Table 1.

Sex differences in nicotine effects across development in rodents

Developmental period of exposure	Measure	Effect of nicotine	Citations
Gestation	Adrenergic function	Decreased β2-adrenergic-mediated adenylyl cyclase activity in males only	Slotkin et al. 2007
	Cholinergic function	In males, decreased ChAT activity and HC3 binding in the cerebral cortex; increased HC3 binding in the hippocampus; decreased basal adenylyl cyclase signaling. In females, increased HC3 binding in the midbrain; decreased basal adenylyl cyclase signaling (less profound than males)	Slotkin et al. 2007
	Serotonergic function	Reduced 5-HT1A binding and increased 5-HT2 binding in males only	Slotkin et al. 2007
	Myelin-associated gene and protein expression	In males, upregulation of myelin-associated genes (e.g., Mbp, Plp1, Gjc3, Mobp, Aspa) in the PFC, CPu, and NAc during adolescence that generally normalized by adulthood. In females, downregulation or normal expression of myelin-associated genes (e.g., Plp1, Gjc3, Mobp, Mbp, Cnp, Mal, Mog) in PFC, CPu, and NAc during adolescence. Downregulation in adult CPu of females	Cao et al. 2013
	Dendritic complexity	In males, increased complexity in AID and NAc but decreased complexity in apical field of Cg3; increased spine density everywhere but NAc; increased dendritic length in NAc and basilar Cg3 but decreased length in basilar PAR. In females, increased complexity in NAc but decreased complexity in AID; increased spine density in AID and PAR but decreased in Cg3 and NAc; reduced dendritic length in NAc, Cg3 and PAR	Mychasiuk et al. 2013
	Expression of KCC2 cotransporter	Greater in males	Damborsky and Winzer-Serhan 2012
	Excitation of adult hippocampal CA1	Increased excitation as measured by fEPSP slope at higher voltage inputs in males only	Damborsky et al. 2012
	Sucrose preference	Eliminates normal sex difference (i.e., females have higher preference than males)	Lichtensteiger and Schlumpf 1985
	Nicotine reward	Increased preference for oral nicotine in adolescent males only	Klein et al. 2003
	Cognitive function	Mild spatial deficit in females only	Eppolito and Smith 2006
		No change	Huang et al. 2007
Adolescence	Nicotine self-administration	In females, a greater percentage acquire self-administration, acquisition is more rapid, and intake is higher compared to males	Lynch 2009; Li et al. 2014; Sanchez et al. 2014
		Adolescent rats of both sexes had higher nicotine self-administration than adults but the effect was more pronounced in adolescent males; responding in males decreased with age but did not in females	Levin et al. 2011
		Acetaldehyde enhances nicotine self-administration in both sexes, but only males reduce responding with age	Belluzzi et al. 2005; Park et al. 2007
		Females are more sensitive to yohimbine-induced increases in motivation for nicotine under progressive ratio responding	Li et al. 2014
	Nicotine reward	Adolescent males displayed enhanced nicotine conditioned place preference compared to adults, but adolescent females were more sensitive than adults to low dose nicotine without a difference in magnitude of preference	Torres et al. 2009
		Adolescent males had higher nicotine-induced preference to a mid-range dose of nicotine than adolescent females	Lenoir et al. 2015
	Motivation for nicotine	Females display higher motivation under progressive ratio testing. Greater motivation is positively correlated with the ratio of estradiol:progesterone and negatively correlated with levels of progesterone alone; does not seem to vary across estrous cycle	Lynch 2009; Donny et al. 2000; Li et al. 2014
	Nicotine withdrawal-related craving	Higher in females	Dickmann et al. 2009
	Anxiolytic effects of acute nicotine	More pronounced in males	Damaj et al. 2001; Cao et al. 2010
	Anxiety-like behavior during nicotine withdrawal	Late-emerging (P60) depression of locomotor activity in open-field testing in females with early adolescent nicotine exposure; no difference in males	Trauth et al. 2000
		Decreased locomotor activity during short-term withdrawal from nicotine in females that normalized after 30 days; males had increased anxiety- and depressive-like activity that emerged after 30 days of withdrawal	Thanos et al. 2013
	Physical symptoms of nicotine withdrawal	No sex differences	Kota et al. 2007; Kota et al. 2008; Torres et al. 2013
	Nicotine-induced changes in nAChR binding	Increased nAChR binding in striatum of adolescent females with no difference in adolescent males	Lenoir et al. 2015
Adulthood	Nicotine self-administration	Higher responding and faster acquisition in females	Donny et al. 2000; Lynch 2009
		Faster acquisition in males	Swalve et al. 2016
		No sex differences in acquisition rates	Feltenstein et al. 2012
	Nicotine intake	Higher intake during maintenance phase of self-administration	Donny et al. 2000; Chaudri et al. 2005; Rezvani et al. 2008; Grebenstein et al. 2013
		No sex differences	Feltenstein et al. 2012; Swalve et al. 2016
	Nicotine metabolism	Repeated nicotine produces higher plasma levels in females than males	Harrod et al. 2007
	Salience of non-drug conditioned cues	Higher in females during self-administration, extinction, and possibly withdrawal/craving	Perkins et al. 1999; Chaudri et al. 2005
	Withdrawal	More robust in females than males, likely due to ovarian hormones	Torres et al. 2015; Torres and O’Dell 2016
	Nicotine reward	Female rats are less sensitive than males; higher doses of nicotine are required to produce significant place preference	Lenoir et al. 2015
		Females display place preference over a wider range of nicotine doses than males	Torres et al. 2009
		No significant preference at any tested dose	Yararbas et al. 2010
		Females had greater magnitude of nicotine place preference than males	Igiegas et al. 2009
	Anxiety-like behavior	Greater in females than males in open-field and elevated plus maze	Elliott et al. 2004; Caldarone et al. 2008; Cao et al. 2010
	Corticosterone levels	Nicotine stimulates HPA axis activity and corticosterone release more in females than males	Cao et al. 2010; Gentile et al. 2011

Abbreviations: AID = agranular insular cortex, CPu = caudate putamen, ChAT = choline acetyltransferase, Cg3 = layer III of anterior cingulate cortex, fEPSP = field excitatory postsynaptic potential, HC3 = [³H]hemicholinium, HPA axis = hypothalamic pituitary adrenal axis, KCC2 = K⁺/Cl⁻ cotransporter 2, nAChR = nicotinic acetylcholine receptor, NAc = nucleus accumbens, PAR = parietal cortex, P = postnatal day, PFC = prefrontal cortex