Overexpression of corticotropin-releasing factor in the nucleus accumbens enhances the reinforcing effects of nicotine in intact female versus male and ovariectomized female rats

Abstract

This study assessed the role of stress systems in the nucleus accumbens (NAc) in promoting sex differences in the reinforcing effects of nicotine. Intravenous self-administration (IVSA) of various doses of nicotine was compared following overexpression of corticotropin-releasing factor (CRF) in the NAc of female and male rats. Ovariectomized (OVX) females were also included to assess the role of ovarian hormones in promoting nicotine reinforcement. Rats received intra-NAc administration of an adeno-associated vector that overexpressed CRF (AAV2/5-CRF) or green fluorescent protein (AAV2/5-GFP). All rats were then given extended access (23 h/day) to an inactive and an active lever that delivered nicotine. Separate groups of rats received intra-NAc AAV2/5-CRF and saline IVSA. Rats were also allowed to nose-poke for food and water during IVSA testing. At the end of the study, the NAc was dissected and rt-qPCR methods were used to estimate CRF overexpression and changes in CRF receptors (CRFr1, CRFr2) and the CRF receptor internalizing protein, β-arrestin2 (Arrb2). Overexpression of CRF in the NAc increased nicotine IVSA to a larger extent in intact female versus male and OVX females. Food intake was increased to a larger extent in intact and OVX females as compared to males. The increase in CRF gene expression was similar across all groups; however, in females, overexpression of CRF resulted in a larger increase in CRFr1 and CRFr2 relative to males. In males, overexpression of CRF produced a larger increase in Arrb2 than females, suggesting greater CRF receptor internalization. Our results suggest that stress systems in the NAc promote the reinforcing effectiveness of nicotine in female rats in an ovarian hormone-dependent manner.

Neurosteroid allopregnanolone (3α,5α-THP) inhibits inflammatory signals induced by activated MyD88-dependent toll-like receptors

“…The differential TLR4 and TLR7 signal activation in a sex-dependent manner and/or the potential TLR-TLR cross talk and its resulting signal regulatory outcome are also not well understood. For example, the neuropeptide corticotropin-releasing factor (CRF) alters different circuits in males and females with brain region specific sensitivity 80 and it promotes sex differences in the reinforcing effects of nicotine 81 . CRF regulates an amplification loop for the innately activated TLR4 signal that is focused on pERK1/2, downstream of TRAF6 activation 32 , a site that also applies to TLR7 signaling (Fig.…”

Sex differences in the impact of electronic nicotine vapor on corticotropin-releasing factor receptor 1 neurons in the mouse ventral tegmental area

“…These data indicate that female VTA CRF1 neurons are under greater inhibitory control which may explain the female-specific decrease in dopamine release in the nucleus accumbens with administration of the nicotinic receptor antagonist, mecamylamine 49 . Overexpression of CRF in the nucleus accumbens has also been shown to enhance the reinforcing effects of nicotine in females 25 , thus future experiments examining the effects of CRF in both female and male VTA-NAc CRF1 neurons may shed light on how stress can affect reward processing in the VTA.…”

“…Overexpression of CRF in the nucleus accumbens has also been shown to enhance the reinforcing effects of nicotine in females 25 , thus future experiments examining the effects of CRF in both female and male VTA-NAc CRF1 neurons may shed light on how stress can affect reward processing in the VTA.…”

“…Human studies report that women are more likely to smoke to manage stress and experience anxiety more intensely during abstinence 16 . The corticotropin-releasing factor (CRF) system regulates stress responding and has been implicated in cocaine [17][18][19] , alcohol [20][21][22][23] , and nicotine addiction 24,25 . Nicotine activates the hypothalamic-pituitary-adrenal (HPA) axis to release CRF in the thalamus 26 .…”

Sex-Related Predisposition to Post-Traumatic Stress Disorder Development—The Role of Neuropeptides

“…For example, estrogen treatment significantly increased CRF mRNA expression in the amygdala and the BNST of ovariectomized mice [ 30 , 31 ]. Estrogen increases the expression of CRF1 and CRF2 in breast cancer cells [ 32 ] and probably in the brain [ 33 ]. Many estrogen effects are mediated by estrogen receptors (ER) that bind to specific estrogen response elements (EREs) in target promoters [ 26 , 31 ].…”