkeys for 17-27 months with haloperidol or olanzapine or placebo, and then looked at CB1R in the animals’ brain tissue. The distribution of CB1R in brain matched the human pattern, and the investigators found no effect of the medications on receptor mRNA levels.

The reduction of CB1R receptors did not seem to occur in response to cannabis use or dependence in the patients. In fact, the data show that mean CB1R mRNA and protein levels were higher in the subset of subjects with schizophrenia who also had a substance use disorder or a history of cannabis use, though not significantly so. This suggests that “these factors might have blunted the decreases in CB1R mRNA and protein levels in schizophrenia,” the authors write.

The results raise the possibility that decreased CB1R in the dorsolateral prefrontal cortex there could reflect the brain’s attempt to normalize cognitive function in the face of a GABA deficit. “This interpretation implies that cannabis use in vulnerable individuals would counteract these compensatory responses, providing a potential mechanism linking cannabis exposure with an increased risk for the cognitive impairments of schizophrenia,” the authors write. In addition to providing a testable hypothesis, they write, the findings suggest novel targets for treating cognitive impairment, including CB1R antagonists.—Pat McCaffrey.

Eggan SM, Hashimoto T, Lewis DA. Reduced cortical cannabinoid 1 receptor messenger RNA and protein expression in schizophrenia. Arch Gen Psychiatry. 2008 Jul;65(7):772-84. Abstract

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