Beleid en debat

Attention deficit hyperactivity disorder (ADHD) is a multifactorial disorder and both genetic and environmental factors have been implicated in its etiology. Yet, the interaction between genes and environment is seldom studied directly. This article considers the plausibility of nicotine exposure during prenatal development as well as postnatal factors in the etiology of ADHD. The few existent studies show inconsistent results, but provide preliminary evidence suggesting that nicotine exposure together with genes in the dopaminergic system confer risk for ADHD.

Nicotinic acetylcholine receptors (nAChRs) regulate critical aspects of brain maturation during the prenatal, early postnatal, and adolescent periods. During these developmental windows, nAChRs are often transiently upregulated or change subunit composition in those neural structures that are undergoing major phases of differentiation and synaptogenesis, and are sensitive to environmental stimuli. Nicotine exposure, most often via tobacco smoke, but increasingly via nicotine replacement therapy, has been shown to have unique effects on the developing human brain. Consistent with a dynamic developmental role for acetylcholine, exogenous nicotine produces effects that are unique to the period of exposure and that impact the developing structures regulated by acetylcholine at that time. Here we present a review of the evidence, available from both the clinical literature and preclinical animal models, which suggests that the diverse effects of nicotine exposure are best evaluated in the context of regional and temporal expression patterns of nAChRs during sensitive maturational periods, and disruption of the normal developmental influences of acetylcholine. We present evidence that nicotine interferes with catecholamine and brainstem autonomic nuclei development during the prenatal period of the rodent (equivalent to first and second trimester of the human), alters the neocortex, hippocampus, and cerebellum during the early postnatal period (third trimester of the human), and influences limbic system and late monoamine maturation during adolescence.

Preclinical studies, using primarily rodent models, have shown acetylcholine to have a critical role in brain maturation via activation of nicotinic acetylcholine receptors (nAChRs), a structurally diverse family of ligand-gated ion channels. nAChRs are widely expressed in fetal central nervous system, with transient upregulation in numerous brain regions during critical developmental periods. Activation of nAChRs can have varied developmental influences that are dependent on the pharmacologic properties and localization of the receptor. These include regulation of transmitter release, gene expression, neurite outgrowth, cell survival, and synapse formation and maturation. Aberrant exposure of fetal and neonatal brain to nicotine has been shown to have detrimental effects on cholinergic modulation of brain development. These include alterations in sexual differentiation of the brain, and in cell survival and synaptogenesis. Long-term alterations in the functional status and pharmacologic properties of nAChRs may also occur, which result in modifications of specific neural circuitry such as the brainstem cardiorespiratory network and sensory thalamocortical gating. Such alterations in brain structure and function may contribute to clinically characterized deficits that result from maternal smoking, such as sudden infant death syndrome and auditory-cognitive dysfunction. Although not the only constituent of tobacco smoke, there is now abundant evidence that nicotine is a neural teratogen.

Here we provide experimental evidence for the effects of prenatal nicotine exposure on measures of attention and impulsivity in adult male rats. Offspring of females exposed during pregnancy to 0.06 mg/ml nicotine solution as the only source of water (daily consumption: 69.6±1.4 ml/kg; nicotine blood level: 96.0±31.9 ng/ml) had lower birth weight and delayed sensorimotor development measured by negative geotaxis, righting reflex and grip strength. In the 5-choice serial reaction time test, adult rats showed increased numbers of anticipatory responses and omissions errors, more variable response times and lower accuracy with evidence of delayed learning of the task demands when the 1 s stimulus duration was introduced. In contrast, prenatal nicotine exposure had no effect on exploratory locomotion or delay-discounting test. Prenatal nicotine exposure increased expression of the D5 dopamine receptor gene in the striatum, but did not change expression of other dopamine-related genes (DRD4, DAT1, NR4A2, TH) in either the striatum or the prefrontal cortex. These data
suggest a direct effect of prenatal nicotine exposure on important aspects of attention, inhibitory control or learning later in life.

Animal models of prenatal nicotine exposure clearly indicate that nicotine is a neuroteratogen. Some of the persisting effects of prenatal nicotine exposure include low birth weight, behavioral changes and deficits in cognitive function, although few studies have looked for neurobehavioral and neurochemical effects that might persist throughout the lifespan. Pregnant rats were given continuous infusions of nicotine (0.96 mg/kg/day or 2.0 mg/kg/day, freebase) continuing through the third trimester equivalent, a period of rapid brain development. Because the third trimester equivalent occurs postnatally in the rat (roughly the first week of life) nicotine administration to neonate pups continued via maternal milk until postnatal day (P) 10. Exposure to nicotine during pre- and early postnatal development had an anxiogenic effect on adult rats (P75) in the elevated plus maze (EPM), and blocked extinction learning in a fear conditioning paradigm, suggesting that pre- and postnatal nicotine exposure affect anxiety-like behavior and cognitive function well into adulthood. In contrast, nicotine exposure had no effect on anxiety-like behaviors in the EPM in adolescent animals (P30). Analysis of mRNA for the α4, α7, and β2 subunits of nicotinic acetylcholine receptors revealed lower expression of these subunits in the adult hippocampus and medial prefrontal cortex following pre- and postnatal nicotine exposure, suggesting that nicotine altered the developmental trajectory of the brain.

Advantage® contains 9.1% imidacloprid, which controls fleas on dogs for up to 30 days. Advantage® (364 mg imidacloprid/dog) was applied topically to six household dogs. The glove and blood samples were collected at 24 h, 72 h, and then on a weekly basis for 5 weeks post-Advantage® application. The glove samples were collected by petting each dog for 5 minutes while wearing a different glove per dog. The blood samples (5 mL from each dog) were collected into EDTA tubes. The imidacloprid residue was determined in the blood extracts and glove samples using RP-HPLC. The highest levels of imidacloprid residues were detected at the 24-h interval in both glove (254.16 ± 25.49 ppm) and blood (54.06 ± 3.00 ppb) samples. The blood imidacloprid residue was reduced by one third at the 72-h interval (18.73 ± 2.00 ppb) and was not detected after 1 week. Imidacloprid residue in the glove samples decreased approximately one third between each collection interval. The residue of imidacloprid in the glove extract by the fourth week was very low (0.08 ± 0.02 ppm) and not detected by the fifth week. The present findings suggest that following topical application of Advantage®, imidacloprid residue can be detected in the dog's blood for up to 72 h, and transferable residue on the dog's coat can be detected for up to 4 weeks. Repeated chronic exposure to imidacloprid may pose possible health risks to veterinarians, veterinary technologists, dog caretakers, and owners.