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NEUROPHARMACOLOGY
Department of Pharmacology, Health Science Center, University of Tennessee, Memphis, Tennessee
Received September 11, 2003; accepted October 23, 2003.
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Abstract |
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; Chassin et al., 1996; Dappen et al., 1996), yet animal models of nicotine treatment and self-administration focus, almost exclusively, on adult males. In the United States, the prevalence of cigarette use increases across genders until the age of 20 (USDHHS, 2001). Thereafter, cigarette use stabilizes and then begins to decline. However, in 2000 compared with 1999, the current use of cigarettes declined in males age 12 to 17, whereas cigarette use in adolescent females remained stable. Thus, there is a need to understand the gender-related neurochemical and behavioral correlates of nicotine intake during adolescence.
The initiation of smoking during adolescence has been associated with mothers who smoke cigarettes (Kandel et al., 1994). Furthermore, after controlling for concurrent maternal smoking and childhood exposure to cigarette smoke, daughters whose mothers smoked during pregnancy were shown to be at greater risk for both the occurrence and persistence of smoking. Despite the recent emphasis on educating the public about the dangers of tobacco use during pregnancy, 18.6% of pregnant women age 15–44 continue to smoke during pregnancy (USDHHS, 2001). Smoking during pregnancy may modify central nervous system responses to nicotine in the offspring, thus affecting their vulnerability to initiate and/or become a chronic smoker. In support of this is Kandel's hypothesis that prenatal exposure to nicotine may modify central nervous system dopaminergic systems, thereby altering the dopaminergic response to nicotine later in life. Significantly, it is the mesocortical limbic dopamine that is known to be central to drug-taking behavior (Di Chiara, 1999).
In a rat model, the administration of nicotine (6 mg/kg/day, via miniosmopump) during gestational days 4 to 21 decreased dopamine content in the cerebral cortex of male and female pups (Navarro et al., 1988). This effect was evident immediately after birth and until postnatal day 20. In contrast, exposure to this dose of nicotine from gestational days 12 through 18 to 19 increased forebrain dopamine content in both male and female rats at postnatal day 15 (Ribary and Lichtensteiger, 1989). That study examined the forebrain content of dopamine and its metabolites, dihydroxyphenyl acetic acid and homovanillic acid, in separate groups of male and female rats at gestational day 18, postnatal day 15 and 2.5 months. In males, a reduction in dopamine turnover was observed at postnatal day 15 and 2.5 months, but in females reduced turnover was not apparent until 2.5 months. The disparate findings reported in these two studies may reflect differences in the rat strains and/or the onset and duration of gestational nicotine exposure. A more recent study showed that postnatal day 22 males exposed to either 6 or 3 mg/kg/day nicotine (via miniosmopump from gestational days 4–21) had decreased dopamine content in both the nucleus accumbens and striatum (Richardson and Tizabi, 1994). This suggests that early gestational exposure to nicotine is pivotal in determining its developmental effects on dopaminergic systems.
Previous studies, examining the effects of gestational nicotine on dopamine content in various brain regions, used an animal model that was established to study the effects of prenatal nicotine exposure on fetal development (Slotkin, 1998). In this model, osmotic minipumps continuously deliver nicotine during gestation, thereby reducing the potential for confounding effects due to the placental hypoxia induced by intermittently high blood levels of nicotine from maternal injections (Slotkin et al., 1987). In light of these findings, the present study used osmotic minipumps to deliver nicotine or vehicle to Lewis dams during gestational days 4 through 21. Lewis rats were studied because of their known susceptibility to a variety of drugs of abuse, including nicotine, which they have a propensity to self-administer (Brower et al., 2002; Kosten and Ambrosio, 2002). Acute administration of nicotine has been reported to increase dopamine release in the nucleus accumbens, with more robust effects evident in the nucleus accumbens shell (Nisell et al., 1997). Therefore, microdialysis was performed to characterize the dopamine response of the nucleus accumbens shell to acute injections of nicotine (i.v.) in both male and female adolescent Lewis rats that had been gestationally exposed to nicotine or vehicle. Cross-fostered and noncross-fostered offspring were evaluated to distinguish the effects of gestational nicotine exposure on dopamine responsiveness in the offspring from the effects of altered maternal care due to nicotine treatment during pregnancy.
