Elsevier

Biological Psychiatry

Volume 61, Issue 3, 1 February 2007, Pages 359-366
Biological Psychiatry

Original article
Estrogen Deficient Male Mice Develop Compulsive Behavior

https://doi.org/10.1016/j.biopsych.2006.01.012Get rights and content

Background

Aromatase converts androgen to estrogen. Thus, the aromatase knockout (ArKO) mouse is estrogen deficient. We investigated the compulsive behaviors of these animals and the protein levels of catechol–O–methyltransferase (COMT) in frontal cortex, hypothalamus and liver.

Methods

Grooming was analyzed during the 20-min period immediately following a water-mist spray. Running wheel activity over two consecutive nights and barbering were analyzed. COMT protein levels were measured by Western analysis.

Results

Six-month old male but not female ArKO mice develop compulsive behaviors such as excessive barbering, grooming and wheel-running. Excessive activities were reversed by 3 weeks of 17β-estradiol replacement. Interestingly, the presentation of compulsive behaviors is accompanied by concomitant decreases (p < .05) in hypothalamic COMT protein levels in male ArKO mice. These values returned to normal upon 17β-estradiol treatment. In contrast, hepatic and frontal cortex COMT levels were not affected by the estrogen status, indicating region- and tissue-specific regulation of COMT levels by estrogen. No differences in COMT levels were detectable between female animals of both genotypes.

Conclusions

This study describes the novel observation of a possible link between estrogen, COMT and development of compulsive behaviors in male animals which may have therapeutic implications in obsessive compulsive disorder (OCD) patients.

Section snippets

Animals

ArKO mice (C57B6J X J129) were generated by disruption of the Cyp19 gene. Homologous null or wild type (WT) offspring were bred by crossing heterozygous ArKO, and genotyped by PCR. Animals were housed under SPF and environmentally enriched conditions and had ad libitum access to water and soy free mouse chow (Glen Forrest Stockfeeders, Glen Forrest, Western Australia, Australia). Mice were killed by cervical dislocation, the brains removed and dissected in RNAlater™ (Ambion Inc, Austin, Texas)

Ambulatory and Wheel-Running Activities

The ambulatory study was completed prior to the commencement of the running wheel study. Male ArKO mice display significant (p < .05) increases in wheel-running activity when compared to WT controls (Figure 1A). This excessive running wheel activity was suppressed upon 17β-estradiol replacement (Figure 1A). In contrast, general ambulatory activity was significantly decreased (p < .05) in the male ArKO compared to WT (Figure 1B), indicating a wheel-running specific increase in activity in male

Discussion

The present study demonstrates that the absence of estrogen in adult male mice leads to excessive barbering, wheel-running and grooming activities, paralleled by a significant decrease in COMT protein expression in the hypothalamus. By contrast, we have not noticed stereotypy behaviors (such as barmouthing, jumping, somersaulting or route-tracing) in our ArKO colony during the behavior studies, day-to-day handling of the animals or after performing an observation analysis on our animals (first

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