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The mean age of first voluntary tobacco inhalation is 12.3 years (DiFranza et al., 2004). 60% of smokers start smoking before the age of 14 and 90% are dependent before reaching the age of 19. Females are typically more sensitive to nicotine than males yet few studies examine the effects of nicotine on the reward systems in pre-adolescent female subjects. This study utilized the single trial conditioned place preference (CPP) test in very young (postnatal day 25-27) rats of both sexes. Latent effects on anxiety and amphetamine response were determined 5 and 7 days following a second nicotine exposure. Results show that 0.05 mg/kg nicotine induced CPP in females following a single trial while both sexes showed CPP following the 0.5 mg/kg dose. Five days later, rats dosed with 0.05 mg/kg show increased time on the open arm of the elevated plus maze, an anxiolytic response. While baseline activity was increased in nicotine-exposed males 7 days following dosing, amphetamine response was not affected by the treatments in either sex. Therefore, our data suggest that young females are more sensitive to nicotine reward than males supporting a heightened sensitivity of the mesolimbic dopamine system in very young females. However, alterations in baseline activity were only seen in males suggesting that different components of the system are affected by nicotine in each sex. An anxiolytic response to nicotine 5 days after dosing may suggest that this very young age group is uniquely affected by this very low nicotine dose. Clearly, nicotine has substantial acute and lasting effects during pre-adolescence at doses substantially lower than seen at older ages as reported by others. These effects, which could potentially result from cigarette or e-cigarette smoking by 11-12 year old children , focus attention on the vulnerability of this age group to nicotine., (Copyright © 2014 Elsevier Inc. All rights reserved.)

In previous studies, acutely administered oral methylphenidate (MPD, 3mg/kg) prior to testing improved performance on the radial arm maze in juvenile rats. In order to examine the mechanisms producing this improvement we administered MPD once prior to each test of anxiety, locomotor activity and attention. On postnatal day (PND) 22 on an elevated plus maze, rats spent more time beyond the rails on the open arms and showed altered risk-assessment behaviors suggesting an anxiolytic-like effect of MPD. Grid crossings on the plus maze indicated that MPD increased locomotor activity, as did activity recording on PND 23. In another group of juveniles, MPD improved performance in a multi-trial attention task in an age-dependent fashion. These data suggest that oral MPD has multifaceted effects on juvenile rats that together improve performance on cognitive tests such as the radial arm maze. In addition, our data support human studies finding multifaceted effects of MPD., (2010 Elsevier B.V. and ECNP. All rights reserved.)

The distribution of 3'-azido-3'-deoxythymidine (AZT, zidovudine), an antiviral drug used in the treatment of human immunodeficiency virus, was investigated in gestation day-20 (G-20) fetuses and in postnatal day-20 (PND-20) rats. At both ages, a single dose of 150 mg/kg (1.78 mmol/kg) AZT was administered orally along with tracer amounts of 14C-AZT, and rats were randomly killed at 15, 30, 60, 120, or 240 min after dosing. The fetuses, brains, and spinal cords were processed for autoradiography. The peak concentrations of AZT in plasma of G-20 and PND-20 rats were 92.2 microg/mL (0.345 micromol/mL) and 56.6 microg/mL (0.21 micromol/mL) at 15 and 30 min after intubation, respectively. The peak concentration of fetal tissue occurred in the colon at 60 min and was 205.8 microg/g tissue. In the G-20 rats, the brain showed higher levels of AZT than spinal cord only at the 30-min sample time, whereas in the PND-20 rats, greater radioactivity was found in the spinal cord up to the 240-min sample time. This pattern of AZT distribution in the central nervous system may hypothetically be attributed to the postnatal development of an organic anion carrier system believed to be responsible for transporting AZT from the brain to the blood, resulting in relatively greater overall exposure of the spinal cord to AZT than observed in the brain., (Copyright 2001 Wiley-Liss, Inc. and the American Pharmaceutical Association)