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Methods and Materials |
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Cross-Fostering. A standard model of cross-fostering was used (Ribary and Lichtensteiger, 1989; Cabrera et al., 1999; Nyirenda et al., 2001). Cross-fostering was conducted to acquire the following experimental groups: 1) "control group", in which pups from sodium bitartrate-treated dams remained with their own mothers; 2) "cross-fostered control group", in which pups from sodium bitartrate-treated dams were fostered to nicotine-treated dams; 3) "nicotine group", in which pups from nicotine-treated dams remained with their own mothers; and 4) "cross-fostered nicotine group", in which pups from nicotine-treated dams were fostered to mothers who had received sodium bitartrate during their own pregnancy. Separate litters were used to form nonfostered and cross-fostered groups. In the cross-fostered nicotine and cross-fostered control groups, pups were cross-fostered within 48 h of delivery. When pups reached 45 to 55 g, they were weaned from the dams, stereotaxically implanted with guide cannulae, and housed individually.
Animal Surgery. Twenty-four control female, 26 control male, 24 nicotine female, 20 nicotine male, 8 cross-fostered nicotine female, 14 cross-fostered nicotine male, 9 cross-fostered control female, and 9 cross-fostered control male adolescent Lewis rats were anesthetized with ketamine-xylazine (13 plus 87 mg/kg body weight, respectively, i.p.) and a chronic guide cannula (20-gauge) was stereotaxically implanted into the nucleus accumbens shell, according to the atlas coordinates of Paxinos and Watson (1986). The coordinates for nucleus accumbens were AP, +1.0 mm; DV, –6.0 mm; and ML, 0.4 mm, from bregma, with a flat skull. Immediately after stereotaxic surgery, animals received antibiotic injections of Baytril (9.1 mg/kg i.m.; Bayer Corp., Shawnee Mission, KS). Three days later, jugular catheters, constructed from 10 mm of silastic tubing attached to PE-50, were implanted under ketamine-xylazine and exited through the animal's back. Thereafter, rats received an injection of Baytril (7.6 mg/kg i.v.).
Microdialysis. The microdialysis method and probes have been described previously (Fu et al., 1997). Briefly, each 1-mm concentric microdialysis probe was constructed from cellulose fiber tubing (mol. wt. cutoff, 13,000 Da; outer diameter, 235 µm; Spectrum, Laguna Hills, CA) and silica tubing (outer diameter, 148 µm; inner diameter, 73 µm; Polymicron Technologies Inc., Phoenix, AZ). The recovery efficiency of individual probes was determined by in vitro dialysis for 60 min at 22°C in a solution containing dopamine 100 pg/8 µl. The mean efficiency was 3.7 ± 0.5% (n = 6).
Animals were acclimated to a 12/12-h reversed light cycle (lights off at 11:00 AM) before the microdialysis experiments, to facilitate experiments during an animal's active (dark) phase. On the day of microdialysis, offspring, ranging in age from 29 to 36 days, were housed in alert-rat microdialysis chambers (CMA, Acton, MA) in an isolated darkroom lit with a red safe-light. Microdialysis probes were perfused at 1 µl/min with a solution of Krebs-Ringer buffer (147 mM NaCl, 2.7 mM KCl, 1.2 mM CaCl2, and 0.85 mM MgCl2, in polished water; 0.2-µm filter sterilized and degassed) containing 5 µM nomifensine. Nomifensine was added to the perfusate to ensure the detection of basal dopamine levels.
