Prenatal nicotine exposure is associated with an increase in [125I]epibatidine binding in discrete cortical regions in rats

Previously, it was reported that hyperactive male offspring of dams exposed to nicotine (6 mg/kg/day) during gestation had an increase in cortical alpha4-beta2 nicotinic receptor subtype density as determined by [3H]cytisine binding in tissue homogenate [Tizabi Y, Popke EJ, Rahman MA, Nespor SM, Grunberg NE. Hyperactivity induced by prenatal nicotine exposure is associated with an increase in cortical nicotinic receptors. Pharmacol, Biochem Behav 1997;58:141-6]. [125I]Epibatidine labels alpha4beta2 nicotinic receptors with higher affinity than [3H]cytisine. In the present study, using quantitative autoradiography, we evaluated the effects of in-utero exposure to nicotine (9 mg/kg/day) on [125I]epibatidine binding in 46 discrete brain regions of 36-day-old male offspring of Sprague-Dawley rats. This dosage of nicotine administered during pregnancy to same rats was shown to result in increased vertical activity in the male offspring [Tizabi Y, Russell LT, Nespor SM, Perry DC, Grunberg NE. Prenatal nicotine exposure: effects on locomotor activity and central [125I]alpha-BT binding in rats. Pharmacol, Biochem Behav (in press).]. Prenatal nicotine exposure resulted in increases in receptor densities of the somatosensory cortex (90%) and the visual cortex (107%) only. Moreover, these increases were restricted to cortical layer 1. Collectively, these results indicate that prenatal nicotine exposure affects specific nicotinic receptors in selective cortical regions of male offspring. These neurochemical effects may be responsible for some of the behavioral abnormalities seen in such offspring.     

The ontogeny of benzodiazepine receptors in selected regions of the rat brain: effect of perinatal exposure to diazepam

The postnatal development of the binding of [3H]flunitrazepam to benzodiazepine receptors has been studied in the frontal cortex, cerebellum, striatum, hypothalamus and hippocampus of the rat after prenatal, perinatal and postnatal exposure to diazepam. The dams were injected subcutaneously with single daily doses of 1 mg/kg of diazepam from day 7-20 of gestation or from day 15 of gestation day 6 after birth. Offspring of untreated dams were injected in the same way from postnatal day 7-20. The developmental profiles of the binding of [3H]flunitrazepam obtained in both control and diazepam-treated groups of animals were very similar. This supported the idea of a sequential development of benzodiazepine receptors in relation to the different rates of maturation of certain structures of the brain. Prenatal administration of diazepam resulted in an increase of the binding of [3H]flunitrazepam in the frontal cortex by 20% at postnatal day 90 and in a decrease of binding in the hippocampus by 14% at postnatal day 60 and an increase of binding by 18% at postnatal day 90. Perinatal exposure to diazepam did not affect the binding of [3H]flunitrazepam in the hippocampus in young adult offspring. Postnatal application of diazepam resulted in a transiently decreased binding of [3H]flunitrazepam in the cerebellum by 20% at postnatal day 28. The results obtained point to the necessity for a prolonged evaluation of events after exposure to diazepam in early stages of development of the brain.     

Exposure to nicotine enhances the behavioral stimulant effect of nicotine and increases binding of [3H]acetylcholine to nicotinic receptors

Rats were given daily injections of nicotine sulfate in doses ranging from 0.1 to 0.4 mg/kg. The behavioral effect of these injections was measured as locomotor activity in photocell cages. Repeated administration of the same dose to each rat resulted in an enhancement of the stimulant effect of nicotine. This enhanced behavioral effect was quite pronounced within 5 days of repeated injection. Tissue from the cerebral cortex of these rats, exposed to nicotine for 5 days, was assayed for binding of [3H]acetylcholine to nicotinic receptors. These relatively small doses of nicotine resulted in 18-26% increases in cortical nicotinic receptors, compared to saline-treated rats. Rats exposed to 0.2 mg/kg of nicotine for 5 days and then given saline for 7 days still showed an enhanced behavioral response to nicotine on the eighth day after exposure, and nicotinic binding in the cortex was still elevated. However, 21 days after exposure to nicotine both the behavioral response to nicotine and the binding values had returned to the same values as those of saline-treated rats. These data imply that increased binding of [3H]acetylcholine to nicotinic sites and the enhanced behavioral effect of nicotine are functionally linked.     

