Distribution of lead in lactating mice and suckling offspring with special emphasis on the mammary gland

 The distribution of lead in lactating mice and suckling offspring was studied with whole body autoradiography at 4 and 24 h after a single intravenous injection of ²⁰³Pb (50 nmol Pb/kg) to the dams. In the lactating mice on day 14 of lactation, the highest uptake of radioactivity at 4 h after administration was recorded in renal cortex, skeleton and liver. A high uptake was also evident in the mammary gland. At 24 h after administration, the radioactivity had decreased in most organs except in the skeleton. In the suckling pups, exposed to lead only via dams’ milk for 24 h, the highest level of radioactivity was present in the intestinal mucosa and a much lower level of radioactivity was present in the skeleton. The mammary glands from mice given three daily intravenous injections of 240 μmol Pb/kg were examined with X-ray microanalysis. At 4 h after the last injection, lead was found associated with casein micelles both inside the alveolar cell and in the milk lumen, indicating that lead is excreted into the milk, bound to casein, via the Golgi secretory system. Received 8 May 1995 / Accepted 16 July 1995     

发育期铅染毒对大鼠学习和记忆的持续性效应

目的研究不同发育期铅染毒对大鼠学习和记忆的持续性效应。方法大鼠分别在断乳前和断乳后进行铅染毒，分别测试20、40和60天龄大鼠Y迷宫学习、短时记忆和长时记忆能力。结果(1)断乳前铅染毒组大鼠20天龄时，0、10min和24h逃避达标率显著低于对照组；停止染毒40d后，10min逃避达标率与对照组相比，差异无显著性；但0min和24h逃避达标率显著低于对照组。(2)断乳后，铅染毒组大鼠0min和24h逃避达标率显著低于对照组，24h逃避达标率显著高于断乳前铅染毒组。结论(1)断乳前铅染毒可损伤大鼠的空间学习、短时和长时记忆能力；停止染毒后短时记忆可得到恢复，而学习和长时记忆的损伤仍持续存在。(2)断乳后铅染毒可损伤大鼠的空间学习和长时记忆能力，但损伤较断乳前铅染毒轻。     

Differential experience following developmental lead exposure: effects on brain and behavior

Long Evans hooded rat pups were exposed to lead (Pb) via the maternal milk supply from Postnatal Day 1 (PN 1) to PN 25. Mothers were fed diets containing either 4% Pb CO3 (High Pb), 0.4% Pb CO3 (Low Pb) or 2.2% Na2 CO3 (Controls) throughout this period. Pups were weaned at PN 30 and littermates randomly assigned to either an Enriched or Isolated environment for a period of 30 days. Increases in activity levels and decreases in passive avoidance latencies were observed in Pb exposed animals. However, there were minimal effects due to Pb on symmetrical maze performance. Experience in the enriched environment had no effect on open field activity levels but resulted in a marked reduction in symmetrical maze errors. While enrichment had no effect on passive avoidance performance in High Pb animals, it was capable of raising latencies in Low Pb animals to Control values. Thus, the therapeutic value of environmental enrichment in Pb exposed animals depends on both the task employed and the severity of the pre-enrichment brain damage. From both brain regional analysis and behavioral testing results, it appeared that the hippocampus was a major site of Pb action. From comparison of blood Pb levels of our animals and those reported in children, it became apparent that the rat may have a greater tolerance for Pb, and as such, caution must be used in making direct comparisons between the two species in terms of blood Pb levels.     

Influence of parental lead exposure on subsequent learning ability of offspring.

