Differential effect of amphetamine on c-fos expression in female aromatase knockout (ArKO) mice compared to wildtype
Carolina Chavez1, Andrea Gogos, Rachel Hill
1Behavioural Neuroscience Laboratory, Mental Health Research Institute of Victoria, Parkville, Melbourne, Australia.
Abstract:
Estrogen may be involved in psychosis by an interaction with central dopaminergic activity. Aromatase knockout mice are unable to produce estrogen and have been shown to display altered behavioural responses and effects of the dopamine releaser, amphetamine. This study investigates the effect of gonadal status on amphetamine-induced c-fos expression in the brains of female aromatase knockout and wildtype mice. Six groups of mice were treated intraperitoneally with saline or 5mg/kg amphetamine. Fos immunoreactivity was assessed in the cingulate cortex, caudate putamen and nucleus accumbens. Aromatase knockout mice showed markedly reduced amphetamine-induced Fos immunoreactivity compared to wildtype mice. However, the amphetamine response was restored in aromatase-knockout mice after ovariectomy, which reduced this effect in wildtype controls. Estrogen supplementation reversed the effect of ovariectomy in wildtype mice but had no additional significant effect in aromatase-knockout mice. These results indicate that mechanisms involved in amphetamine-induced c-fos expression are altered in aromatase knockout mice and that the primary hormone involved in this effect is not estrogen, but may be another factor released from the ovaries, such as an androgen. These results provide new insight into the effect of gonadal hormones on amphetamine induced c-fos expression in this mouse model of estrogen deficiency. These results could be important for our understanding of the role of sex steroid hormones in psychosis.
Insights
Aromatase knockout mice show reduced amphetamine responses, suggesting estrogen is not the primary factor. Ovariectomy restored responses in knockout mice, indicating ovarian factors influence amphetamine-induced brain activity.
Area of Science:
- Neuroendocrinology
- Psychopharmacology
Background:
- Estrogen's role in psychosis is linked to central dopaminergic activity.
- Aromatase knockout (ArKO) mice lack estrogen production and exhibit altered behavioral responses to amphetamine.
Purpose of the Study:
- To investigate the impact of gonadal status on amphetamine-induced c-fos expression in female ArKO and wildtype mice.
- To explore the role of estrogen versus other ovarian factors in modulating brain responses to amphetamine.
Main Methods:
- Female ArKO and wildtype mice were treated with saline or amphetamine (5mg/kg).
- Fos immunoreactivity, a marker of neuronal activation, was measured in the cingulate cortex, caudate putamen, and nucleus accumbens.
- Mice underwent ovariectomy and/or estrogen supplementation to manipulate gonadal hormone levels.
Main Results:
- ArKO mice displayed significantly lower amphetamine-induced Fos immunoreactivity than wildtype mice.
- Ovariectomy normalized amphetamine-induced Fos expression in ArKO mice but decreased it in wildtype mice.
- Estrogen supplementation reversed the ovariectomy effect in wildtype mice but had no additional impact on ArKO mice.
Conclusions:
- Amphetamine-induced c-fos expression mechanisms are altered in estrogen-deficient mice.
- Ovarian factors other than estrogen, potentially androgens, play a crucial role in modulating amphetamine responses.
- These findings offer insights into sex steroid hormone involvement in psychosis and drug-induced neuroactivity.