Regulation of nicotinic receptors in rat brain following quasi-irreversible nicotinic blockade by chlorisondamine and chronic treatment with nicotine.

1. Chronic administration of nicotinic agonists in vivo increases the density of brain nicotinic binding sites. It has been proposed that this up-regulation results from agonist-induced functional blockade of nicotinic receptors. This hypothesis was tested by examining post mortem [3H]-nicotine and [125I]-alpha-bungarotoxin ([125I]-alpha BTX) binding following treatment in vivo with the quasi-irreversible and insurmountable CNS nicotinic blocker chlorisondamine, given either alone or in combination with chronic nicotine administration. 2. In rats that had not received chlorisondamine pretreatment, chronic nicotine administration (0.6 mg kg-1 s.c., twice daily for 12 days) increased [3H]-nicotine binding density (Bmax) in forebrain tissue sections by 19%, with no change in the apparent dissociation constant (KD). Chlorisondamine (10 mg kg-1, s.c.), given once prior to the chronic treatment phase, neither increased [3H]-nicotine binding by itself, nor altered the extent of nicotine-induced up-regulation. Nevertheless, chlorisondamine pretreatment resulted in a persistent blockade of CNS nicotinic receptors, as demonstrated by complete block of acute locomotor responses to nicotine. 3. In a second experiment, [3H]-nicotine and [125I]-alpha BTX binding was measured in tissue homogenates prepared from several brain regions. In the absence of chlorisondamine pretreatment, chronic nicotine administration (1 mg kg-1 s.c., twice daily for 12 days) increased the Bmax of [3H]-nicotine binding in the cerebral cortex (by 34%), striatum (by 28%), midbrain (by 16%) and hippocampus (by 36%); KD was unchanged. As before, this up-regulation was neither mimicked nor blocked by chlorisondamine pretreatment (10 mg kg-1, s.c., given twice), despite persistent blockade of acute locomotor responses to nicotine.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of differential rearing environments on nicotine-stimulated locomotor activity and nicotinic acetylcholine receptor subtypes

OBJECTIVE Individuals vary in sensitivity to the behavioral effects of nicotine,resulting in differences in their vulnerability to addiction.The role of rearing environment in determining individual sensitivity to nicotine is unclear.The neuropharmacological mechanisms mediating the effect of rearing environment on the actions of nicotine are also understood.Thus,the contribution of rearing environment in determining the sensitivity to the locomotor effects of nicotine and regulating α4β2*-and α7-nicotinic acetylcholine(n ACh) receptor expressionwas determined in rats reared in isolated(IC) or enriched(EC) conditions.METHODS To measure locomotor activity,adolescent rats(postnatal day 21-51)were injected with saline(1 mL·kg~(-1)) or nicotine(0.3 mg·kg~(-1)) subcutaneously,then placed in chamberswhere ambulatory activity was monitored for 30-min by computer for 14 daily sessions.α4β2*-andα7-n ACh receptor expression in the mesolimbic dopamine pathway was determined by quantitative autoradiography of [125 I]-epibatidine and [125 I]-bungarotoxinbinding,respectively,in 16 μmol·L~(-1) coronal sections.Values for receptor expression in fmol are ±s of 8 brains and compared by two-tailed,unpaired t-test with P<0.05 considered significant.RESULTS EC-rats are similarly sensitive as IC-rats to the locomotor effects of nicotine.[125 I]-epibatidine binding in the ventral tegmental area of EC-rats was reduced(2.8±0.3 fmo L) compared to IC-rats(4.0±0.4 fmo L);there was no difference in the nucleus accumbens.There was no difference between EC-and IC-rats in α7-n ACh receptor expression in the mesolimbic dopamine pathway.CONCLUSION Rearing environment differentially regulates n ACh receptor subtypes in EC and IC rats.These data suggest regulation of n ACh receptors by environmental factors may be a mechanism for the protective effect of enrichment against altered sensitivity to nicotine in genetically vulnerable individuals.The characterization of these mechanisms will aid in development of novel pharmacological tools mimicking the protection afforded by environmental enrichment in nicotine-sensitive individuals.     

