Effects of Early Life Exposure to Sex Hormones on Neurochemical and Behavioral Responses to Psychostimulants in Adulthood: Implications in Drug Addiction.

Early life exposure to sex hormones affects several brain areas involved in regulating locomotor and motivation behaviors. Our group has shown that neonatal exposure to testosterone propionate (TP) or estradiol valerate (EV) affected the brain dopamine (DA) system in adulthood. Here, we studied the long-lasting effects of neonatal exposure to sex hormones on behavioral and neurochemical responses to amphetamine (AMPH) and methylphenidate (MPD). Our results show that AMPH-induced locomotor activity was higher in female than male control rats. The conditioned place preference (CPP) to AMPH was only observed in EV male rats. In EV female rats, AMPH did not increase locomotor activity, but MPD-induced CPP was observed in control, EV and TP female rats. Using in vivo brain microdialysis, we observed that AMPH-induced extracellular DA levels were lower in nucleus accumbens (NAcc) of EV and TP female rats than control rats. In addition, MPD did not increase NAcc extracellular DA levels in EV rats. Using in vivo fast-scan cyclic voltammetry in striatum, MPD-induced DA reuptake was higher in EV than control rats. In summary, our results show that early life exposure to sex hormones modulates mesolimbic and nigrostriatal DA neurons producing opposite neurochemical effects induced by psychostimulant drugs in NAcc or striatum.

Neonatal programming with sex hormones: Effect on expression of dopamine D1 receptor and neurotransmitters release in nucleus accumbens in adult male and female rats.

Steroid sex hormones produce physiological effects in reproductive and non-reproductive tissues, such as the brain. In the brain, sex hormones receptors are expressed in cortical, limbic and midbrain areas modulating memory, arousal, fear and motivation between other behaviors. One neurotransmitters system regulated by sex hormones is dopamine (DA), where during adulthood, sex hormones promote neurophysiological and behavioral effects on DA systems such as tuberoinfundibular (prolactin secretion), nigrostriatal (motor circuit regulation) and mesocorticolimbic (driving of motivated behavior). However, the long-term effects induced by neonatal exposure to sex hormones on DA release induced by D1 receptor activation and its expression in nucleus accumbens (NAcc) have not been fully studied. To answer this question, neurochemical, cellular and molecular techniques were used. The data show sex differences in NAcc DA extracellular levels induced by D1 receptor activation and protein content of this receptor in male and female control rats. In addition, neonatal programming with a single dose of TP increases the NAcc protein content of D1 receptors of adult male and female rats. Our results show new evidence related with sex differences that could explain the dependence to drug of abuse in males and females, which may be associated with increased reinforcing effects of drugs of abuse.