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Biology of obsessive–compulsive disorder

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The biology of obsessive–compulsive disorder primarily involves the brain regions of the striatum, the orbitofrontal cortex and the cingulate cortex. People with OCD evince increased grey matter volumes in bilateral lenticular nuclei, extending to the caudate nuclei, while decreased grey matter volumes in bilateral dorsal medial frontal/anterior cingulate gyri. These findings contrast with those in people with other anxiety disorders, who evince decreased (rather than increased) grey matter volumes in bilateral lenticular / caudate nuclei, while also decreased grey matter volumes in bilateral dorsal medial frontal/anterior cingulate gyri. OCD involves several different receptors, mostly H2, M4, NK1, NMDA, and non-NMDA glutamate receptors. The receptors 5-HT1D, 5-HT2C, and the μ opioid receptor exert a secondary effect. The H2, M4, NK1, and non-NMDA glutamate receptors are active in the striatum, whereas the NMDA receptors are active in the cingulate cortex.

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Receptors

The activity of certain receptors is positively correlated to the severity of OCD, whereas the activity of certain other receptors is negatively correlated to the severity of OCD. Activity of the histamine receptor (H2); the Muscarinic acetylcholine receptor(M4); the Tachykinin receptor (NK1); and non-NMDA glutamate receptors are positively correlated with symptom severity in OCD. Associations for which activity is negatively correlated with severity include the NMDA receptor (NMDA); the Mu opioid receptor (μ opioid); and two types of 5-HT receptors (5-HT1D and 5-HT2C). The central dysfunction of OCD may involve the receptors nk1, non-NMDA glutamate receptors, and NMDA, whereas the other receptors could simply exert secondary modulatory effects.

Decreased binding potential of both D1 and D2 receptors in the dorsal striatum have been found suggesting decreased dopaminergic signaling, but the results are limited given current imaging technology and few studies. Increased DAT binding has also been found.

Estrogen and OCD

Aromatase is an enzyme expressed in several gonadic tissue sites. It is the rate limiting step in the conversion of androgens to estrogen. This conversion can significantly impact estrogen levels in brain areas. Low estrogen levels in turn lead to behavioral changes that have been displayed in obsessive compulsive disorder (OCD) in humans. These OCD-linked effects have been demonstrated by Aromatase knockout mice (ArKO), who lack a functional enzyme to convert androgens to estrogen. This ArKO knockout strategy has provided a model to examine the physiological impact of lower than normal amounts of estrogen.

Studies with ArKO mice have been used to show that varying levels of estrogen affect the onset of Obsessive Compulsive Disorder (OCD) behaviors. Interestingly enough, lower amounts of estrogen are associated with an increase of OCD behaviors in males more than females. Male ArKO mice increase repetitive behaviors such as wheel running and grooming, in comparison to normally developed mice. These repetitive and obsessive-like behaviors revert to typical levels with 17beta-estradiol replacement therapy, providing even more evidence that low levels of estrogen increases risk for OCD behaviors in males. Male ArKO mice also showed a decrease in levels of catechol-O-methyl transferase (COMT) protein. Low levels of COMT protein are associated with susceptibility to OCD, especially within human males. While a decrease in estrogen levels in males shows an increase in OCD behaviors, females show the opposite effect.

Variation in estrogen can lead to increased levels of OCD symptoms within women as well. The disorder itself has a later onset in women, and tends to show two distinct peaks of onset. The first peak occurs around puberty and the second around the age of childbearing. These peaks correlate with time periods where estrogen levels are highest in women. Studies within rats further investigated this correlation, finding that OCD behavior varied during the estrous cycle, being highest at late diestrus and proestrus when estrogen levels are highest, and lowest after estrogen has decreased. in addition, women with OCD have reported changes in the intensity and occurrences of their symptoms during their premenstrual and menstrual period, after pregnancy, and following menopause. Research found that the absence of estrogen in ArKO female mice decreased barbering (cleaning), wheel running, and grooming tendencies associated with OCD behavior. This correlates with other findings that increased levels of estrogen increase OCD behaviors in females.

Pharmaceuticals

Pharmaceuticals that may directly counteract the core mechanisms are aprepitant (nk1 antagonist), riluzole (glutamate release inhibitor), and tautomycin (NMDA receptor sensitizer). Also, the anti-Alzheimer's drug memantine is being studied by the International OCD Foundation in its efficacy in reducing OCD symptoms due to it being an NMDA antagonist. One case study published in The American Journal of Psychiatry suggests that "memantine may be an option for treatment-resistant OCD, but controlled studies are needed to substantiate this observation." The drugs that are popularly used to fight OCD may be limited by their inaction upon what are believed to be the core mechanisms. Many trials are currently underway to investigate the efficacy of a variety of agents that affect these 'core' neurotransmitters, particularly glutamatergic agents. Other genes and receptors under investigation for possible links to OCD include GABBR1, SLC1A1, GRIN2B, TPH2, DRD2, DRD3, DRD4, COMT, and MAO-A.

References

Biology of obsessive–compulsive disorder Wikipedia


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