Brain growth spurt-prenatal ethanol exposure and the guinea pig hippocampal glutamate signaling system

This study tested the hypothesis that prenatal ethanol exposure (PEE) during the brain growth spurt (BGS) in the guinea pig suppresses the glutamate-NMDA receptor-nitric oxide synthase (NOS) signaling system in the developing hippocampus. Pregnant guinea pigs [term, about gestational day (GD) 68] received daily oral administration of 2 g ethanol/kg maternal body weight/day on GD 43 and/or GD 44 and then 4 g ethanol/kg maternal body weight/day from GD 45 to GD 62, isocaloric-sucrose/pair-feeding or water. Offspring were studied at GD 63 (near-term fetus) and postnatal day (PD) 10 (young postnatal life). Maternal blood ethanol concentration during ethanol treatment, pregnancy outcome variables, no change in spontaneous locomotor activity, and decreased brain and cerebral cortical weight data were reported previously [Neurotoxicol. Teratol. 23 (2001) 355]. This BGS-PEE regimen did not affect hippocampal stimulated glutamate release in young postnatal offspring, NMDA receptors as assessed by [3H]MK-801 binding, or NOS activity in near-term fetal offspring. Furthermore, BGS-PEE did not affect the number of hippocampal CA1 and CA3 pyramidal cells and dentate gyrus granule cells in defined locations of these three regions in the hippocampal formation. These findings are in contrast to the effects of chronic prenatal exposure to this ethanol regimen throughout gestation, including suppression of the hippocampal glutamate-NMDA receptor-NOS signaling system, decreased number of hippocampal CA1 pyramidal cells, increased spontaneous locomotor activity, and impaired performance in the Morris water maze.     

Subchronic treatment of rats with nicotine: effects on tolerance and on [3H]acetylcholine and [3H]nicotine binding in the brain

The effects of subchronic nicotine treatment on the development of tolerance and on two nicotinic ligand binding sites were investigated. After subcutaneous injection of nicotine (0.45 mg nicotine base/kg) or saline twice a day for 14 days the body weight of rats was significantly lower than that of control animals. A significant tolerance to the acute effects of nicotine on locomotor activity and body temperature was observed after the treatment period. Nicotine treatment also resulted in a significant increase in [3H]acetylcholine (3H-ACh) binding in the midbrain (48.3% increase in comparison with controls) and hippocampus (38.3% increase), whereas the binding of [3H]nicotine (3H-NIC) was unaffected in all brain areas investigated. These results indicate that subchronic s.c. injections of nicotine can differentially affect the binding of two different nicotinic ligands in the brain. It is also concluded that the development of tolerance to the acute effects of nicotine on locomotor activity and temperature is not directly dependent upon changes in binding of [3H]nicotine to the brain.     

Imidacloprid induces neurobehavioral deficits and increases expression of glial fibrillary acidic protein in the motor cortex and hippocampus in offspring rats following in utero exposure

Imidacloprid, a neonicotinoid, is one of the fastest growing insecticides in use worldwide because of its selectivity for insects. The potential for neurotoxicity following in utero exposure to imidacloprid is not known. Timed pregnant Sprague-Dawley rats (300-350 g) on d 9 of gestation were treated with a single intraperitoneal injection (i.p.) of imidacloprid (337 mg/kg, 0.75 x LD50, in corn oil). Control rats were treated with corn oil. On postnatal day (PND) 30, all male and female offspring were evaluated for (a) acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) activity, (b) ligand binding for nicotinic acetylcholine receptors (nAChR) and muscarinic acetylcholine receptors (m2 mAChR), (c) sensorimotor performance (inclined plane, beam-walking, and forepaw grip), and (d) pathological alterations in the brain (using cresyl violet and glial fibrillary acidic protein [GFAP] immunostaining). The offspring of treated mothers exhibited significant sensorimotor impairments at PND 30 during behavioral assessments. These changes were associated with increased AChE activity in the midbrain, cortex and brainstem (125-145% increase) and in plasma (125% increase). Ligand binding densities for [3H]cytosine for alpha4beta2 type nAchR did not show any significant change, whereas [3H]AFDX 384, a ligand for m2mAChR, was significantly increased in the cortex of offspring (120-155% increase) of imidacloprid-treated mothers. Histopathological evaluation using cresyl violet staining did not show any alteration in surviving neurons in various brain regions. On the other hand, there was a rise in GFAP immunostaining in motor cortex layer III, CA1, CA3, and the dentate gyrus subfield of the hippocampus of offspring of imidacloprid-treated mothers. The results indicate that gestational exposure to a single large, nonlethal, dose of imidacloprid produces significant neurobehavioral deficits and an increased expression of GFAP in several brain regions of the offspring on PND 30, corresponding to a human early adolescent age. These changes may have long-term adverse health effects in the offspring.     

