Strain Differences In Sensitivity Research Articles

Effect of Estrous Cycle on Behavior of Females in Rodent Tests of Anxiety.

Anxiety disorders are more prevalent in women than in men. In women the menstrual cycle introduces another variable; indeed, some conditions e.g., premenstrual syndrome, are menstrual cycle specific. Animal models of fear and anxiety, which form the basis for research into drug treatments, have been developed almost exclusively, using males. There remains a paucity of work using females and the available literature presents a confusing picture. One confound is the estrous cycle in females, which some authors consider, but many do not. Importantly, there are no accepted standardized criteria for defining cycle phase, which is important given the rapidly changing hormonal profile during the 4-day cycle of rodents. Moreover, since many behavioral tests that involve a learning component or that consider extinction of a previously acquired association require several days to complete; the outcome may depend on the phase of the cycle on the days of training as well as on test days. In this article we consider responsiveness of females compared to males in a number of commonly used behavioral tests of anxiety and fear that were developed in male rodents. We conclude that females perform in a qualitatively similar manner to males in most tests although there may be sex and strain differences in sensitivity. Tests based on unconditioned threatening stimuli are significantly influenced by estrous cycle phase with animals displaying increased responsiveness in the late diestrus phase of the cycle (similar to the premenstrual phase in women). Tests that utilize conditioned fear paradigms, which involve a learning component appear to be less impacted by the estrous cycle although sex and cycle-related differences in responding can still be detected. Ethologically-relevant tests appear to have more translational value in females. However, even when sex differences in behavior are not detected, the same outward behavioral response may be mediated by different brain mechanisms. In order to progress basic research in the field of female psychiatry and psychopharmacology, there is a pressing need to validate and standardize experimental protocols for using female animal models of anxiety-related states.

Up-regulation of neurotrophin-related gene expression in mouse hippocampus following low-level toluene exposure

To investigate the role of strain differences in sensitivity to low-level toluene exposure on neurotrophins and their receptor levels in the mouse hippocampus, 8-week-old male C3H/HeN, BALB/c and C57BL/10 mice were exposed to 0, 5, 50, or 500 ppm toluene for 6 h per day, 5 days per week for 6 weeks in an inhalation chamber. We examined the expressions of neurotrophin-related genes and receptors in the mouse hippocampus using real-time reverse transcription polymerase chain reaction (RT-PCR). The expression of nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), tyrosine kinase (Trk) A, and TrkB mRNAs in the C3H/HeN mice hippocampus was significantly higher in the mice exposed to 500 ppm toluene. Among the three strains of mice, the C3H/HeN mice seemed to be sensitive to toluene exposure. To examine the combined effect of toluene exposure and allergic challenge, the C3H/HeN mice stimulated with ovalbumin were exposed to toluene. The allergy group of C3H/HeN mice showed significantly elevated level of NGF mRNA in the hippocampus following exposure to 50 ppm toluene. Then, we also examined the expression of transcription factor, dopamine markers and oxidative stress marker in the hippocampus of sensitive strain C3H/HeN mice and found that the expression of CREB1 mRNA was significantly increased at 50 ppm toluene. In immunohistochemical analysis, the density of the NGF-immunoreactive signal was significantly stronger in the hippocampal CA3 region of the C3H/HeN mice exposed to 500 ppm toluene in non-allergy group and 50 ppm in allergy group. Our results indicate that low-level toluene exposure may induce up-regulation of neurotrophin-related gene expression in the mouse hippocampus depending on the mouse strain and an allergic stimulation in sensitive strain may decrease the threshold for sensitivity at lower exposure level.

Neural basis for a heritable phenotype: differences in the effects of apomorphine on startle gating and ventral pallidal GABA efflux in male Sprague-Dawley and Long-Evans rats.

RationalePrepulse inhibition (PPI) of startle is a measure of sensorimotor gating that is heritable and deficient in certain psychiatric disorders, including schizophrenia. Sprague–Dawley (SD) rats are more sensitive to PPI disruptive effects of dopamine (DA) agonists at long interstimulus intervals (60–120 ms) and less sensitive to their PPI-enhancing effects at short (10–30 ms), compared with Long–Evans (LE) rats. These heritable strain differences in sensitivity to the PPI disruptive effects of DA agonists must ultimately reflect neural changes "downstream" from forebrain DA receptors.ObjectiveThe current study evaluated the effects of the DA agonist, apomorphine (APO), on ventral pallidal (VP) gamma-aminobutyric acid (GABA) and glutamate efflux and PPI in SD and LE rats.MethodsPPI was tested in SD and LE rats after vehicle or APO (0.5 mg/kg, subcutaneously (s.c.)) in a within-subject design. In different SD and LE rats, VP dialysate was collected every 10 min for 120 min after vehicle or APO (0.5 mg/kg, s.c.) and analyzed for GABA and glutamate content by capillary electrophoresis (CE) coupled with laser-induced fluorescence (LIF).ResultsAs predicted, SD rats exhibited greater APO-induced PPI deficits at long intervals and less APO-induced PPI enhancement at short intervals compared to LE rats. APO significantly reduced VP GABA efflux in SD but not in LE rats; glutamate efflux was unaffected in both strains.ConclusionHeritable strain differences in PPI APO sensitivity in SD vs LE rats parallel, and may be mediated by, strain differences in the VP GABA efflux.

