Offspring of Prenatal IV Nicotine Exposure Exhibit Increased Sensitivity to the Reinforcing Effects of Methamphetamine

Maternal smoking during pregnancy is associated with increased substance abuse in offspring. Preclinical research shows that in utero exposure to nicotine, the primary psychoactive compound in tobacco smoke, influences the neurodevelopment of reward systems and alters motivated behavior in offspring. The present study determined if prenatal nicotine (PN) exposure altered the sensitivity to the reinforcing and aversive effects of methamphetamine (METH) in offspring using a low dose, intravenous (IV) exposure method. Pregnant dams were administered nicotine (0.05 mg/kg/injection) or prenatal saline (PS) 3×/day on gestational days 8–21, and adult offspring were tested using METH self-administration (experiment 1) or METH-induced conditioned taste aversion (CTA; experiment 2) procedures. For METH self-administration, animals were trained to respond for IV METH (0.05 mg/kg/infusion; fixed-ratio 3) and they were tested on varying doses of the reinforcer (0.0005–1.0 mg/kg/infusion). For METH CTA, rats received three saccharin and METH pairings (0, 0.3, or 0.5 mg/kg, sc) followed by 14 daily extinction trials. Experiment 1: PN and PS animals exhibited inverted U-shaped dose-response curves; however, the PN animal’s curve was shifted to the left, suggesting PN animals were more sensitive to the reinforcing effects of METH. Experiment 2: METH CTA was acquired in a dose-dependent manner and the factor of PN exposure was not related to the acquisition or extinction of METH-induced CTA. There were no sex differences in either experiment. These results indicate that IV PN-exposed adult offspring exhibited increased sensitivity to IV METH. This suggests that PN exposure, via maternal smoking, will alter the reinforcing effects of METH during later stages of development, and furthermore, will influence substance use vulnerability in adult human offspring

Effects of Low Sulfur Fuel and a Catalyzed Particle Trap on the Composition and Toxicity of Diesel Emissions

In this study we compared a “baseline” condition of uncontrolled diesel engine exhaust (DEE) emissions generated with current (circa 2003) certification fuel to an emissions-reduction (ER) case with low sulfur fuel and a catalyzed particle trap. Lung toxicity assessments (resistance to respiratory viral infection, lung inflammation, and oxidative stress) were performed on mice (C57Bl/6) exposed by inhalation (6 hr/day for 7 days). The engine was operated identically (same engine load) in both cases, and the inhalation exposures were conducted at the same exhaust dilution rate. For baseline DEE, this dilution resulted in a particle mass (PM) concentration of approximately 200 μg/m(3) PM, whereas the ER reduced the PM and almost every other measured constituent [except nitrogen oxides (NO(x))] to near background levels in the exposure atmospheres. These measurements included PM, PM size distribution, PM composition (carbon, ions, elements), NO(x), carbon monoxide, speciated/total volatile hydrocarbons, and several classes of semi-volatile organic compounds. After exposure concluded, one group of mice was immediately sacrificed and assessed for inflammation and oxidative stress in lung homogenate. Another group of mice were intratracheally instilled with respiratory syncytial virus (RSV), and RSV lung clearance and inflammation was assessed 4 days later. Baseline DEE produced statistically significant biological effects for all measured parameters. The use of low sulfur fuel and a catalyzed trap either completely or nearly eliminated the effects

Prenatal IV Cocaine: Alterations in Auditory Information Processing

One clue regarding the basis of cocaine-induced deficits in attentional processing is provided by the clinical findings of changes in the infants’ startle response; observations buttressed by neurophysiological evidence of alterations in brainstem transmission time. Using the IV route of administration and doses that mimic the peak arterial levels of cocaine use in humans, the present study examined the effects of prenatal cocaine on auditory information processing via tests of the auditory startle response (ASR), habituation, and prepulse inhibition (PPI) in the offspring. Nulliparous Long–Evans female rats, implanted with an IV access port prior to breeding, were administered saline, 0.5, 1.0, or 3.0 mg/kg/injection of cocaine HCL (COC) from gestation day (GD) 8–20 (1×/day-GD8–14, 2×/day-GD15–20). COC had no significant effects on maternal/litter parameters or growth of the offspring. At 18–20 days of age, one male and one female, randomly selected from each litter displayed an increased ASR (>30% for males at 1.0 mg/kg and >30% for females at 3.0 mg/kg). When reassessed in adulthood (D90–100), a linear dose–response increase was noted on response amplitude. At both test ages, within-session habituation was retarded by prenatal cocaine treatment. Testing the females in diestrus vs. estrus did not alter the results. Prenatal cocaine altered the PPI response function across interstimulus interval and induced significant sex-dependent changes in response latency. Idazoxan, an α2-adrenergic receptor antagonist, significantly enhanced the ASR, but less enhancement was noted with increasing doses of prenatal cocaine. Thus, in utero exposure to cocaine, when delivered via a protocol designed to capture prominent features of recreational usage, causes persistent, if not permanent, alterations in auditory information processing, and suggests dysfunction of the central noradrenergic circuitry modulating, if not mediating, these responses

Intravenous Prenatal Nicotine Exposure Alters METH-Induced Hyperactivity, Conditioned Hyperactivity, and BDNF in Adult Rat Offspring

In the USA, approximately 15% of women smoke tobacco cigarettes during pregnancy. In utero tobacco smoke exposure produces somatic growth deficits like intrauterine growth restriction and low birth w

Lobeline attenuates d-methamphetamine self-administration in rats

ABSTRACT ␣-Lobeline inhibits d-amphetamine-evoked dopamine release from striatal slices in vitro, appearing to reduce the cytosolic pool of dopamine available for reverse transport by the dopamine transporter. Based on this neurochemical mechanism of action, the present study determined if lobeline decreases d-methamphetamine self-administration. Rats were surgically implanted with jugular catheters and were trained to lever press on a fixed ratio 5 schedule for intravenous d-methamphetamine (0.05 mg/kg/infusion). To assess the specificity of the effect of lobeline, another group of rats was trained to lever press on a fixed ratio 5 schedule for sucrose reinforcement. Pretreatment of rats with lobeline (0.3-3.0 mg/kg, 15 min prior to the session) decreased responding for both d-methamphetamine and sucrose reinforcement. Following repeated lobeline (3.0 mg/kg) administration, tolerance developed to the decrease in responding for sucrose; however, the lobeline-induced decrease in responding for d-methamphetamine persisted. Furthermore, the lobeline-induced decrease in responding for d-methamphetamine was not surmounted by increasing the unit dose of d-methamphetamine. These results suggest that lobeline produces a nonspecific rate suppressant effect following acute administration, to which tolerance develops following repeated administration. Importantly, the results also suggest that repeated administration of lobeline specifically decreases responding for d-methamphetamine in a noncompetitive manner. Thus, lobeline may be an effective, novel pharmacotherapy for d-methamphetamine abuse