Effects of continuous oral nicotine administration on brain nicotinic receptors and responsiveness to nicotine in C57Bl/6 mice

 The route of drug delivery is an important consideration in studies that evaluate the long-term biobehavioral adaptations that occur in response to chronic drug administration. Continuous infusions (intravenous or subcutaneous) or intermittent intraperitoneal (or subcutaneous) injections are the most commonly utilized routes of chronic drug delivery in these studies. The purpose of the present study was to determine the effects of chronic oral nicotine exposure on sensitivity to nicotine and brain nicotinic cholinergic receptors in female C57Bl/6 mice. Mice were randomized to different treatment groups that received 2% saccharin, containing 0–200 μg/ml nicotine (free base). In preliminary experiments, radiotelemetry devices were implanted in the mice; consumption of the nicotine-containing drinking solution caused a significant increase in home-cage nocturnal (but not diurnal) activity and also altered circadian alterations in body temperature. Oral nicotine exposure resulted in dose-related elevations in plasma levels of cotinine, a primary nicotine metabolite. Continuous exposure (30 days) to oral nicotine (200 μg/ml) resulted in the expression of significant tolerance to the locomotor depressant and hypothermic actions of acute nicotine challenge. This tolerance was accompanied by a significant increase in brain nicotinic receptor number assessed by quantitative autoradiography using [³H]-cytisine (α4 nAChr) and [¹²⁵I]-α-bungarotoxin (α7 nAChr) as radioligands. These results suggest that chronic oral nicotine delivery to female C57Bl/6 mice results in behavioral and biochemical changes that resemble changes that occur following other routes of chronic nicotine delivery. Received: 30 January 1998 / Final version: 25 June 1998     

Mecamylamine but not the alpha7 receptor antagonist alpha-bungarotoxin blocks sensitization to the locomotor stimulant effects of nicotine

The involvement of alpha7 receptors in the locomotor stimulant effects of nicotine has been examined by determining the ability of intracerebroventricular (i.c.v.) administration of the alpha7 receptor antagonist alpha-bungarotoxin (alpha-bgt) to modify sensitization to the locomotor activating effects of chronic nicotine. Intracerebroventricular administration of alpha-bgt (0.02 - 8 nmoles) produced a dose dependent increase in convulsive behaviour. At doses less than 1.0 nmole, minimal convulsive behaviour occurred but larger doses evoked convulsions in all rats which displayed a more rapid onset time as the dose increased. The binding distribution of alpha7 receptors 20 min and 3 h following an i.c.v. administration of [(125)I]-alpha-bgt (0.02 nmoles) revealed clear binding in the hippocampus, cingulate cortex and hypothalamus which was more intense after 3 h. Rats chronically treated with nicotine (0.4 mg kg(-1)) and exposed to the locomotor activity apparatus daily acquired an increase in locomotor activity relative to the control group after 3 days of treatment which reached a maximum after 7 days of treatment and was maintained for the 2 week treatment period. Pre-treatment with mecamylamine (1 mg kg(-1)) prevented the expression of the locomotor stimulant effects of nicotine but pre-treatment with i.c.v. alpha-bgt (0.02 nmoles) did not affect nicotine-induced changes in locomotor activity. The results of this study support the conclusion that nicotinic receptors of the alpha4beta2 subtype rather than the alpha7 subtype are important in mediating the expression of the locomotor stimulant effects of nicotine.     