In order to determine whether developmental cocaine exposure altered the functional responses of dopamine systems, the behavioral responses to selective D1 or D2/D3 agonists were examined and compared to rats treated during the same period with a selective inhibitor of the dopamine transporter, GBR 12909. Sprague-Dawley rats were administered cocaine or GBR 12909 at 25 or 50 mg/kg/day during postnatal days (PND) 11-20. At 60+ days of age, rats were administered a challenge drug (either SKF 82958, a full D1 agonist, at 1.0 or 10 mg/kg, or quinpirole, a D2/D3 agonist, at 0.08 or 0.5 mg/kg, or saline) and subjected to 1 h of behavioral assessment. The cocaine or GBR treatments produced significant effects in three behavioral categories: distance traveled, sniffing, and rearing. For distance traveled, preweaning treatments interacted with sex since in the males, all cocaine- and GBR-treated groups showed relatively flat patterns of locomotor activity across time blocks, while in the treated females, locomotor activity typically increased across the time blocks. For other behaviors, the treatments generally produced enhanced responses to the challenge drugs. These results suggest that intermittent inhibition of the dopamine transporter with either cocaine or GBR during PND 11-20 produces long-term alterations in the functional responses of dopaminergic systems but that the neural substrates for these effects depend upon the sex of the animal.

The impact of cocaine exposure during development on behavioral sensitization as measured by locomotor activity and stereotypy following repeated intermittent administration of amphetamine is examined. Male and female Sprague-Dawley rats were exposed to cocaine at 50 mg/kg/day during postnatal days (PND) 11-20 and, as adults (PND193-212), were administered seven daily injections of 2.0 mg/kg amphetamine. Both locomotor activity and stereotypic behavior were assessed following the first and seventh injections. Control males and females showed sensitized behavior following repeated amphetamine injections with females showing greater locomotion while males showed increased stereotypy. Male rats pretreated with cocaine failed to develop sensitized locomotor or stereotypic responses following repeated amphetamine injections consistent with dampened D(1) receptor activity. Females pretreated with cocaine did not show a sensitized locomotor response but did display sensitization of stereotypy following repeated amphetamine administration. Thus, it appears that postnatal cocaine treatment produces differential effects on the circuits mediating sensitization behavior in male and female rats.

Because AZT (azidothymidine, zidovudine, ZDV) has become the standard of care for preventing HIV transmission during pregnancy, we conducted a study to assess the possible neurobehavioral effects of this drug, using a rat model. Each litter was randomly assigned to a treatment group: vehicle, AZT 50, 100, or 150 mg/kg, or no treatment. Treatments were administered once daily via gastric intubation, prenatally from gestation day (G) 19-22 and then postnatally from postnatal day (PND) 2-20, except the nontreated group, which was only weighed every 4 days. On PND21 each rat was given a single dose of amphetamine (0.25, 0.50, 0.75, or 1.0 mg/kg) or saline and placed in the Accuscan activity chamber for 1 h of data collection and video taping. Results show that all of the behaviors analyzed produced statistically significant main effects of perinatal treatment, challenge drug, and time block. For distance traveled, there was a significant three-way interaction between treatment, sex, and time block, an effect that was independent of the effects of handling and injecting the rats. That is, within the males, the AZT 150 group displayed the greatest amount of locomotion, while among the females, the AZT 50 group was the most active. Furthermore, the AZT 50 group showed significantly less margin time (wall hugging) and more grooming than the nontreated control group. However, handling contributed to these differences because they were not observed when the vehicle-intubated group was used as the control. Across all treatment groups, amphetamine increased locomotion, the duration of rearing, and sniffing, while it decreased wall hugging, grooming, and time spent quiet. Complex interactions between amphetamine dose and time block were also seen for each behavior. In summary, these data indicate that amphetamine, at the doses used in the current study, alters behavior in the rat at 21 days of age, and that perinatal AZT exposure alters behavior in a single domain, locomotion with the threshold for this effect depending on genders.

Sixty-day-old rats treated with cocaine (50 mg/kg SC) during postnatal days (PND) 11-20 received daily injections of apomorphine (2.0 mg/kg SC) for 10 consecutive days to examine the development of sensitization to a direct dopamine agonist. Behavior was monitored on days 1, 5, and 10, using a photobeam system, and on day 10 using the videotape assessments as well. Locomotor sensitization to apomorphine developed in the preweaning vehicle-treated males only. Neither the cocaine-treated males nor any females exhibited locomotor sensitization to repeated apomorphine injections at 2 mg/kg. There were no other treatment-related effects except for grooming, which showed an interaction between treatment and gender. Overall, every behavior analyzed showed significant apomorphine effects, except rearing. Margin time (wall hugging), grooming, and quiet were significantly decreased by apomorphine, while locomotion and the duration of sniffing were increased. In summary, these data indicate that with respect to locomotor activity, the development of sensitization to apomorphine at 2.0 mg/kg is prevented by preweaning cocaine administration in males. These data further suggest that developmental cocaine exposure produces long-term alterations in DA D1 receptor-mediated responses in male rats.