Microdialysis began 150 min after insertion of the probes through the guide cannulae; consecutive 15-min samples were collected into vials containing 1 µl of 5% perchloric acid. Three baseline samples were collected for analysis before an initial i.v. injection of either 0.07 mg/kg nicotine or 0.105 mg/kg nicotine in 100 µl of 0.9% sodium chloride over 70 s. The dose of 0.07 mg/kg nicotine, defined as maximally stimulative (see Results), produced maximal dopamine secretion in the nucleus accumbens of adolescent noncross-fostered control rats without adverse behavioral effects. In this treatment group, 0.105 mg/kg nicotine did not stimulate adverse behaviors nor did it induce a greater dopamine response than 0.07 mg/kg nicotine. However, higher doses were not used because they elicited adverse behavioral effects. After the first injection of 0.07 mg/kg, nicotine, six samples were collected and then a second identical injection was delivered and four additional samples were obtained. After 0.105 mg/kg nicotine, four samples were collected to determine the peak response to a single injection at this dose. At the end of the experiments, the position of each probe was verified histologically. Only data from animals with probes located in the shell of the nucleus accumbens were used.
HPLC-Electrochemical Analysis. Chromatographic separation of dopamine was achieved with a 150 x 2 mm ODS C18 column (ESA, Inc., Chelmsford, MA) connected to an ESA model 580 HPLC pump. The mobile phase (0.5 ml/min) contained 50 mM sodium dihydrogen phosphate monohydrate, 2.0 mM decanesulfonic acid, 0.7 mM EDTA, 11% acetonitrile, and 11% methanol, pH 6.0. Samples (15 µl) were automatically injected by a CMA 200 refrigerated autosampler and were analyzed by an ESA Coulochem II 5200A electrochemical detector with an ESA 5041 high-sensitivity analytical cell and an ESA 5020 guard cell (ESA, Inc.). Electrochemical detection was performed at 220 mV and 10 nA, with the guard cell at 350 mV. Under these conditions, the limit of detection for dopamine was 100 fg/injection.
Analysis of Nucleus Accumbens Dopamine Content. Twenty-eight-day-old female Lewis rats, treated during gestation with nicotine (n = 8) or vehicle (n = 8), were used to obtain nucleus accumbens tissue samples for dopamine and protein content. The methods used were similar to those described previously (Bergstrom et al., 2001). Briefly, brains were removed and placed in cold saline. The brains were then aligned on a tissue slicer (Stoelting, Wood Dale, IL), using the anterior optic chiasm and middle meningeal arteries as reference points, shifted 6 mm forward, and sliced into 1.5-mm sections with a razor blade. The nucleus accumbens tissue was microdissected, using a punch with an internal diameter of 2 mm, placed in a vial containing 500 µl of perchloric acid, homogenized, and then centrifuged. Dopamine levels in the supernatants were measured by HPLC with electrochemical detection, as described above. The precipitates were dissolved in NaOH and assayed for protein content, using a BCA kit (Pierce Chemical, Rockford, IL).
Data Analysis and Statistics. Chromatographic data were collected and analyzed with the PowerChrom system (AD Instruments, Castle Hill, NSW, Australia). Data (mean ± S.E.M.) were expressed as a percentage of basal dopamine levels. Basal values were defined as the average dopamine levels detected in the samples obtained before administering each injection of nicotine (three or two samples before the first or second injection, respectively). Peak responses were detected in the samples collected 15 min after each injection of nicotine. Statistical analysis was performed based upon the number of litters. Each litter was represented by a single value, which was the average of one or more pups. Data were analyzed by analysis of variance and unpaired t tests, using SPSS software (version 8.0; Prentice Hall, Chicago, IL). The dependent variable was the peak dopamine increment expressed as a percentage of basal dopamine.