Locomotor behavioral effects of prenatal and postnatal nicotine exposure in rat offspring

The purpose of this study was to determine if prenatal/postnatal nicotine exposure results in hyperactive offspring. Rat offspring were exposed to nicotine, through implantation of osmotic minipumps in dams, at levels of 0.75, 1.5 and 3.0 mg/kg/day, for 19 days prenatally and 16 days postnatally. Offspring were measured for gestation length, body weight, litter size, sex difference and locomotor activity. No significant effects were shown for gestation length, litter size or male to female pup ratio. However, higher percentage of pup deaths resulted from nicotine-exposed dams than from control dams. Significantly less litter body weight was shown in nicotine-exposed offspring on postnatal day 1 when compared to controls. However, these offspring surpassed the control groups in litter body weight on postnatal day 14 and 21. Hyperactivity was shown in offspring exposed to prenatal/postnatal nicotine at levels of 0.75 and 3.0 mg/kg/day on postnatal day 14, but not on postnatal day 21 or at the 1.5 mg/kg/day condition. Results are consistent with the hypothesis that rat offspring are susceptible to the neurochemical and neurobehavioral effects of prenatal/postnatal nicotine exposure.     

Effects of maternal intravenous nicotine administration on locomotor behavior in pre-weanling rats

Maternal tobacco use is associated with adverse developmental outcomes in offspring, including hyperactivity. Animal studies attempting to model this phenomenon have primarily used continuous s.c. nicotine infusion as the method of nicotine administration, which does not model the intermittent bolus delivery of nicotine associated with smoking in humans. The purpose of the present experiment was to examine the locomotor activity of pre-weanling offspring of pregnant rats exposed to an i.v. nicotine dosing protocol that approximates the pattern of nicotine exposure in moderate to heavy smokers. Pregnant rats were administered an i.v. bolus of 0.03 mg/kg nicotine (N=13) or saline (N=10) every 14 min for 16 h/day, resulting in a total daily dose of 2 mg/kg (base), from gestational day 4 to delivery. Pups from each litter were tested for spontaneous locomotor activity on postnatal days (PND) 19-21 and nicotine-induced locomotor activity on PND 22. Mean birth weight was significantly lower in nicotine-exposed pups compared to controls, but body weights were equivalent between groups by the time of behavioral testing. Mean total distance traveled, vertical counts, and stereotypy counts were lower on PND 19 in nicotine-exposed pups compared to controls, but only the difference in mean stereotypy counts was statistically significant. Within-session analysis revealed that both distance traveled and stereotypy were significantly decreased in nicotine-exposed pups in the first 5 min of the session on PND 19. Total time spent in the center of the field was also lower in nicotine-exposed pups. Nicotine-induced increases in activity on PND 22 did not differ according to gestational exposure. These findings demonstrate that prenatal nicotine exposure in a model that mimics the pattern of nicotine exposure from cigarette smoking in humans results in offspring that exhibit low birth weight and hypoactivity in a novel environment.     

Brain cholinergic, behavioral, and morphological development in rats exposed in utero to methylparathion

The purpose of this study was to determine the effects of subchronic administration of the organophosphate methylparathion (MPTH) during gestation on behavior and development of brain cholinergic neurons in the offspring. Pregnant rats received daily po doses of MPTH from Day 6 through Day 20 of gestation at doses causing no (1.0 mg/kg) or minimal (1.5 mg/kg) visible signs of maternal toxicity. Acetylcholinesterase (AChE) and choline acetyltransferase (CAT) activities, and [3H]quinuclidinyl benzilate (QNB) binding to muscarinic receptors, were determined in several brain regions at 1, 7, 14, 21, and 28 days postnatal age and in maternal brain at Day 19 of gestation. Prenatal exposure to 1.5 mg MPTH/kg reduced AChE and increased CAT activity in all brain regions at each developmental period and in maternal brain. Similar exposure to 1.0 mg MPTH/kg caused a significant but smaller and less persistent reduction in AChE activity but no change in brain CAT activity of the offspring. Both doses of MPTH decreased the Bmax of 3H-QNB binding in maternal frontal cortex but did not alter the postnatal pattern of 3H-QNB binding. In parallel studies, prenatal exposure to MPTH did not affect a variety of behaviors. However, cage emergence, accommodated locomotor activity, and operant behavior in a mixed paradigm were impaired in rats exposed to 1.0 but not to 1.5 mg/kg MPTH. No morphological changes were observed in hippocampal or cerebellar tissue. Thus, subchronic prenatal exposure to MPTH altered postnatal development of cholinergic neurons and caused subtle alterations in selected behaviors of the offspring.     