This study was designed to assess the learning ability of rat offspring following the exposure of one or both parents to lead acetate (Pb) from 30-90 days of age. At that time, parents were mated to yield four groups: Group Pb-Pb, both parents had received Pb; Group Pb-N, only the mother had received Pb; Group N-Pb, only the father had received Pb; Group N-N, the control parents. Mothers were continued on their respective treatments throughout gestation and nursing. Testing of offspring began at 30 days of age, employing a black-white discrimination water T maze. Analysis of results revealed that the three Pb groups made more errors than the controls, but did not differ from one another. However, offspring in Group Pb-Pb had longer swimming times than those in Groups Pb-N and N-Pb, who, in turn, had longer swimming times than Group N-N. Thus dual parental exposure was more severe than single parental exposure, which, however, still exerted a detrimental effect compared to control performance.     

In utero and lactational exposure to triclocarban: reproductive effects on female rat offspring

Triclocarban (TCC) is an antimicrobial compound widely used in personal care products such as soaps, toothpaste, and shampoo. This agent is incompletely removed by wastewater treatment and represents an environmental contaminant. Recent studies have shown that TCC is associated with some endocrine disruptions. The aim of the present study was to evaluate if TCC exposure during critical periods of development (gestation and lactation) could lead to adverse effects on reproductive and behavior parameters of female offspring. Pregnant female Wistar rats were divided into four groups (n = 8–11/group): Control; TCC 0.3 mg/kg (TCC 0.3); TCC 1.5 mg/kg; TCC 3.0 mg/kg (TCC 3.0); and treated daily by oral gavage from gestational day 0 to lactational day 21. The female pups (F1 generation) were weaned on post-natal day 21 and included in the study. No litter-mates were used for the same group. There was a decrease in estradiol levels in the TCC 0.3 and TCC 3.0 groups. Moreover, there was a decrease in progesterone levels and an increase in pre-implantation loss in the TCC 3.0 group in adulthood. It is suggested, in this study, that the decrease in progesterone biosynthesis could interfere with implantation process. The exposure window to TCC is an important factor, as we found alterations only in the offspring.     

Age of testing as a factor in the behavioral effects of early lead exposure in rats

The behavioral effects of postnatal administration of lead during weaning were tested in young and adult rats. Rats received either 10 mg/kg IP lead acetate or equimolar sodium acetate daily for the first twenty days of life. Tests of performance on an 8-arm radial maze and a passive avoidance task were begun at 25 days after birth or 90 days after birth. Lead-treated rats did not perform significantly different than control rats on the radial arm maze at either age tested. Young lead-treated rats performed with significantly longer lick latencies than young control rats on the passive avoidance task. Adult lead-treated rats performed with shorter food latencies than adult control rats. A group of young rats was retested on the passive avoidance task at 150 days after birth. Performance on the retest was similar to their early performance. Differences in performance of young and adult lead-treated animals on the passive avoidance task are discussed in terms of an interaction of the effects of lead exposure, maturation, and early experience.     

Placental transfer and fetal distribution of lead in mice after treatment with dithiocarbamates

The distribution of i.v. administered lead (²⁰³Pb-acetate; 50 nmol/kg b.w.) was studied by means of autoradiography and impulse counting in pregnant C57BL mice (day 18) treated orally with dithiocarbamates. Diethyldithiocarbamate (DEDTC), disulfiram or thiram (2×1 mmol/kg b.w.) or vehicle (gelatine) alone, was given by gavage 2 h before and immediately after the injection of lead. All three dithiocarbamates, especially thiram, changed the distribution pattern of lead. Thiram and DEDTC had the greatest effect at 4 h after lead administration, disulfiram at 24 h. In the mother, most notably the brain concentration increased (70-fold for thiram at 4 h) while that of erythrocytes and skeleton decreased (50- and 4-fold, respectively). The total fetal concentration unexpectedly showed only a moderate increase (2-fold for thiram), which may be due partly to the low maternal plasma lead concentration. The partition within the fetal tissues was, however, changed by the dithiocarbamates in much the same way as in the mothers, e.g., the fetal brain of thiram treated animals had increased by a factor 15, while skeletal and blood concentrations were lowered compared to controls. In melanin containing structures of the maternal and fetal eyes a dramatic increase in lead concentration resulted from dithiocarbamate treatment (lead ions are known to bind to melanin in vitro). The pattern of changes in lead distribution caused by dithiocarbamates is consistent with the formation in the body of lipid soluble lead-dithiocarbamate complexes that pass biological barriers more easily than lead inorganic (to brain, fetus, melanocytes etc.), probably followed by a dissociation of the complexes in the tissues.     

