Sexually diergic hypothalamic–pituitary–adrenal (HPA) responses to single-dose nicotine, continuous nicotine infusion, and nicotine withdrawal by mecamylamine in rats

Abstract

Hypothalamic-pituitary-adrenal (HPA) responses to single-dose nicotine (NIC) are sexually diergic: Female rats have higher adrenocorticotropic hormone (ACTH) and corticosterone (CORT) responses than do males. In the present study we determined HPA responses in male and female rats following single doses of NIC, a single-dose of NIC immediately following continuous NIC for two weeks, and NIC withdrawal by single-dose mecamylamine (MEC) following continuous NIC infusion for two weeks. Blood sampling occurred before and after MEC and NIC administrations for determination of ACTH and CORT. In accordance with our previous findings, female ACTH and CORT responses to single-dose NIC were greater than male responses. This sex difference remained after single-dose NIC followed continuous NIC infusion, but HPA responses in both sexes were significantly lower in magnitude and duration than in the single-dose NIC alone groups. Sex differences also were observed following NIC withdrawal by MEC: The HPA responses to pretreatment with MEC were significantly higher in magnitude and duration in the continuous NIC groups than in the single-dose NIC groups. These results demonstrate that HPA responses to NIC are reduced and transient following continuous NIC infusion but are enhanced and sustained following NIC withdrawal by MEC after continuous NIC, suggesting that NIC habituation and withdrawal influence the stress responses in a diergic manner. These findings highlight the importance of sex differences in the effect of NIC on HPA axis activity and stress responsiveness, which may have implications for directing NIC-addiction treatment specifically towards men and women.

Nicotine Withdrawal Increases Stress-Associated Genes in the Nucleus Accumbens of Female Rats in a Hormone-Dependent Manner

“…This is consistent with findings from other laboratories showing that female rodents display an increase in anxiety-like behavior and plasma corticosterone levels during nicotine withdrawal. [31][32][33][34] The present study also revealed a different pattern of changes in CRF receptor gene expression during nicotine exposure and withdrawal. Specifically, both CRF-R1 and CRF-R2 gene expression was decreased during nicotine exposure in intact females.…”

Sex Differences in Animal Models: Focus on Addiction

“…Female rats showed greater adrenocorticotropic hormone levels during nicotine withdrawal. Corticosterone increased only in females in response to nicotine after continuous nicotine exposure, and corticosterone responses were increased in females after the precipitation of withdrawal (Gentile et al, 2011). In other studies, female rats exhibited greater symptoms of nicotine withdrawal, including an exaggerated stress response, compared with males (Torres and O'Dell, 2015).…”

A mechanistic hypothesis of the factors that enhance vulnerability to nicotine use in females

“…For example, plasma corticosterone levels are increased to a greater extent in female versus male rats following repeated injections (Gentile et al, 2011; Moidel et al, 2006; Rhodes et al, 2001; 2004; Skwara et al, 2012) and continuous delivery (Faraday et al, 2005) of nicotine. In an in vitro perfusion system, the presence of nicotine increased CRF and ACTH levels to a greater extent in hypothalamic tissue that was collected from female versus male rats (Mcklveen et al, 2010; Moidel et al, 2006).…”