Changes in brain volume in response to estradiol levels, amphetamine sensitization and haloperidol treatment in awake female rats.

Estrogen has been shown to further ameliorate symptoms when administered in conjunction with antipsychotics in patients with schizophrenia. We have previously shown that chronic haloperidol (HAL) treatment reduces amphetamine (AMPH)-induced locomotor activity in AMPH-sensitized rats, but only when paired with high levels of the estrogen, 17-β estradiol. In addition, we reported estradiol-dependent responses to AMPH in AMPH-sensitized rats as measured by functional magnetic resonance imaging. It is thus clear that estradiol and antipsychotics both affect the rat brain, however the mechanism by which this occurs is unknown. The aim of the current study was to assess this interaction by investigating the effects of estradiol, AMPH and HAL on brain volume changes in awake female rats. Repeated exposure to AMPH resulted in an overall reduction in brain volume, regardless of hormonal status (i.e. no, low or high estradiol). Similarly, chronic HAL treatment further reduced brain volume compared to acute treatment. Hormonal status affected hippocampal volume with rats receiving low estradiol replacement showing larger volume; this difference was no longer significant after repeated exposure to AMPH. Finally, we found changes in volume in response to AMPH throughout hippocampal components (i.e. CA1-CA3 and dentate) as well as components of the mesocortical system. In conclusion, brain volume seems to be influenced by hormonal status, as well as exposure to AMPH and haloperidol treatment. These findings implicate areas where estradiol, amphetamine and antipsychotics may be producing volumetric changes in the brain, pointing the way to where future studies should focus.