Programming of Dopaminergic Neurons by Early Exposure to Sex Hormones: Effects on Morphine-Induced Accumbens Dopamine Release, Reward, and Locomotor Behavior in Male and Female Rats

Abstract

Neonatal programming with sex hormones produces long-term functional changes in various tissues, including the brain. Previously, we demonstrated a higher content of dopamine and an increase in potassium-induced dopamine release in the nucleus accumbens of adult rats exposed to estradiol valerate. On the other hand, sex hormones also affect the opioid system increasing the expression of the μ opioid receptor and β-endorphins. Here, we investigated if neonatal programming with sex hormones alters the response to morphine during adulthood in rats and predispose them to neurochemical, rewarding and behavioral activating effects. We examined the effects of neonatal exposure to a single dose of estradiol valerate or testosterone propionate on morphine-induced (5 mg/kg, i.v.) dopamine release in the nucleus accumbens and morphine-induced (3 mg/kg, s.c.) locomotor activity and conditioned place preference when these rats were adults. Our results showed a significant increase in morphine-induced dopamine release in the nucleus accumbens of rats that were exposed neonatally to estradiol compared with control rats. This effect was correlated with higher place preference and locomotor activity induced by morphine in adult rats neonatally exposed to estradiol valerate. However, the effect of morphine on dopamine release and behaviors was similar in rats treated with testosterone compared to control rats. Additionally, the expression of mu (μ) opioid receptor, dopamine receptor type 1 (D 1 ) and dopamine receptor type 2 (D 2 ) in the nucleus accumbens of adult rats was not different after treatment with sex hormones. Taken together, our results demonstrated an enhancement of pharmacological effects produced by morphine in rats neonatally programmed with estradiol valerate, suggesting that early exposure to sex hormones could represent a vulnerability factor in the development of addiction to opioid drugs such as morphine and heroin in adulthood.

No basal or drug‐induced sex differences in striatal dopaminergic levels: a cluster and meta‐analysis of rat microdialysis studies

“…Alterations in striatal dopamine levels of female rats (n = 81) were measured for 5, 20 and 30 mg/kg of acute morphine injections (Maisonneuve, et al, 1991;Pearl, et al, 1996;Maisonneuve and Glick, 1999;Szumlinski, et al, 2000a;Steinmiller, et al, 2003;Velasquez, et al, 2019). Morphine at doses of 5 and 20 mg/kg increases dopamine levels in both regions nucleus accumbens (5 mg/kg: 194.29 AE 17.5%, 20 mg/kg: 212.5 AE 37.5%) and caudate putamen (5 mg/ kg: 160.0 AE 15.27%) with no significant differences between the regions (F 1,7 = 1.47, p = 0.26).…”

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

“…Animals of both sexes were injected during the first hours of postnatal (PN) life with a single dose of EV (0.1 mg/50 µL of sesame oil s.c.), TP (1 mg/50 µL of sesame oil s.c.) or vehicle (control group: 50 µL of sesame oil s.c.). Sex hormone doses were previously published [ 17 , 18 , 32 , 36 ], demonstrating the estrous cycle to be in a permanently diestrus phase [ 37 ]. Female control rats were used between PN days (PND) 60 to 62 to maintain the same phase of the estrous cycle.…”

“…Rats used for CPP were assigned to the following experimental groups: female control ( n = 22), male control ( n = 21), female EV ( n = 26), male EV ( n = 25), female TP ( n = 21) and male TP ( n = 20). The CPP apparatus and the experimental protocol were previously used [ 17 , 36 ]. Briefly, the CPP protocol consisted of three parts: pre-test (one day before the conditioning period), the conditioning period and the test (24 h after the last injection).…”

“…Microdialysis experiments were performed on anesthetized rats, following a previously published protocol [ 36 ]. Briefly, a microdialysis probe (2 mm membrane length, model MAB 2.14.2, 35,000 Da cut-off, Microbiotech AB, Stockholm, Sweden) was implanted in the NAcc (anteroposterior: +1.5 mm; mediolateral: +1.5 mm; dorsoventral: −7.8 mm).…”

Sex Differences in Opioid-Mediated Effects: Role of Androgens

“…Chronic treatment with exogenous androgens significantly decreases morphine-inducedc-fos and JunB gene expression in the caudate putamen (Harlan et al, 2000), suggesting that androgens can functionally antagonize the effects of mu opioids under some conditions. Some of the effects of androgens on opioid-mediated responses can be attributed to activational rather than developmental effects, given that a single bolus dose of testosterone on postnatal day 1 does not alter the expression of mu opioid receptors, morphine-induced dopamine release, morphine-induced locomotor effects, or morphine-induced conditioned place preference in adulthood in either male or female rats (Velásquez et al, 2019).…”