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Humans often start smoking during adolescence. Recent results suggest that rodents may also be particularly vulnerable to nicotine dependence during adolescence. We examined the effect of chronic nicotine exposure on gene expression profiles during adolescence in female rats, who were dosed with nicotine (and control animals were dosed with saline) via subcutaneously implanted osmotic minipumps. Brain samples were collected at four ages: before puberty (postnatal day 25), at about the time of puberty in females (postnatal day 35), and after puberty (postnatal days 45 and 55). The expression of 7931 genes in three brain areas was measured using DNA microarrays. Quantitative RT-PCR was also employed to confirm the expression patterns of selected genes. We used a novel clustering technique (principal cluster analysis) to classify 162 nicotine-regulated genes into five clusters, of which only one (cluster A) showed similar patterns of gene expression across all three brain areas (ventral striatum, prefrontal cortex, and hippocampus). Three clusters of genes (A, B, and C) showed dramatic peaks in their nicotine responses at the same age (p35). The other two clusters (D1 and D2) showed smaller peaks and/or valleys in their nicotine responses at p35 and p45. Thus, the age of maximal gene expression response to nicotine in female rats corresponds approximately to the age of maximal behavioral response and the age of puberty.

Use of addictive substances by human juveniles and adolescents is common, including use to intoxication and progression from one drug to other drugs. Until quite recently, animal studies have not addressed the periadolescent period as a time of special vulnerability to substance abuse. For ethanol (EtOH), the most studied drug in periadolescent animals, it has become clear that effects of alcohol are similar in some ways, but different in others, compared to the effects seen in adult animals. Sparse data suggest that this conclusion may apply to other drugs as well. Recent work in rats indicates that periadolescent substance use may disrupt normal pubertal development, and may induce stronger effects on systems subserving plasticity and cognition than in adults. Animal data also indicate that some drugs may produce altered subsequent sensitivity to the same or a different drug, changes in adult cognitive capabilities, and even CNS damage. It is now clear that there can be no presumption that all studies of abusable substances carried out in adult animals will generalize readily to periadolescents. Some data suggest that continuing developmental changes in receptor expression may underlie age-related changes in drug effects. However, the biological characteristics of periadolescence which predispose toward consumption to intoxication, and the mechanisms underlying drug progression and persisting drug effects, still remain to be well defined.

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 (0.96mg/kg/day or 2.0mg/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 alpha4, alpha7, and beta2 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. These long-term behavioral and neurochemical changes strengthen the case for discouraging cigarette smoking during pregnancy and clearly indicate that the use of the patch as a smoking cessation aid during pregnancy is not a safe alternative.

We examined the acute rewarding as well as the long-term psychomotor altering effects of nicotine in early adolescent and adult male Sprague-Dawley rats. Place conditioning was used to examine nicotine-induced reward after a single drug pairing. A single pairing of nicotine with the initially non-preferred side of the place conditioning apparatus produced a conditioned place preference (CPP) in early adolescent but not adult animals. One month later, animals were given a nicotine challenge and locomotor activity observed in the open field to characterize age differences in the lasting alterations resulting from this single injection. Adult rats showed tolerance to the locomotor depressant effects of a low dose of nicotine whereas adolescent rats showed tolerance to a higher dose. Regardless of treatment group, animals tested during adolescence responded to the nicotine challenge with less hypoactivity when compared with animals tested as adults. The present results are in agreement with previous studies showing that early adolescent rats are more sensitive to nicotine's rewarding effects and are in accord with studies showing a unique profile of neurobehavioral alterations following nicotine exposure when compared with adults. Such findings are extended here by showing that these differences are seen following only a single pretreatment dose and persist for at least one month after pretreatment.

Pregnant Long-Evans hooded rats were dosed subcutaneously with 1 or 5 mg/kg/day naloxone hydrochloride, or an equal volume of vehicle, from gestational Day 4 (GD4) through GD19. Offspring were assessed for development of righting reflex, negative geotaxis, and open field activity, and for acquisition of a Warden maze; offspring sacrificed at postnatal Day (PND) 21 were assessed for several parameters of cerebellar, hippocampal, and motor cortical morphology. Five mg/kg/day naloxone accelerated development of negative geotaxis and righting reflex, while 1 mg/kg/day naloxone tended to slow development. Low dose females had significantly more errors than controls on the first day of maze learning. The high dose group had a significantly higher concentration of granule cells in the curvature of the dentate gyrus than controls; other neuroanatomical measures were unaffected by dosing. These findings confirm and extend previous work indicating that prenatal exposure to naloxone may alter neurobehavioral development in the rat.

Pregnant Long-Evans hooded rats were dosed via injections into the gum with 3, 6, or 9 mg/kg lidocaine, or vehicle, or were uninjected, on gestational day 4 (GD4), GD11, or GD18. Offspring (8–11 litters/group) were tested on a variety of tests of behavioral development and adult behavior. No effects of any dose at any time of administration were found upon maternal weight gain in gestation, litter size, or initial birth weight or weight gain of the pups. Administration at GD4 produced few effects; only footshock sensitivity showed a significant effect of dosing, although there were trends toward dosing effects on spontaneous alternation. For administration on GD11, lidocaine was associated with slight but significant alterations in sex ratios, and a trend toward drug effects on development of spontaneous alternation. Vehicle administration at this age reduced barbiturate sleep time in offspring and slightly altered footshock sensitivity. Lidocaine dosing on GD18 was associated with a number of significant alterations of behavior, including visual discrimination, shuttlebox avoidance, tail flick, and water maze errors; there were also both vehicle and lidocaine effects on water maze latencies. These data reinforce our previous report that lidocaine may be a behavioral teratogen, and suggest that administration in later gestation in the rat may alter a broader range of behaviors than earlier in gestation.

Sperm-positive female Long-Evans hooded rats were dosed subcutaneously with 10 mg/kg/day cocaine or an equal volume of vehicle (0.9% sterile saline) from gestation day 4 (GD4) through GD18. Offspring were assessed for development of negative geotaxis, righting reflex, spontaneous alternation, and open field activity, and for adult behaviors including DRL-20 acquisition, water maze, visual discrimination, barbiturate sleep time, shuttlebox avoidance, footshock sensitivity, and tail flick latency. Cocaine dosing produced no significant effects on dam weight gain, any measure of litter size and weight, or early postnatal behavioral tests, but there were significant drug effects on development of spontaneous alternation, development of open field activity, DRL-20 acquisition, water maze performance, tail flick, and footshock sensitivity. These data suggest that chronic administration of a modest dose of cocaine during gestation in the rat alters a number of behaviors in the offspring.