A morphological analysis of the short-term effects of benzene on the development of the hematological cells in the bone marrow of mice and the effects of interleukin-1α on the process

 Chronic exposure of humans to benzene (BZ), a widely used industrial chemical and a ubiquitous environmental pollutant, causes aplastic anemia and acute myeloid leukemia. The purpose of the studies reported here was to determine whether the observed depression of bone marrow (BM) cellularity in mice administered benzene was reflected in a suppression of development of all of the hematopoietic lineages and to confirm the ability of interleukin-1α (IL-1α) to prevent BZ-induced BM cell depression. We report that BZ, administered twice per day for 2 days to C57Bl/6J mice at a dose of 600 mg/kg body weight, caused a significant depression of the total number of nucleated BM cells per femur when measured on day 3. The observed depression reflects a complex situation that represents the net effect of a decrease in the total number of cells of the lymphocytic and erythroid lineages, along with an increase in the number of intermediate and terminally differentiated cells of the granulocytic lineage. An experiment to monitor the effects of BZ over a 7-day period showed a progressive depressive effect on the lymphocytes and an initial depression of the erythroid cells at day 3 that remained constant until day 7. Conversely, the numbers of intermediate and terminally differentiated granulocytes progressively increased over the 7 days. The BM appeared to recover from the depressive effects of BZ immediately upon cessation of exposure, as the number of nucleated BM cells began to rise by day 5 and was equal to that of the control group by day 7. The results expand our earlier finding (Renz and Kalf 1991) that the overall depression of BM cellularity occurs because of an inability of the stromal fibroblast to produce colony-stimulating factors essential for stem and progenitor cell survival. This results from inhibition by the BZ metabolite, hydroquinone (HQ), of the processing of pre-IL-1α to the mature cytokine. The ability of exogenously administered biologically active, but not heat inactivated, recombinant IL-1α to prevent BZ-induced depression of total BM cellularity as a function of dose, when added concomitantly with BZ, and to augment the recovery from BZ exposure up to day 5 supports this hypothesis. IL-1α administered alone showed no effect on the total number of nucleated cells in the BM; however, analysis of its effects on the cells of the various lineages indicated that lymphocytes were unaffected, nucleated erythroid cell were decreased and the immature and mature granulocytic forms were increased. It is of interest that granulopoiesis is not decreased during BZ-induced inhibition of IL-1α production, but rather significantly stimulated. Received: 6 June 1994/Accepted: 10 August 1994     

The effects of early postnatal stimulation on Morris water-maze acquisition in adult mice: genetic and maternal factors

 Following stressor exposure BALB/cByJ mice exhibit hypersecretion of corticosterone and marked brain catecholamine alterations. In addition, mice of this strain exhibit impairments of performance in a Morris water-maze, which may be exacerbated by footshock application. In the present investigation it was demonstrated that early-life handling of mouse pups (coupled with brief separation periods from the dam over the course of 21 days postpartum) reduced the learning impairments seen when mice were tested in the Morris water-maze at 120 days of age and also prevented stress-induced disturbances in this task. Likewise, cross-fostering BALB/cByJ mice with a C57BL/6ByJ dam prevented the performance deficits. In contrast, C57BL/6ByJ mice cross-fostered to a BALB/cByJ dam exhibited proficient performance. Thus, maternal factors may be important in determining the Morris water-maze disturbances, provided that this was applied on the BALB/cByJ genetic background. Stressor exposure exacerbated the performance disturbances in BALB/cByJ mice, while diazepam treatment disrupted Morris water-maze performance in both BALB/cByJ and C57BL/6ByJ mice. Paralleling the behavioral changes associated with handling, the stress-induced hypercorticosterone secretion characteristic of the BALB/cByJ mouse was attenuated by the early handling procedure. Stressor exposure also produced strain-dependent variations of NE and 5-HT, but these effects were not appreciably influenced by the handling procedure. These data are consistent with the proposition that performance disturbances of BALB/cByJ mice tested in the Morris water-maze task are associated with excessive hypothalamic-pituitary-adrenal reactivity. Moreover, it appears that the influence of early-life stimulation may interact with genetic factors in determining endocrine and behavioral stress responses. Received: 11 October 1995 / Final version: 22 June 1996     

