A prenatal nicotine exposure mouse model of methylphenidate responsive ADHD‐associated cognitive phenotypes

Abstract

Prenatal exposure to nicotine via cigarette smoke or other forms of tobacco use is a significant environmental risk factor for attention deficit hyperactivity disorder (ADHD). The neurobiological mechanisms underlying the link between prenatal nicotine exposure (PNE) and ADHD are not well understood. Animal models, especially rodent models, are beginning to bridge this gap in knowledge. Although ADHD is characterized by hyperactivity, inattention, impulsivity and working memory deficits, the majority of the animal models are based on only one or two ADHD associated phenotypes, in particular, hyperactivity or inattention. We report a PNE mouse model that displays the full range of ADHD associated behavioral phenotypes including working memory deficit, attention deficit and impulsive-like behavior. All of the ADHD-associated phenotypes respond to a single administration of a therapeutic equivalent dose of methylphenidate. In an earlier study, we showed that PNE produces hyperactivity, frontal cortical hypodopaminergic state and thinning of the cingulate cortex. Collectively, these data suggest that the PNE mouse model recapitulates key features of ADHD and may be a suitable preclinical model for ADHD research.

Nicotine exposure of male mice produces behavioral impairment in multiple generations of descendants

“…Preclinical studies [ 4 , 5 , 12 – 16 ] and clinical studies [ 3 , 17 – 20 ] show that prenatal nicotine exposure produces significant attention deficits. Therefore, we used an object-based attention test [ 13 , 21 , 22 ] to examine the effects of paternal nicotine exposure on attention in the F1 mice. Paternal treatment produced a significant main effect on attention (two-way ANOVA; treatment: F [1, 35] = 9.23; p < 0.01).…”

“…Working memory and cognitive flexibility are components of executive function [ 23 – 27 ] impacted by drug exposure [ 28 , 29 ]. We have previously reported that nicotine or cocaine exposure of pregnant mice impairs working memory and cognitive flexibility in the offspring [ 22 , 30 ]. We analyzed spatial working memory in F1 mice using the Y-maze.…”

“…However, paternal treatment (of the founder or F0 generation) had a significant main effect on latency to escape during reversal learning in the F2 generation (two-way ANOVA; treatment: F (2,42) = 4.354, p < 0.05). Because comparisons were made against a single group of F2 control mice (derived from F1 male or female mice descending from F0 male mice that were exposed to plain drinking water), we used Dunnet’s multiple comparisons test for analysis of the differences among the groups [ 22 ]. Male F2 mice derived from female F1 founders showed significant deficits in reversal learning when latency to find the escape hole (t = 3.838; df = 42; p < 0.001; Fig 3B and S4 Data ) was considered as the parameter.…”

“…Spatial working memory was assayed using a custom-built clear Plexiglas Y-maze [ 22 ]. Each of the 3 arms of the maze was 35 cm long by 6 cm wide by 10 cm high; distinct visual cues were placed on the walls of each arm and on the walls of the testing room.…”

Gestational exposure to nicotine and/or benzo[a]pyrene causes long‐lasting neurobehavioral consequences

“…These findings are in agreement with previous nicotine work and suggest a key area of risk for BaP exposure. Fetal nicotine exposure has been previously associated with poor rodent attention tasks, such as the 5-choice serial response time task (Schneider, Bizarro, Asherson, & Stolerman, 2012;Schneider et al, 2011) and the object-based attention test (Alkam et al, 2013;Zhu et al, 2017). This particular attention task had not previously been found to be sensitive to prenatal nicotine effects when used by Hall et al (2016) although that data set did find deficits in novel object recognition, which is believed to rely on another form of attention.…”