Gestational exposure to nicotine and monoamine oxidase inhibitors influences cocaine-induced locomotion in adolescent rats

Rationale Many pregnant women continue to smoke, despite a strong association between maternal smoking and neurobehavioral deficits in the offspring. Although gestational nicotine (GN) treatment in rodents is used as the primary animal model of maternal smoking, tobacco smoke contains more than 4,000 constituents, including monoamine oxidase inhibitors (MAOIs). Objectives The aim of this study was to determine whether there are interactions between the effects of gestational exposure to nicotine and MAOIs on cocaine-induced locomotor sensitization in adolescent rats. Materials and methods Pregnant rats were implanted on day 4 of gestation with osmotic minipumps delivering saline, nicotine (3 mg/kg per day), the MAOIs clorgyline and deprenyl (1 and 0.25 mg/kg per day, respectively), or nicotine/clorgyline/deprenyl (GMN). Adolescent female offspring were tested for cocaine-induced locomotor sensitization. Animals were treated with saline or cocaine (5 or 15 mg/kg, intraperitoneally) daily from postnatal (P) days 32–36 and challenged with cocaine (15 mg/kg) on P51 (day 20). Results Group differences were observed in chronic but not acute effects of cocaine. Whereas gestational MAOI treatment, with or without nicotine, increased ambulatory response to cocaine on day 5, the opposite was found for vertical activity. Different adaptive responses were observed on cocaine challenge day. GNM animals exhibited enhanced locomotor activity in the cocaine-associated environment before cocaine challenge on day 20. In contrast, only GN animals exhibited significant locomotor sensitization to the cocaine challenge. Conclusions Gestational nicotine and MAOIs both influence brain development. Such interactions may sensitize adolescents to drug abuse and should be considered in animal models of maternal smoking.     

脑N受体α_7亚型同源性上行性调节的药理学特征

目的　研究脑N受体α7亚型同源性上行性调节的药理学特征。方法　在体外培养的海马神经元中加入不同浓度的胆碱、烟碱及甲基牛扁碱 ,孵育 7d ,用γ计数器检测[12 5I]α 银环蛇毒素结合位点的变化情况。结果　胆碱(0 0 0 1～ 1μmol·L-1) ,烟碱 (>10 μmol·L-1)以及甲基牛扁碱 (>10 μmol·L-1)长期作用后 ,都可以增加 [12 5I]α 银环蛇毒素的结合量 (P <0 0 5 ) ,但对解离常数 (Kd)无影响 (P >0 0 5 )。结论　在一定浓度范围内 ,胆碱、烟碱和甲基牛扁碱长期作用可使海马神经元上的N受体α7亚型数目上调 ,且胆碱与烟碱上调α7受体的药理学特征不同。     

Locomotor activation and dopamine release produced by nicotine and isoarecolone in rats.

1. Isoarecolone was approximately 250 times less potent than nicotine as an inhibitor of [3H]-nicotine binding to rat brain membranes. Isoarecolone failed to inhibit the binding of the nicotinic ligand [125I]-alpha-bungarotoxin or of the muscarinic ligand [3H]-QNB. 2. Nicotine (0.01-30 microM) evoked the release of [3H]-dopamine from striatal and frontal cortex synaptosomes, with EC50 values of approximately 0.5 microM in each case. This release was largely mecamylamine-sensitive. 3. Isoarecolone (1-200 microM) evoked predominantly mecamylamine-sensitive dopamine release from both striatal and cortical synaptosomes, with a potency at least 20 times less than that of nicotine. The maximum effect of isoarecolone was less than that of nicotine, particularly in the frontal cortex preparation. 4. In control rats treated chronically with saline, neither nicotine nor isoarecolone had clear effects on locomotor activity at the doses tested. Chronic treatment with nicotine clearly sensitized rats to the locomotor activating effect of isoarecolone was seen at a dose about 40 times larger than that of nicotine. 5. The low potency and efficacy of isoarecolone in facilitating sensitized locomotor activity resembled its lower potency and efficacy, compared with nicotine, in evoking dopamine release in vitro. The agonist profile of the nicotinic receptor population mediating dopamine release may determine the pharmacological characteristics of consequent locomotor behaviour.     