Neuroleptic-induced striatal damage in rats: a study of antioxidant treatment using accelerometric and immunocytochemical methods

Rationale: Investigators have postulated that neuroleptic medications may affect the motor system through the creation of free radicals. Also, structural brain changes related to oxidative damage may disrupt normal striatal function. Objective: The goals of this study were to examine whether an antioxidant diet reduced the abnormal movements caused by long-term neuroleptic exposure and to examine structural effects within specific striatal regions in rats. Methods: Rats were given a basal diet or a diet high in antioxidants for 4 months, and treated with 10 mg/kg fluphenazine decanoate or sesame seed oil IM every 2 weeks. At baseline and after treatment, head movements were quantified by accelerometry, and immunocytochemically stained cholinergic neurons in the ventrolateral, mediodorsal, and ventromedial regions of the striatum were quantified. Results: Rats treated with fluphenazine had significantly lower neuron densities than those that did not receive antioxidants. Rats exposed to a diet consisting of antioxidants had significantly higher neuron densities than those that did not receive antioxidants in each of the three regions tested. Rats treated with fluphenazine had a greater increase in the number of accelerometric peaks recorded per minute compared with untreated animals. The increase in the number of accelerometric peaks recorded per minute was lower for animals exposed to antioxidant diets compared with unexposed animals. Lastly, there was a significant correlation between the accelerometric peak change score and cholinergic neuron density in all three regions. Conclusions: Our results suggest that long-term neuroleptic treatment is associated with an increase in head movements and a reduction in ChAT-stained striatal cholinergic neurons and that these abnormalities are reduced by antioxidants. Received: 2 April 1999 / Final version: 23 August 1999     

Biotransformation of trichloroethene: dose-dependent excretion of 2,2,2-trichloro-metabolites and mercapturic acids in rats and humans after inhalation

 Chronic bioassays with trichloroethene (TRI) demonstrated carcinogenicity in mice (hepatocellular carcinomas) and rats (renal tubular cell adenomas and carcinomas). The chronic toxicity and carcinogenicity is due to bioactivation reactions. TRI is metabolized by cytochrome P450 and by conjugation with glutathione. Glutathione conjugation results in S-(dichlorovinyl) glutathione (DCVG) and is presumed to be the initial biotransformation step resulting in the formation of nephrotoxic metabolites. Enzymes of the mercapturic acid pathway cleave DCVG to the corresponding cysteine S-conjugate, which is, after translocation to the kidney, cleaved by renal cysteine S-conjugate β-lyase to the electrophile chlorothioketene. After N-acetylation, cysteine S-conjugates are also excreted as mercapturic acids in urine. The object of this study was the dose-dependent quantification of the two isomers of N-acetyl-S-(dichlorovinyl)-L-cysteine, trichloroethanol and trichloroacetic acid, as markers for the glutathione- and cytochrome P450-mediated metabolism, respectively, in the urine of humans and rats after exposure to TRI. Three male volunteers and four rats were exposed to 40, 80 and 160 ppm TRI for 6 h. A dose-dependent increase in the excretion of trichloroacetic acid, trichloroethanol and N-acetyl-S-(dichlorovinyl)-L-cysteine after exposure to TRI was found both in humans and rats. Amounts of 3100 μmol trichloroacetic acid+trichloroethanol and 0.45 μmol mercapturic acids were excreted in urine of humans over 48 h after exposure to 160 ppm TRI. The ratio of trichloroacetic acid+trichloroethanol/mercapturic acid excretion was comparable in rats and humans. A slow rate of elimination with urine of N-acetyl-S-(dichlorovinyl)-L-cysteine was observed both in humans and in rats. However, the ratio of the two isomers of N-acetyl-S-(dichlorovinyl)-L-cysteine was different in man and rat. The results confirm the finding of the urinary excretion of mercapturic acids in humans after TRI exposure and suggest the formation of reactive intermediates in the metabolism of TRI after bioactivation by glutathione also in humans. Received: 22 June 1995 / Accepted: 5 October 1995     

