Intravenous Prenatal Nicotine Exposure Alters METH-Induced Hyperactivity, Conditioned Hyperactivity, and BDNF in Adult Rat Offspring

Abstract

In the USA, approximately 15% of women smoke tobacco cigarettes during pregnancy. In utero tobacco smoke exposure produces somatic growth deficits like intrauterine growth restriction and low birth weight in offspring, but it can also negatively influence neurodevelopmental outcomes in later stages of life, such as an increased incidence of obesity and drug abuse. Animal models demonstrate that prenatal nicotine (PN) alters the development of the mesocorticolimbic system, which is important for organizing goal-directed behavior. In the present study, we determined whether intravenous (IV) PN altered the initiation and/or expression of methamphetamine (METH)-induced locomotor sensitization as a measure of mesocorticolimbic function in adult rat offspring. We also determined whether PN and/or METH exposure altered protein levels of BDNF (brain-derived neurotrophic factor) in the nucleus accumbens, the dorsal striatum, and the prefrontal cortex of adult offspring. BDNF was of interest because of its role in the development and maintenance of the mesocorticolimbic pathway and its ability to modulate neural processes that contribute to drug abuse, such as sensitization of the dopamine system. Dams were injected with IV nicotine (0.05 mg/kg/injection) or saline, 3×/day on gestational days 8-21. Testing was conducted when offspring reached adulthood (around postnatal day 90). Following 3 once daily habituation sessions the animals received a saline injection and baseline locomotor activity was measured. PN and prenatal saline (PS)-exposed offspring then received 10 once daily injections of METH (0.3 mg/kg) to induce locomotor sensitization. The animals received a METH injection (0.3 mg/kg) to assess the expression of sensitization following a 14-day period of no injections. A day later, all animals were injected with saline and conditioned hyperactivity was assessed. Brain tissue was harvested 24 h later. PN animals habituated more slowly to the activity chambers compared to PS controls. PN rats treated with METH showed significant enhancement of locomotor behavior compared to PS rats following acute and repeated injections; however, PN did not produce differential initiation or expression of behavioral sensitization. METH produced conditioned hyperactivity, and PN rats exhibited a greater conditioned response of hyperactivity relative to controls. PN and METH exposure produced changes in BDNF protein levels in all three regions, and complex interactions were observed between these two factors. Logistic regression revealed that BDNF protein levels, throughout the mesocorticolimbic system, significantly predicted the difference in the conditioned hyperactive response of the animals: both correlations were significant, but the predicted relationship between BDNF and context-elicited activity was stronger in the PN (r = 0.67) compared to the PS rats (r = 0.42). These findings indicate that low-dose PN exposure produces long-term changes in activity and enhanced sensitivity to the locomotor effects of METH. The enhanced MET...

Neuroinflammatory and Behavioral Outcomes Measured in Adult Offspring of Mice Exposed Prenatally to E-Cigarette Aerosols

“…Decades of research on conventional cigarette smoke have reported the toxicological effects of smoking and nicotine on brain development. For example, studies utilizing various exposure paradigms to assess the developmental effects of prenatal and/or postnatal nicotine exposure in rodents reported increased hyperactivity (Lacy et al 2016;Newman et al 1999), impaired cognitive ability in terms of memory and attention, altered pre-pulse inhibition (Alkam et al 2013;Zhang et al 2018), and increased prevalence of anxiety-or depressive-like behaviors in adulthood (Lee et al 2016;Pinheiro et al 2015;Zhang et al 2019). Importantly, some of these behavioral alterations (e.g., increased activity) were reported in offspring of pregnant mice exposed to 2.4% nicotine through e-cigarette aerosol exposure (Smith et al 2015).…”

Prenatal Cocaine Exposure Alters BDNF-TrkB Signaling in the Embryonic and Adult Brain

“…As an example, maternal cigarette smoking during pregnancy influences BDNF expression in the prenatally exposed offspring [57,58] . Additionally, a number of studies using animal models also report significant effects of prenatal nicotine exposure on BDNF expression in multiple brain regions in both males and females [59][60][61][62] . Lastly, prenatal stress results in decreased BDNF mRNA expression in the frontal cortex and hippocampus, with alterations in DNA methylation at the Bdnf gene proposed as the underlying mechanism [63] .…”

Testing environment shape differentially modulates baseline and nicotine-induced changes in behavior: Sex differences, hypoactivity, and behavioral sensitization

“…IV nicotine exposure was largely conducted away from the testing chambers to limit context-drug (conditional stimulus-unconditional stimulus) pairings, and ultimately, context-elicited changes in activity. Lacy et al, (2016) described conditioned hyperactivity in adult male and female rats when saline was substituted for once daily methamphetamine injection, creating a context-only test of activity and demonstrating context-elicited changes in activity. Although associations of contextual cues with nicotine exposure are implicated in the etiology of nicotine dependence (Perkins, 1999; Chaudrhi et al, 2005), the possibility of nicotine-induced contextual conditioning was limited in order to assess the influence of nicotine alone on sensitized behavior.…”

“…Baseline sex differences in activity are commonly reported, and females generally exhibit more baseline activity than males (Booze et al, 1999; Kanyt et al, 1999; Zakharova et al, 2012; Lacy et al, 2016; also see Hamilton et al, 2009; Hamilton et al, 2014). Because the primary research question of the current experiment was in regards to the unique influence of chamber shape on nicotine-induced changes in behavior, we first determined if biological sex was a justified covariate by testing for sex differences in baseline activity.…”