Hyperactivity Induced by Prenatal Nicotine Exposure Is Associated with an Increase in Cortical Nicotinic Receptors

Prenatal exposure to nicotine may lead to hyperactivity. To evaluate possible involvement of central nicotinic receptors in this condition, pregnant Sprague–Dawley rats were implanted with osmotic minipumps to receive nicotine (6 mg/kg/day) or saline throughout gestation. A total of 222 pups (118 males and 104 females) from 24 dams were measured for locomotor activity. Male and female hyperactive and nonhyperactive offspring from each treatment group were selected and analyzed for nicotinic receptor concentrations in various brain regions. Hyperactive male offspring that were prenatally exposed to nicotine exhibited a significant increase in the cortical receptor densities without a change in binding affinity. Hyperactive offspring of saline-treated dams did not show an increase in cortical nicotinic receptors. These results suggest that hyperactive male offspring of nicotine-exposed dams are also susceptible to neurochemical effects of intrauterine nicotine exposure.     

Neurobehavioral effects of prenatal lamivudine (3TC) exposure in preweaning mice.

The present study provides a characterization of the behavioral changes induced in preweaning mice by prenatal exposure to lamivudine (3TC), an antiviral drug recently entered in the clinical practice to treat HIV patients. Pregnant CD1 mice were given per os bidaily either 3TC at different doses (125, 250, or 500 mg/kg) or vehicle solution (saline 0.9%) from pregnancy day 10 to delivery. Data on reproductive performance, such as gestation length, litter size, and offspring viability, were collected. Offspring were then examined for a series of different somatic and behavioral end points, including sensorimotor development, ontogenetic pattern of ultrasonic vocalization, passive avoidance learning, and locomotor activity. In the absence of gross changes in somatic and sensorimotor development, a slight change in ultrasound emission was found on postnatal day (PND) 3, with 125 and 500 mg/kg 3TC-treated offspring emitting a lower number of ultrasounds. Learning and retention performances of a passive-avoidance task on PND 20-21 were unaffected by 3TC treatment, while decreased habituation in an automated locomotor activity test was evident in male offspring exposed to 250 and 500 mg/kg 3TC.     

Effects of chronic lead (Pb) exposure on neurobehavioral function and dopaminergic neurotransmitter receptors in rats

Sprague-Dawley rats were maternally and permanently exposed to Pb (1000 ppm in their drinking water as lead acetate). Behavioral functions were examined starting at post-natal day (PN) 84. Lead exposure did not change spatial learning in the radial arm maze, but induced higher locomotor activity as observed in the open-field and in the radial arm maze. Lead treatment did not impact motor coordination. Autoradiographic analysis of brain sections indicated that Pb-exposure did produce a decrease in [125I]sulpride (D2 receptor antagonist) binding in the cerebral cortex, but not in the striatum and thalamus nucleus. No change was found in [125I]SCH-23982 (D1 receptor antagonist) binding. Since the cortical dopaminergic system is critical for cognitive processes and motor behavior, it is possible that Pb-related change in D2 receptors may mediate to it induced hyperlocomotor activity.     

Receptor mechanisms of nicotine-induced locomotor hyperactivity in chronic nicotine-treated rats

Rats were pretreated with saline or nicotine (1.5 mg/kg per day) by subcutaneously implanting each animal with an Alzet osmotic mini-pump which continuously released saline or nicotine for 1, 5 and 14 days. At the end of each pretreatment period, animals were used for (i) determining their locomotor response to acutely injected nicotine (0.2 mg/kg, s.c.) and (ii) measuring the density of L-[3H]nicotine and [3H]spiperone binding sites in the striatum. We observed no changes in nicotine-induced locomotor response, striatal L-[3H]nicotine and [3H]spiperone binding in the animals pretreated with nicotine for 1 day. In rats which were pretreated with nicotine for 5 days, there was a significant increase in the nicotine-stimulated locomotor response which was associated with an increase in the number of L-[3H]nicotine binding sites and also with an elevated dopamine (DA) level in the striatum. The number of striatal [3H]spiperone binding sites was not affected. In animals pretreated with nicotine for 14 days, the nicotine-induced locomotor response remained to be potentiated. However, this response was correlated with an elevated number of striatal [3H]spiperone binding sites, whereas the number of striatal L-[3H]nicotine binding sites and the striatal DA level were normal. These results suggest that chronic nicotine-treated rats develop locomotor hyperactivity in response to nicotine initially due to increases of both the density of nicotinic receptors and DA concentration, followed by inducing DA receptor supersensitivity in the striatum.