Buprenorphine alters ethanol self-administration in rats: dose-response and time-dependent effects

 Buprenorphine is a partial opioid agonist derived from thebaine and has high affinity for μ and κ opioid receptors. The present study investigated dose-response (0.03, 0.15, 0.3, 3 mg/kg) and time-dependent effects of buprenorphine (1.5 or 4 h post-treatment) on EtOH self-administration in outbred Sprague-Dawley rats. Freely feeding and drinking rats were trained to initiate EtOH self-administration for 1 h daily using the ascending concentration procedure, wherein they were provided with increasing concentrations of EtOH at 2, 5, 7, 9 and 11% (v/v), respectively. Water was concurrently available with each concentration. Animals were maintained on a given concentration of EtOH for 5 days. By day 21, animals began their stabilization on the 11% regimen and remained on this concentration throughout the remainder of the study. EtOH and water consumption were recorded daily at both 10- and 60-min intervals. At 1.5 h post-buprenorphine, all test doses greatly suppressed both EtOH and water intake at the 10-min interval. At the 60-min interval, all but the lowest dose (0.03 mg/kg) significantly suppressed EtOH intake, while only the highest dose (3 mg/kg) suppressed water intake. In contrast to the suppressant profile observed at 1.5 h post-buprenorphine, at 4 h post-buprenorphine the lower doses (0.03 and 0.15 mg/kg) significantly increased EtOH intake while the higher doses (0.3 and 3 mg/kg) continued to suppress intake. None of the doses of buprenorphine altered water intake 4 h post-buprenorphine. The results support previous research demonstrating the utility of low doses of buprenorphine in suppressing behavior rewarded by a non-opioid drug. Received: 11 September 1997 / Final version: 21 February 1998     

A lack of tolerance to the anxiolytic effects of diazepam on the plus-maze: comparison of male and female rats

Rationale: The demonstration of tolerance to the anxiolytic effects of benzodiazepines remains inconsistent. Objectives: The present study tested the hypothesis that intact and gonadectomized male and female rats might exhibit differential tolerance to the anxiolytic effects of diazepam (DZ). Methods: Following acute (3 days) or chronic (3 weeks) DZ exposure, all animals were tested on the elevated plus-maze and immediately sacrificed for analysis of corticosterone, adrenocorticotropin hormone, estrogen and progesterone levels in serum. In experiment 2, following acute or chronic DZ exposure, animals were treated with a DZ challenge dose on the test day. Results: In experiment 1, both acute and chronic DZ treatment similarly enhanced percentage open arm time and entries, regardless of the hormonal status of the animal. The results of experiment 2 showed that both acute and chronic DZ-treated animals exhibited a significantly higher percentage open arm time than control animals after the DZ challenge dose, and males and females did not differ in their responses to DZ exposure. Conclusions: The findings from these experiments suggest that tolerance to the anxiolytic effects of DZ did not develop in males or females, and that the hormonal status of the animal does not significantly alter the anxiolytic effects of DZ following either acute or chronic exposure. Following plus-maze exposure, females had significantly higher corticosterone levels than males and acute DZ treatment diminished this stress response. Received: 23 February 1999 / Final version: 28 July 1999     