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Results |
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Females. The first experiment, shown in Fig. 2, determined the levels of nucleus accumbens dopamine in adolescent female offspring in response to sequential treatments with nicotine (0.07 mg/kg). Comparison of the dopamine responses in the noncross-fostered control groups shown in Figs. 2 (left) and 3 demonstrates that nicotine 0.07 and 0.105 mg/kg stimulated similar changes in dopamine release. Thus, 0.07 mg/kg nicotine was maximally stimulative. Prenatal nicotine exposure attenuated nucleus accumbens dopamine secretion in response to the first injection of 0.07 mg/kg nicotine [F(1,19) = 16.47, p < 0.01; Fig. 2, left]. In noncross-fostered offspring, gestational nicotine attenuated the dopamine response; peak dopamine levels were 35 ± 6% above baseline in the noncross-fostered gestational nicotine cohort (see Table 1 for a summary of peak dopamine levels) compared with 71 ± 9% in the noncross-fostered gestational control group [F(1,11) = 9.79, p < 0.05]. Similarly, in cross-fostered offspring gestational nicotine attenuated the dopamine response. Cross-fostered prenatal nicotine offspring showed only a 15 ± 10% increase in peak dopamine levels compared with 49 ± 8% in the cross-fostered controls [F(1,8) = 6.91, p < 0.05]. In summary, gestational nicotine attenuated dopamine release in both noncross-fostered and cross-fostered female offspring: in noncross-fostered cohorts, there was a 50% reduction, whereas in cross-fostered groups a 70% reduction was observed. Thus, in both noncross-fostered and cross-fostered adolescent female offspring, gestational nicotine depressed the nucleus accumbens dopamine response to the first injection of a maximally stimulative dose of nicotine.
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Figure 2 (left) also shows that cross-fostering per se reduced nucleus accumbens dopamine responses to 0.07 mg/kg nicotine in females [F(1,19) = 5.11, p < 0.05]. Cross-fostered adolescent rats that received gestational vehicle had a dopamine increase of 48.8 ± 8.4% above baseline, whereas the increase was 71 ± 9% in noncross-fostered offspring. Moreover, cross-fostered offspring that had gestational nicotine treatment failed to release dopamine in response to the acute injection of nicotine (15 ± 9%; p > 0.05), whereas the noncross-fostered gestational nicotine females showed an increase of 35 ± 6% (p < 0.005). No interaction between cross-fostered and gestational treatment was observed for dopamine secretion in response to an acute injection of nicotine.
Figure 2 (right) shows that prenatal control female off-spring had a diminished dopamine response to the second injection of nicotine. However, this did not occur in any of the other groups, in that the dopamine response to the second injection was not attenuated in comparison with the first injection.
To identify the main effects and interactions of treatments, basal dopamine levels were compared between all treatment groups that received acute injections of nicotine (see Table 2 for a summary of basal dopamine values). In female offspring that had received gestational nicotine, baseline dopamine levels were unaffected (1.6 ± 0.2 versus 1.5 ± 0.2 pg/10 µl for gestational nicotine versus control, respectively; F(1,49) = 0.21; p > 0.05). In contrast, cross-fostering reduced baseline dopamine levels in offspring, regardless of prenatal treatment (0.9 ± 0.1 compared with 1.7 ± 0.2 pg/10 µl in noncross-fostered offspring; F(1,49) = 7.12; p < 0.05). No interaction between cross-fostering and gestational treatment was observed [F(1,49) = 1.16; p > 0.05]. Nucleus accumbens dopamine content, determined in a separate group of noncross-fostered offspring that had been exposed to gestational vehicle versus nicotine, was also unaffected by prenatal treatment [93 ± 19 (n = 8) versus 94 ± 13 ng/mg protein (n = 8)]. This analysis of nucleus accumbens dopamine content was limited to noncross-fostered offspring because 1) cross-fostering did not interact with gestational treatment on basal dopamine levels or nicotine-induced dopamine secretion; and 2) the primary purpose of these investigations was to determine the effects of gestational exposure to nicotine. In summary, gestational nicotine had no effect on baseline extracellular nucleus accembens dopamine levels or on total dopamine content.
