Progesterone modulation of α5 nAChR subunits influences anxiety‐related behavior during estrus cycle

Abstract

Smokers often report an anxiolytic effect of cigarettes. In addition, stress-related disorders such as anxiety, posttraumatic stress syndrome and depression are often associated with chronic nicotine use. To study the role of the a5 nicotinic acetylcholine receptor subunit in anxiety-related responses, control and a5 subunit null mice (a5 2/2 ) were subjected to the open field activity (OFA), light-dark box (LDB) and elevated plus maze (EPM) tests. In the OFA and LDB, a5 2/2 behaved like wild-type controls. In the EPM, female a5 2/2 mice displayed an anxiolytic-like phenotype, while male a5 2/2 mice were undistinguishable from littermate controls. We studied the hypothalamus-pituitary-adrenal axis by measuring plasma corticosterone and hypothalamic corticotropin-releasing factor. Consistent with an anxiolyticlike phenotype, female a5 2/2 mice displayed lower basal corticosterone levels. To test whether gonadal steroids regulate the expression of a5, we treated cultured NTera 2 cells with progesterone and found that a5 protein levels were upregulated. In addition, brain levels of a5 mRNA increased upon progesterone injection into ovariectomized wild-type females. Finally, we tested anxiety levels in the EPM during the estrous cycle. The estrus phase (when progesterone levels are low) is anxiolyticlike in wild-type mice, but no cycle-dependent fluctuations in anxiety levels were found in a5 2/2 females. Thus, a5-containing neuronal nicotinic acetylcholine receptors may be mediators of anxiogenic responses, and progesterone-dependent modulation of a5 expression may contribute to fluctuations in anxiety levels during the ovarian cycle.

Nicotine Addiction and Psychiatric Disorders

“…Additionally, there is also evidence showing that other nAChR subtypes may play a role in modulating anxiety as well. For example, Gangitano, Salas, Teng, Perez, and De Biasi (2009) demonstrated that α5 KO animals showed altered hypothalamus–pituitary–adrenal axis function as they were shown to have lower basal corticosterone levels. In addition, while α5 KO animals showed no behavioral changes in the OF and light–dark box paradigms, female KO mice, but not male mice, showed reduced anxiety-like behavior in the EPM.…”

“…In addition to the β2 and α7 nAChRs, α5 may also be involved in the modulation of depressive-like behavior. For example, using a tail-suspension test and α5 nAChR-null mice, Gangitano et al (2009) found that female but not male α5 KO mice showed reduced depressive-like behavioral phenotype. These studies suggest that inactivation of β2-containing nAChRs along with α7 nAChR activation results in reduction of depression-like behavior in the animal models of depression.…”

Antagonism of progesterone receptor suppresses carotid body responses to hypoxia and nicotine in rat pups

“…Interestingly, progesterone enhances the mRNA expression of the nicotine acetylcholine receptor α5 subunit in mice (Gangitano et al, 2009). To our knowledge, additional data on the regulation of nAChR expression by progesterone are not available in the literature.…”

Unorthodox Acetylcholine Binding Sites Formed by α5 and β3 Accessory Subunits in α4β2* Nicotinic Acetylcholine Receptors

“…(␣4␤2) 2 ␣5 and (␣4␤2) 2 ␤3 nAChRs are found in the brain, as are (␣6␤2)(␣4␤2)␤3 nAChRs (3, 16 -20). ␣5 and ␤3 subunits have been implicated in nicotine addiction and are likely to be involved in many diseases associated with nAChRs (21)(22)(23)(24)(25)(26)). An ␣5 D398N and some ␤3 polymorphisms are associated with susceptibility to smoking (26,27).…”