The effect of lead exposure on some inflammatory biomarkers of lung lavage fluid in rats

This study was designed to examine the association between lead exposure and inflammatory responses in the lung lavage of rats. Thirty rats were randomly allocated into control (group C), sensitized (group S), and three exposed to lead (Pb) (groups 0.1M Pb and 0.4M Pb). Animal were sensitized with i.p. injected and aerosolized ovalbumin (OA). Pb-exposed groups inhaled 0.1M and 0.4M lead acetate for 1?h, thrice a week for two weeks. The levels of total protein, IgE and histamine were measured in the lung lavage of rats. The results of the present study showed significant increase in the levels of total protein, IgE and histamine in the lung lavage of rats exposed to high lead concentration and that of total protein and histamine in animal exposed to low lead concentration compared to control animals. The similar findings were also observed in sensitized animals. In addition, the levels of IgE and histamine in lung lavage of group exposed to high lead concentration significantly increased compared to group exposed to low lead concentration. The findings of the present study showed that exposure to inhaled lead acetate may lead to asthma like disease via inducing inflammatory responses in the lung lavage of rats.     

An oral self-administration model of nicotine preference in rats: effects of mecamylamine

 A new oral model of nicotine self-administration in rats has been described. The model utilizes a two-lever operant procedure with rats having a choice between nicotine and water reinforcement. Most (16 of 20) rats exhibited reliable preferences for nicotine solutions equal to or less than 32 μg/ml; preferences were inversely related to the concentration of nicotine. Mecamylamine (0.25–5.0 mg/kg), a nicotinic antagonist, reduced preferences for a low nicotine concentration (4 μg/ml) and enhanced preferences for a high nicotine concentration (32 μg/ml). The relationship of nicotine concentration to nicotine preference appeared to be consistent with previous reports of nicotine self-administration using the intravenous route in rats as well as the respiratory route (i.e., smoking) in humans. The mecamylamine-induced changes in nicotine preference were consistent with its nicotinic antagonist action as well as with effects of mecamylamine reported in humans. This model should be useful in the preclinical assessment of new agents as potential therapies in smoking cessation programs. Received: 22 June 1996 / Final version: 30 August 1996     

Lasting effects of repeated cocaine administration on acoustic and fear-potentiated startle in rats

  Rationale: Following cocaine withdrawal, humans may experience an abstinence syndrome with high levels of anxiety. Studying anxious behavior in animals following repeated cocaine administration may help elucidate important variables that contribute to a withdrawal syndrome. Objectives: This study investigated whether repeated cocaine pre-exposure produced lasting increases in conditioned fear as measured by fear-potentiated startle responses in rats. Methods: Startle was measured in response to 50 ms acoustic stimuli of 95, 105 and 115 dB. Cocaine (20 mg/kg, IP) or saline was administered for 7 days and after each injection rats were either placed in startle chambers for 30 min or returned to the home cage. After a 1-week cocaine-free period, most rats were given ten light-footshock pairings in the startle chamber. Fear-potentiated startle was tested by presenting acoustic startle-eliciting stimuli of 95, 105 and 115 dB in the presence or absence of the light. Rats that were not fear conditioned received acoustic stimuli one week after 7 days of 20 mg/kg cocaine. Results: Startle responses, both in the presence and absence of the light CS, were greater in fear-conditioned rats that received cocaine pre-exposure in the startle chamber than in saline pre-exposed rats. Startle responses in the presence of the light CS were further augmented at 115 dB. In contrast, home-cage exposure to cocaine did not enhance startle responses. In rats that were not fear conditioned, cocaine pre-exposure reduced acoustic startle. Conclusions: Repeated cocaine pre-exposure can increase, decrease or not change acoustic startle depending on whether fear conditioning occurred and whether cocaine was given in the testing chamber. The data suggest that cocaine pre-exposure may act as a contextually conditioned occasion setting stimulus that can facilitate anxious behavior similar to the postulated human cocaine abstinence syndrome. Received: 22 April 1998 / Final version: 21 December 1998     