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In adolescent females, the absence of an interaction between gestational nicotine treatment and cross-fostering (Fig. 2) makes it unlikely that cross-fostering would alter the peak response to a higher dose of acute nicotine. Therefore, further experiments evaluated the acute stimulation of dopamine release by a higher dose of nicotine in noncross-fostered offspring exposed to gestational nicotine. Figure 3 demonstrates nucleus accumbens dopamine release in response to an acute injection of 0.105 mg/kg nicotine. In contrast to nicotine 0.07 mg/kg, there was no difference in dopamine release between female offspring that had received gestational control versus gestational nicotine. In these groups, dopamine release increased by 63 ± 9 and 82 ± 10% above baseline levels, respectively. Moreover, these dopamine responses to 0.105 mg/kg nicotine were no different than those observed to 0.07 mg/kg nicotine in noncross-fostered gestational control animals (Fig. 2). Thus, a higher dose of nicotine (0.105 mg/kg) is required to stimulate maximal nucleus accumbens dopamine release in female offspring that were exposed to nicotine during gestation. The dopamine response to this dose of nicotine was not accompanied by adverse behavioral responses in females, but higher doses were and, therefore, could not be tested.
Males. In male adolescent offspring, baseline dopamine levels were unaffected by prenatal nicotine treatment (1.6 ± 0.4 versus 2.0 ± 0.5 pg/10 µl for gestational nicotine versus control, respectively). Furthermore, in contrast to the data obtained with females, cross-fostering did not affect baseline dopamine levels in males. Cross-fostered males had baseline dopamine levels of 1.6 ± 0.4 compared with 1.9 ± 0.4 pg/10 µl in noncross-fostered males. No interaction was observed between cross-fostering and gestational treatment.
Figure 4 shows that gestational nicotine exposure resulted in a reduction in the dopamine response to a maximally stimulative injection of 0.07 mg/kg nicotine in adolescent male offspring, similar to that seen in their female counterparts (Fig. 2). In noncross-fostered male adolescents, the first nicotine injection induced peak dopamine levels that were 39 ± 10% above baseline in offspring exposed to gestational nicotine compared with 86 ± 11% in controls [F(1,14) = 9.73, p < 0.01]. Similarly, in cross-fostered males, peak responses were 38 ± 8% in gestational nicotine versus 83 ± 20% in controls (n = 5) [F(1,9) = 5.26, p < 0.05]. Thus, gestational nicotine treatment consistently reduced the acute dopamine response by approximately 55%. As observed in females, there were no differences across all treatment groups in the nucleus accumbens dopamine responses to a second injection of 0.07 mg/kg nicotine. Moreover, within treatments, the dopamine responses to the first and second injections were not significantly different. In summary, gestational nicotine treatment attenuated nucleus accumbens dopamine release to an acute injection of 0.07 mg/kg nicotine in both female and male adolescent rats. However, cross-fostering per se failed to attenuate dopamine release in male (Fig. 4) compared with female offspring (Fig. 2). To evaluate the effects of a higher dose of nicotine on dopamine release in male offspring exposed to prenatal nicotine, experiments were again focused on noncross-fostered offspring, because no interaction between gestational nicotine and cross-fostering was demonstrated. Figure 5 demonstrates that, similar to the observations made in adolescent females, gestational nicotine treatment did not affect the dopamine response in male offspring to the higher 0.105-mg/kg dose of nicotine (increase above baseline: 49 ± 16 versus 71 ± 11% in gestational nicotine versus control, respectively). Moreover, these dopamine responses were similar to those observed with 0.07 mg/kg nicotine in noncross-fostered gestational control males (Fig. 4). As with females, no adverse behavior responses were elicited by this higher dose.
