Neonatal nicotine exposure impairs nicotinic enhancement of central auditory processing and auditory learning in adult rats

Abstract

Children of women who smoke cigarettes during pregnancy display cognitive deficits in the auditory-verbal domain. Clinical studies have implicated developmental exposure to nicotine, the main psychoactive ingredient of tobacco, as a probable cause of subsequent auditory deficits. To test for a causal link, we have developed an animal model to determine how neonatal nicotine exposure affects adult auditory function. In adult control rats, nicotine administered systemically (0.7 mg/kg, s.c.) enhanced the sensitivity to sound of neural responses recorded in primary auditory cortex. The effect was strongest in cortical layers 3 and 4, where there is a dense concentration of nicotinic acetylcholine receptors (nAChRs) that has been hypothesized to regulate thalamocortical inputs. In support of the hypothesis, microinjection into layer 4 of the nonspecific nAChR antagonist mecamylamine (10 microM) strongly reduced sound-evoked responses. In contrast to the effects of acute nicotine and mecamylamine in adult control animals, neither drug was as effective in adult animals that had been treated with 5 days of chronic nicotine exposure (CNE) shortly after birth. Neonatal CNE also impaired performance on an auditory-cued active avoidance task, while having little effect on basic auditory or motor functions. Thus, neonatal CNE impairs nicotinic regulation of cortical function, and auditory learning, in the adult. Our results provide evidence that developmental nicotine exposure is responsible for auditory-cognitive deficits in the offspring of women who smoke during pregnancy, and suggest a potential underlying mechanism, namely diminished function of cortical nAChRs.

Gender-Specific Effects of Prenatal and Adolescent Exposure to Tobacco Smoke on Auditory and Visual Attention

“…Recent preclinical work indicates that nicotine exposure during early postnatal development, corresponding to the third trimester of pregnancy in humans, resulted in impaired function of nAChRs in primary auditory cortex localized on neurons that regulate thalamocortical inputs (Liang et al, 2006). Although gender differences in this effect of prenatal exposure alone were not noted in these studies, the present findings suggest that, in males, when prenatal exposure is followed by adolescent exposure to tobacco smoke, neurocircuitry supporting auditory attention may be more vulnerable to the developmental toxicity of nicotine than neurocircuitry supporting visual attention.…”

“…Stimulation of nAChRs by nicotine during prenatal development produces persistent cholinergic and serotonergic hypoactivity, and reductions in neural cell membrane complexity, alterations in neurotransmitter responses mediated through adenyl cyclase and alterations in serotonin receptor expression (Navarro et al, 1989;Slotkin, 2004;Slotkin et al, 2007). The vulnerability of the developing brain to nicotine extends into the early postnatal period in the rodent (corresponding to the third trimester in humans), where exposure disrupts auditory learning and nicotinic regulation of primary auditory cortex (Liang et al, 2006).…”

Developmental Excitation of Corticothalamic Neurons by Nicotinic Acetylcholine Receptors

“…In the human brain, nicotinic binding is highest toward the end of gestation (Court et al, 2000). The drug nicotine is a partial agonist of these nicotinic acetylcholine receptors and may disrupt the trophic effects of acetylcholine during a critical stage of development (Navarro et al, 1989;Slotkin, 2004;Liang et al, 2006). Substantial literature suggests that in humans, prenatal exposure to nicotine through maternal cigarette smoking harms the development of prefrontal attention circuitry (Langley et al, 2005;Rodriguez and Bohlin, 2005).…”

“…Recent transgenic work shows that nicotinic receptors are expressed by corticothalamic neurons and are present in corticothalamic terminals in mice (King et al, 2003). Nicotinic acetylcholine receptors have been suggested to play a trophic role in the development of cortical neurons and brain circuitry (Belluardo et al, 1999;Brown and Kolb, 2001;Liang et al, 2006).…”

Prenatal and Adolescent Exposure to Tobacco Smoke Modulates the Development of White Matter Microstructure

“…Stimulation of nAChRs by nicotine during gestation disrupts neurodevelopment, possibly by disrupting the trophic actions of acetylcholine (Navarro et al, 1989;Slotkin, 2004). Nicotine administration during the early postnatal period in the rodent disrupts auditory learning and nicotinic regulation of primary auditory cortex (Hsieh et al, 2002;Liang et al, 2006). High-affinity nAChRs expressed on corticothalamic efferents during development are critical for normal passive avoidance learning (King et al, 2003).…”