Reduced vascular β-adrenergic receptors and catecholamine response in rats with lead induced hypertension

β-Adrenergic receptor-mediated relaxation of blood vessels declines in lead induced hypertension although the mechanism is unknown. We have utilized the aorta of lead hypertensive rats to investigate this problem. In an effort to elucidate the mechanism responsible for this alteration we examined plasma catecholamine levels, vascular β-adrenergic receptor density, and cyclic adenosine monophosphate (cAMP) production in lead hypertensive rats. The density of β-adrenergic receptors was 41% lower in the blood vessels of lead hypertensive rats compared with control rats. The corresponding apparent K _d values were not significantly different between two groups. The plasma catecholamine level was significantly higher in lead hypertensive rats compared with controls (P < 0.001). Stimulation of the vascular β-adrenoceptor resulted in significantly lower levels of cAMP in lead hypertensive rats compared with controls (P < 0.001). The present results suggest that there is reduced β-adrenoceptor density and diminished cAMP accumulation in blood vessels from lead hypertensive rats. Plasma catecholamine may play a role in the diminished β-adrenoceptor and responsiveness to cAMP-mediated vascular relaxation in lead exposure. Received: 18 March 1997 / Accepted: 3 June 1997     

Acute and chronic effects of nornicotine on locomotor activity in rats: altered response to nicotine

Rationale: Nicotine, a tobacco alkaloid, is known to be important in the acquisition and maintenance of tobacco smoking. Nornicotine, an active nicotine metabolite, stimulates nicotinic receptors and may produce psychomotor effects similar to nicotine. Objective: The present study determined the effects of acute and repeated administration of nornicotine on locomotor activity and compared its effects with those of nicotine. Methods: R(+)-Nornicotine (0.3–10 mg/kg), S(–)-nornicotine (0.3–10 mg/kg), S(–)-nicotine (0.1–1 mg/kg) or saline was administered s.c. to rats acutely or repeatedly (eight injections at 48-h intervals). Activity was recorded for 50 min immediately after each injection. Results: S(–)-Nicotine produced transient hypoactivity, followed by dose-related hyperactivity. Repeated S(–)-nicotine administration resulted in tolerance to the hypoactivity and sensitization to the hyperactivity. Subsequent testing following a saline injection revealed evidence of conditioned hyperactivity. Acute administration of 0.3 mg/kg or 1 mg/kg R(+)- or S(–)-nornicotine produced no effect. Transient hypoactivity was observed at 3 mg/kg and 10 mg/kg R(+)-nornicotine and at 10 mg/kg S(–)-nornicotine. However, rebound hyperactivity was not observed following acute administration of either nornicotine enantiomer, suggesting that nornicotine-induced psychomotor effects differ qualitatively from those of S(–)-nicotine. Repeated R(+)-nornicotine resulted in tolerance to the transient hypoactivity, however hyperactivity was not observed. Repeated S(–)-nornicotine resulted in tolerance to the hypoactivity and the appearance of hyperactivity. Repeated administration of either nornicotine enantiomer resulted in a dose-dependent alteration in response to a 1 mg/kg S(–)-nicotine challenge, suggesting some commonalities in the mechanism of action. Conclusion: Nornicotine likely contributes to the neuropharmacological effects of nicotine and tobacco use. Received: 11 January 1999 / Final version: 25 March 1999     