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Discussion |
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In the present study, cross-fostering also affected nucleus accumbens dopamine secretion in adolescent females but not in males. In adolescent females, the effect of cross-fostering per se on the nucleus accumbens dopamine response to the lower dose of acute nicotine was similar to that seen with gestational nicotine treatment. Thus, cross-fostering reduced the dopamine response to 0.07 mg/kg nicotine. In fact, with the combination of cross-fostering and gestational nicotine exposure, adolescent females failed to show any dopamine response to 0.07 mg/kg nicotine. It should be noted that nucleus accumbens dopamine baseline levels were lower in cross-fostered versus noncross-fostered females. Such a reduction may reflect an increase in inhibitory tone, affecting the activity of dopaminergic neurons, which project from the ventral tegmental area to the nucleus accumbens. Increased inhibitory tone, perhaps due to developmental effects of cross-fostering on interactions between GABAergic and dopaminergic neurons (Ikemoto et al., 1997; Erhardt et al., 2002), might reduce both basal and nicotine-stimulated dopamine release in the nucleus accumbens of cross-fostered female adolescents. Exposure to nicotine throughout gestation decreased the sensitivity to nicotine-stimulated nucleus accumbens dopamine during adolescence, after a nicotine-free interval of approximately 35 d. Although the mechanism(s) underlying this reduced sensitivity to nicotine is unknown, basal dopamine secretion was unaffected by gestational nicotine in both male and female rats. Furthermore, nucleus accumbens dopamine content, tested in females only, was also unaffected by gestational nicotine treatment. These findings suggest that the dopamine secretory pool in nucleus accumbens dopaminergic neurons was unaffected. Similarly, both the activity of basal inputs and the intrinsic activity of these dopaminergic neurons seem to be unaltered, insofar as this can be inferred from the basal nucleus accumbens dopamine levels.
Nicotine exposure has been shown to alter the number and relative expression levels of nicotinic receptor subtypes in both the prenatal human brain in vitro and the perinatal monkey brain in vivo (Hellstrom-Lindahl et al., 2001; Slotkin et al., 2002). Prenatal human cortical neurons displayed increased [3H]epibatidine (0.2 nM) and [3H]cytisine (2 nM) binding after 3 days of nicotine in vitro (Hellstrom-Lindahl et al., 2001). In addition, increased expression of 
3 and 7 mRNAs, but not 4, was reported. In rhesus monkeys, perinatal exposure to nicotine selectively up-regulated nicotinic receptors in the brainstem and cerebral cortex. These findings support the hypothesis that nicotinic cholinergic receptor expression may be developmentally modified in the present model of chronic gestational nicotine treatment. For example, if gestational nicotine reduced the number of functional nicotinic receptors (i.e., up-regulated the desensitized fraction) and/or altered the ratio of the various nicotinic cholinergic receptor holoproteins expressed by mesolimbic dopaminergic neurons (Hsu et al., 1996; Klink et al., 2001), reduced sensitivity to nicotine might be observed during adolescence. Moreover, similar developmental changes in receptor subunit expression might be related to the difference in dopamine responsiveness to the second versus the first injection of nicotine that was observed in females in the gestational control, but not the gestational nicotine group (Fig. 2).
It may seem paradoxical that an animal model of human vulnerability to nicotine dependence, as reported in adolescent daughters of mothers who smoked during pregnancy, would demonstrate reduced sensitivity to nicotine-induced dopamine secretion. This seems paradoxical in view of the fact that nucleus accumbens dopamine secretion is directly associated with the rewarding properties of addictive drugs (Di Chiara, 1999). However, it has been suggested that lower levels of nucleus accumbens dopamine are related to drug abuse (Gardner, 1999). Blum and colleagues postulated the existence of a reward deficiency syndrome linking addictive, impulsive, and compulsive disorders to the basal dysfunction of dopamine reward systems (Blum et al., 1995, 1996). This hypothesis was, in part, based on animal studies showing that dopamine agonists decreased self-administration and reduced drug seeking (Dyr et al., 1993; Pulvirenti and Koob, 1994). In addition, alcohol preference in rats has been linked to low levels of nucleus accumbens dopamine (McBride et al., 1995). Therefore, it is possible that a lesser dopamine response to nicotine would require higher doses of the drug to drive the mesolimbic system and obtain adequate dopamine-dependent reinforcement. Thus, a human subject with reduced dopamine responsiveness would probably obtain sufficient dopamine-dependent reinforcement from nicotine by smoking more.
An increase in cigarette smoking would be expected to lead to stronger behavioral conditioning that may underlie the vulnerability of gestational nicotine exposed female adolescents to become dependent on cigarette smoking. Viewed in terms of learning theory, higher fixed ratio schedules (ratio of smoking responses to nicotine reinforcement) would result in increased difficulty in achieving extinction. Thus, gestational nicotine exposure would compromise the ability of female adolescents to quit smoking.
