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<p>Sex differences in drug addiction are mediated in part by effects of the ovarian
hormone estradiol (E2) within the ascending dopamine (DA) system from the midbrain
to the striatum. Estradiol enhances the effects of psychostimulants, but the exact
underlying mechanisms are unknown. Mice could serve as an ideal genetically-tractable
model for mechanistic studies into sex and hormone effects within the DA system but
have been under-utilized. This study sought to: 1) characterize psychostimulant-induced
behavior in mice as an indirect but quantifiable measure of DA neurotransmission,
and 2) elucidate the mechanism underlying E2's enhancement of psychostimulant effects
in females using surgical, pharmacological, and genetic manipulations. The spontaneous
behavior of mice during habituation to a novel environment and after the psychostimulants
d-amphetamine (AMPH; 1, 2.5, and/or 5 mg/kg) and cocaine (COC; 5, 15, and/or 30 mg/kg)
were assessed in open field chambers using both automated photobeam interruptions
and behavioral observations. Behaviors were assessed in the following groups of mice:
intact males and females; ovariectomized mice replaced with either E2 for 2 days or
30 minutes or with estrogen receptor-selective agonists; and female mice lacking either
ERα (αERKO) or ERβ (βERKO) versus wildtype (WT) littermates.
Brain psychostimulant concentrations and tissue content of DA and its metabolites
were determined at the time of maximum behavioral stimulation. Psychostimulants induced
behavioral activation in mice including both increased locomotion as detected with
an automated system and a sequence of behaviors progressing from stereotyped sniffing
at low doses to patterned locomotion and rearing at high doses. Intact female mice
exhibited more patterned locomotion and a shift towards higher behavior scores after
psychostimulants despite having lower AMPH and equivalent COC brain levels as males.
Actively ovariectomized mice exhibited fewer ambulations and lower behavior scores
during habituation and after psychostimulants than Sham females. Two days but not
30 minutes of E2 replacement restored COC-induced behavioral responses to Sham levels.
ERα-selective PPT replacement in ovariectomized mice and genetic ablation of
ERα in αERKO mice altered COC-stimulated behavior. Immunohistochemistry
revealed that midbrain DA neurons in mice express ERβ but not ERα, and
that non-DA cells in the midbrain and the striatum express ERα. These results
indicate that E2 enhances COC-stimulated locomotion in mice through an indirect effect
of ERα. ERα may alter behavior through presynaptic effects on DA neuron
activity and/or through postsynaptic effects on transcription and signal transduction
pathways within striatal neurons.</p>
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