Programming of Dopaminergic Neurons by Neonatal Sex Hormone Exposure: Effects on Dopamine Content and Tyrosine Hydroxylase Expression in Adult Male Rats

Abstract

We sought to determine the long-term changes produced by neonatal sex hormone administration on the functioning of midbrain dopaminergic neurons in adult male rats. Sprague-Dawley rats were injected subcutaneously at postnatal day 1 and were assigned to the following experimental groups: TP (testosterone propionate of 1.0 mg/50 μL); DHT (dihydrotestosterone of 1.0 mg/50 μL); EV (estradiol valerate of 0.1 mg/50 μL); and control (sesame oil of 50 μL). At postnatal day 60, neurochemical studies were performed to determine dopamine content in substantia nigra-ventral tegmental area and dopamine release in nucleus accumbens. Molecular (mRNA expression of tyrosine hydroxylase) and cellular (tyrosine hydroxylase immunoreactivity) studies were also performed. We found increased dopamine content in substantia nigra-ventral tegmental area of TP and EV rats, in addition to increased dopamine release in nucleus accumbens. However, neonatal exposure to DHT, a nonaromatizable androgen, did not affect midbrain dopaminergic neurons. Correspondingly, compared to control rats, levels of tyrosine hydroxylase mRNA and protein were significantly increased in TP and EV rats but not in DHT rats, as determined by qPCR and immunohistochemistry, respectively. Our results suggest an estrogenic mechanism involving increased tyrosine hydroxylase expression, either by direct estrogenic action or by aromatization of testosterone to estradiol in substantia nigra-ventral tegmental area.

Neonatal exposure to oestradiol increases dopaminergic transmission in nucleus accumbens and morphine‐induced conditioned place preference in adult female rats

“…Sex hormones can influence different brain functions such as cognition, motor regulation and rewarding behaviour, and modulate the release and content of neurotransmitters . We have recently shown that the neonatal administration of EV and testosterone propionate (TP) in male rats produces an increase in the content and release of DA in SN‐VTA and NAcc, respectively . These effects on dopaminergic neurones could be produced by an oestrogenic action (EV or by the partial aromatisation of TP to E 2 ) because neonatal exposition to dihydrotestosterone (a non‐aromatisable androgen) did not change TH expression, DA content or DA release .…”

“…In summary, the results of the present study show that neonatal programming by EV modulates the dopaminergic neurotransmitter system and enhances morphine‐induced conditioning. We have shown that neonatal programming with sex hormones (EV and TP) affects long‐term mesolimbic and nigrostriatal pathways . In humans, it has been recently demonstrated that prenatal exposure to androgens correlates with an increased dependence on alcohol in adult life .…”

“…NAcc were microdissected at 4°C using a micro‐punch (Harris Micro‐Punch, diameter 2.0 mm; Ted Pella Inc., Redding, CA, USA). NAcc were weighed on analytical balance (model JK‐180; Chyo Balance Corp, Tokyo, Japan) and homogenisated as described previously . Briefly, the tissue was collected in 400 μL of 0.2 mol L ‐1 perchloric acid and then homogenised in a sonicator (model XL2005; Microson Ultrasonic Cell Disruptor; Heat Systems, Newtown, USA).…”

Sex Hormones: Role in Neurodegenerative Diseases and Addiction

“…In addition, when male rats are exposed to estradiol or testosterone, DA levels and TH expression are increased in substantia nigra-ventral tegmental in addition to increased dopamine release in nucleus accumbens. This effect is not seen when rats are exposed to a nonaromatizable androgen, dihydrotestosterone, suggesting an estrogenic mechanism involving increased TH expression, either by direct estrogenic action or by aromatization of testosterone to estradiol in substantia nigra-ventral tegmental area [10].…”

“…Using the same model of neonatal administration of estradiol valerate [7], it observed an increase in dopamine (DA) and noradrenaline content in dopaminergic neurons of tuberoinfundibular [8], nigrostriatal, and mesolimbic pathways [9] of the adult. Indeed, neonatal administration of estradiol valerate and testosterone propionate increases DA content and tyrosine hydroxylase (TH), (rate limiting enzyme of dopamine synthesis) expression in substantia nigra (SN), and ventral tegmental area (VTA) of adult male rats [10]. Others works have shown that neonatal administration of testosterone reduces spatial memory and TH positive terminals in prefrontal cortex in an animal model of attention deficit disorder with hyperactivity [11].…”