Strychnine effects on ultrasound-elicited behaviours in Lister hooded rats

 Previous studies have demonstrated that Lister hooded rats will exhibit characteristic bursts of locomotion when exposed to a 20-kHz acoustic stimulus; this ultrasound-induced locomotion has been suggested as a potential model for panic attacks. Although ultrasound presentation rarely induces convulsions, the locomotor bursts exhibited resemble pre-convulsant running. The present studies examined the interactions between strychnine treatment and experimenter-presented ultrasounds on behaviour in male Lister hooded rats. Strychnine was selected because it is a potent and effective convulsion-inducing agent which is not known to induce anxiety in humans. Behaviour in a circular arena (75 cm diameter) was observed live, videotaped and traced electronically. In experiments 1 and 2, moderate (60 s) or relatively brief (15 s) exposure to an ultrasound stimulus (20 kHz, 98 dB, SPL) typically resulted in 5- to 10-s bursts of locomotion in saline-treated subjects; strychnine treatment (0.5, 0.7, 1.0 mg/kg, injected IP, 10 min prior to testing) significantly increased this ultrasound-induced locomotion in a dose-dependent manner. Experiment 3 demonstrated that the strychnine enhancement of the ultrasound response was not different in naive animals when compared to those subjects which had received occasional strychnine and/or ultrasound treatment previously. Experiment 3 also demonstrated that strychnine treatment can cause at least modest running in subjects exposed to a 2 kHz tone (96 dB SPL). In experiment 4, exposure to the 20 kHz, 98 dB ultrasound stimulus for a much longer period, 9 min, resulted in irregular cycles of bursts of locomotion, followed immediately by periods of relative inactivity in saline-treated animals; approximately 10% of these subjects exhibited tonic-clonic convulsions. No convulsions occurred in strychnine-treated subjects during the period 10–20 min post-injection in the absence of ultrasound exposure; in contrast, the frequency of occurrence of convulsions in strychnine-treated subjects (10–20 min post-injection) exposed to the ultrasound stimulus was greater than 50%; these convulsions typically occurred at the end of a locomotor burst. The results of the present studies suggest that there may be a relationship between ultrasound-induced locomotor bursts and convulsant activity. Received: 15 May 1997/Final version: 28 August 1997     

Comparison of the neurophysiological effects of allopregnanolone and ethanol in rats

Rationale: The central nervous system actions of allopregnanolone (3α-hydroxy-5α-pregnan-20-one) and ethanol are at least partially mediated by modulation of γ-aminobutyric acid (GABA)-A receptors. Although ethanol and allopregnanolone have similar behavioral effects, their macro-electrophysiological profiles have not been directly compared. Objective: The purpose of this study was to compare the effects of allopregnanolone and ethanol on the electroencephalogram (EEG) and event-related potentials (ERPs). Methods: Male Wistar rats were implanted with cortical and amygdalar electrodes. The rats were then administered allopregnanolone (0.0–10 mg/kg), ethanol (0.0–1.0 g/kg), or a combination of the two before recording. Results: Allopregnanolone and ethanol had similar effects on ERPs. When administered alone, both decreased cortical P1-N1 ERP amplitude by 25–50% and N1 amplitude in the amygdala by 75–80%. Combined administration of ethanol (0.50 g/kg) and allopregnanolone (5.0 mg/kg), doses which were ineffective alone, decreased N1 amplitude in the amygdala by 60%. Allopregnanolone and ethanol had dissimilar EEG effects. Allopregnanolone increased high frequency power in the cortex and amygdala by 25–30%. Ethanol decreased cortical and amygdalar power in the same high frequency bands by 25–45%. Allo- pregnanolone, but not ethanol, also shifted cortical frequency in the 32- to 50-Hz band. Combined administration of allopregnanolone and ethanol had no effect on EEG power but enhanced allopregnanolone’s effect on cortical frequency. Conclusions: These data suggest that allopregnanolone’s macro-electrophysiological profile resembles barbiturates and benzodiazepines more than ethanol. Further, the interactions of allopregnanolone and ethanol appear complex, with multiple effects observed (enhancement or reversal) depending on the neurophysiological variable assessed. Received: 14 May 1999 / Final version: 8 December 1999