Figure 2 shows the reduction in dopamine responsiveness to a second dose of nicotine in the gestational control females; in contrast, reduced responsiveness was not evident in the gestational nicotine group. Thus, regardless of gestational treatment, the dopamine responses to the second dose of acute nicotine were the same. This lack of a difference may suggest that an increased number of responses (e.g., cigarette smoking) would not be required to achieve reinforcement in individuals gestationally exposed to nicotine. However, there are two facts that are likely to invalidate this conjecture: 1) in the present study, nicotine was delivered by forced injections, rather than self-administered; and 2) the second injection was delivered 1.5 h after the first.
During acquisition of cigarette smoking, many adolescents are likely to have large time intervals between cigarette use due to factors such as school, parental restrictions, and the irregular occurrence of social interactions that stimulate smoking. In fact, the initial symptoms of nicotine dependence can develop without daily episodes of cigarette smoking (DiFranza et al., 2002), and decreased responsiveness is unlikely to be present at the initiation of the next episode, which often occurs a day or more later. As proposed in the preceding discussion, the increased strength of the stimulus-response (i.e., cigarette presentation-cigarette smoking) association would enhance the susceptibility to becoming dependent on cigarette smoking.
These investigations also demonstrated a similar degree of reduced nucleus accumbens dopamine responsiveness to nicotine in male adolescent offspring with gestational nicotine exposure. This may suggest that dopamine neurotransmission in nucleus accumbens is tangential to the predisposing influence of gestational nicotine exposure on adolescent female nicotine dependence. However, based on the sexually dimorphic development of the brain, gestational exposure to nicotine may have different neuroanatomical and behavioral consequences. Thus, attenuated nucleus accumbens dopamine responsiveness may be responsible for the following gender-specific consequences: the predisposition to dependence on smoking in female adolescents and the prevalence of the attention deficit hyperactivity disorder (ADHD) in adolescent males exposed to nicotine in utero (Milberger et al., 1996).
During adolescence, sexual dimorphism in dopaminergic systems is evident in the overproduction and pruning of D1 and D2 receptors that is much more prevalent in striatum and accumbens of male than female rats (Andersen and Teicher, 1997). This sex difference, which peaks at the onset of puberty, may be associated with gender differences in the prevalence of ADHD (Andersen et al., 2000). Using an animal model of ADHD, differences have been observed in distribution, affinity, and plasticity of D1 and D2 receptors in the nucleus accumbens, caudate-putamen, and olfactory tubercle (Carey et al., 1998). Using this model, a reduction in electrically stimulated dopamine release in caudate-putamen and prefrontal cortex was also associated with ADHD (Russell et al., 1995). These and other studies indicate that altered dopamine responsiveness may contribute to ADHD (for review, see Biederman and Faraone, 2002,); therefore, the reduced dopamine secretion observed herein could underlie the increase in ADHD in males with gestational nicotine exposure. The reduced nicotine-induced dopamine release during adolescence suggests that a reduction in dopamine responsiveness to other stimuli (e.g., electrical stimulation) may be induced by gestational exposure to nicotine.
In summary, both males and females exposed to nicotine during gestation show diminished nucleus accumbens dopamine responsiveness to nicotine during adolescence. Based on the sexually dimorphic development of the brain and of dopamine neurotransmission, we postulate that the diminished nucleus accumbens dopamine responsiveness, observed herein, may have gender-specific effects on dopamine-dependent brain functions related to motivation. This may lead to different behavioral consequences: ADHD in males and a predisposition to dependence on smoking in females.
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ABBREVIATIONS: HPLC, high-pressure liquid chromatography; ADHD, attention deficit hyperactivity disorder.
Address correspondence to: Dr. Burt M. Sharp, Department of Pharmacology, University of Tennessee Health Science Center, 874 Union Ave., Memphis, TN 38163. E-mail: bsharp{at}utmem.edu
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