Objective: Abnormalities in the production of nitric oxide and endothelin-1 have been implicated in the development of preeclampsia. We postulated that long-term nitric oxide synthase inhibition with L-nitro-arginine methyl ester would induce sustained hypertension, a rise in plasma levels of endothelin-1, and fetal growth restriction., Study Design: Conscious virgin and pregnant Sprague-Dawley rats received infusions of vehicle or L-nitro-arginine methyl ester (2.5 mg/kg/hr) for 11 days. Mean arterial pressure was assessed serially. On day 21 of gestation (or equivalent in virgin rats) plasma was collected for endothelin-1 levels; pup weight and litter size were determined. Data were analyzed with analysis of variance and regression techniques., Results: Mean arterial pressure was constant in virgin control rats (n = 7) but declined in pregnant control rats (n = 11) as gestation advanced. Nitric oxide synthase inhibition in virgin (n = 10) and pregnant (n = 11) rats caused sustained elevations in mean arterial pressure (165 +/- 7 vs 100 +/- 3 mm Hg, L-nitro-arginine methyl ester vs control virgin rats, p < 0.0001; 149 +/- 5 vs 91 +/- 2 mm Hg, L-nitro-arginine methyl ester vs control pregnant rats, p < 0.0001). L-nitro-arginine methyl ester induced a rise in plasma endothelin-1 levels in virgin (4.4 +/- 0.1 vs 3.5 +/- 0.1 pg/ml, L-nitro-arginine methyl ester vs control, p < 0.0001) and pregnant rats (3.0 +/- 0.1 vs 2.6 +/- 0.1 pg/ml, L-nitro-arginine methyl ester vs control, p < 0.0001). Pregnant rats had lower endothelin-1 levels than did virgin rats (p < 0.0001). Mean arterial pressure and endothelin-1 were significantly correlated in pregnant rats. L-nitro-arginine methyl ester decreased pup weight (2.4 +/- 0.4 vs 3.7 +/- 0.2 gm/pup/litter, L-nitro-arginine methyl ester vs control, p < 0.01) and litter size (6.6 +/- 1.3 vs 10.2 +/- 0.9 pups/litter, L-nitro-arginine methyl ester vs control, p < 0.05)., Conclusions: Long-term nitric oxide synthase blockade causes sustained hypertension, elevated levels of endothelin-1, and fetal growth restriction. Although the endocrine and pressor effects are not unique to pregnancy, this model clearly induces some of the changes seen in preeclampsia and may be useful for studying specific interventions.

Either 45 or 60 mg/kg cocaine HCl was administered from days 8-22 of gestation. Pair-fed and nontreated groups served as controls and all treated and control litters were fostered at birth to untreated dams. To examine whether cocaine produces effects on the rest-activity cycle of the offspring, groups of three littermates from each of the treated and control groups were tested for an 8-h observation period on electronic activity monitors at 22 days of age. Neither activity level nor the rest-activity pattern were affected by cocaine. These findings are discussed in relation to previous studies of cannabis and methadone effects on the rest-activity measure.

Experiments were conducted to determine some of the metabolic correlates of tonic opioid activity in the central nervous system under conditions previously examined for changes in monoamine levels. The glucose metabolic rates in seven brain regions were determined by autoradiographic visualization of 14C-deoxyglucose incorporation in female rats after 8 days of chronic exposure to naltrexone pellets and 10 days after pellet removal. Autoradiographs were analyzed on a region-by-region basis to correspond to areas previously dissected and analyzed for changes in monoamine content under similar experimental conditions. Chronic administration of naltrexone resulted in a significant decrease in the metabolic activity of neurons in the striatum. Other brain areas examined under this condition were not significantly affected. Ten days following pellet removal, 14C-deoxy-glucose incorporation was indistinguishable from that determined in placebo treated rats in all brain regions examined. These results indicate that tonic opioid input is an important determinant of metabolic activity in the striatum. In addition, these results indicate that conditions previously shown to alter regional content of monoamines do not necessarily produce concomitant changes in regional glucose utilization.