Strain differences in delay discounting using inbred rats

A heightened aversion to delayed rewards is associated with substance abuse and numerous other neuropsychiatric disorders. Many of these disorders are heritable, raising the possibility that delay aversion may also have a significant genetic or heritable component. To examine this possibility, we compared delay discounting in six inbred strains of rats (Brown Norway, Copenhagen, Lewis, Fischer, Noble and Wistar Furth) using the adjusting amount procedure, which provides a measure of the subjective value of delayed rewards. The subjective value of rewards decreased as the delay to receipt increased for all strains. However, a main effect of strain and a strain x delay interaction indicated that some strains were more sensitive to the imposition of delays than others. Fitting a hyperbolic discount equation showed significant strain differences in sensitivity to delay (k). These data indicate that there are significant strain differences in delay discounting. All strains strongly preferred the 10% sucrose solution (the reinforcer in the delay discounting task) over water and the amount of sucrose consumed was correlated with sensitivity to delay. Locomotor activity was not correlated with delay discounting behavior. Additional research will be required to disentangle genetic influences from maternal effects and to determine how these factors influence the underlying association between heightened delay discounting and neuropsychiatric disorders.

Heritable strain differences in sensitivity to the startle gating-disruptive effects of D2 but not D3 receptor stimulation

Prepulse inhibition (PPI) of the startle reflex is an operational measure of sensorimotor gating that is deficient in several brain disorders and is disrupted in rats by dopamine (DA) agonists. Robust heritable strain differences are observed between Sprague-Dawley (SD) and Long-Evans (LE) strains in sensitivity to the PPI-disruptive effects of DA agonists associated with differential gene expression in the nucleus accumbens. Here, we compared the contribution of D2 versus D3 receptors with this heritable difference, using the D3-preferential agonist (pramipexole), the mixed D3/D2 agonist (quinpirole), the mixed D1/D2-like agonist (apomorphine), and the preferential D2 antagonist (L741,626). All DA agonists disrupted PPI in SD and LE rats. Greater sensitivity for this effect was evident with apomorphine and quinpirole in SD than LE rats, but not with pramipexole. The selective D2 antagonist L741,626 preferentially reversed apomorphine-induced PPI deficits at a dose that did not alter pramipexole-induced PPI deficits. We conclude that the heritable pattern of greater PPI 'disruptability' by DA agonists in SD versus LE rats reflects differences in D2 but not D3 receptor-associated mechanisms.

Effects of strain on MDMA (“ecstasy”)‐induced locomotor hyperactivity and sensitization in mice

MDMA (3,4‐Methylenedioxymethamphetamine; “ecstasy”) is a popular illicit recreational amphetamine congener that possess both stimulant and hallucinogenic properties. It acts by releasing dopamine (DA) and serotonin (5‐HT) via the reuptake transporters. Whereas the locomotor activating effects of amphetamine primarily depend on the DA system, 5‐HT system appears to be essential in mediating MDMA effects. Selective 5‐HT reuptake inhibitors, which inhibit the binding of MDMA to the 5‐HT transporter, blocks hyperactivity stimulated by MDMA and the locomotor response to MDMA is attenuated in knockout mice lacking the 5‐HT1B receptor. It has been reported that DA transporter (DAT) expression is 50% higher in DBA/2 mice than C57BL/6 mice. An altered expression of DAT (the main target of psychostimulants) could influence psychostimulant response. The goals of the current studies were to determine possible strain differences in sensitivity to MDMA and to evaluate the behavioral response to repeated MDMA treatment. Baseline locomotor activity was significantly higher in C57BL/6 mice than in DBA/2 mice. MDMA produced dose‐dependent increase in locomotor activity in C57BL/6 mice but not in DBA/2 mice. In C57BL/6 mice, repeated treatment with MDMA produced behavioral sensitization, believed to model the motivational aspects of psychostimulant addiction. In addition, female mice of either strain exhibited greater sensitivity to MDMA than male mice. The results of these studies will facilitate efforts to elucidate how genetics may impact vulnerability to drug addiction. Supported by NIH grants, DA020677, NS041071 and ES014156.

Radiation sensitivity and genomic instability in the hematopoietic system: Frequencies of micronucleated reticulocytes in whole‐body X‐irradiated BALB/c and C57BL/6 mice

Using flow cytometry, we quantified the number of micronucleated reticulocytes in peripheral blood of whole-body X-irradiated mice in order to evaluate the radiation sensitivity and the induced genomic instability of the hematopoietic system. An acute effect of radiation dose as small as 0.1 Gy was detectable 2 days after irradiation, and the radiation dose effect was significantly greater in BALB/c mice than in C57BL/6 mice, that is, 3.0- and 2.3-fold increases in frequencies of micronuclei were noted in the two groups of mice, respectively. Even 1 year after irradiation, mice irradiated with 2.5 Gy of X-rays showed significantly increased frequencies of micronucleated reticulocytes, that is, 1.6- and 1.3-fold increases in BALB/c and C57BL/6 mice, respectively. However, this delayed effect was not apparent when the same mice were analyzed for T-cell receptor mutant frequencies in splenocytes. A significant mouse strain difference in the delayed radiation effect on micronucleated reticulocyte frequencies was noted as well. The results indicate that delayed genomic effects of irradiation on the murine hematopoietic system can persist in vivo for prolonged periods, and that there are mouse strain differences in sensitivity to radiation-induced genomic instability.

Inhibitory Activity of Colicin E1 against Listeria monocytogenes

Colicins are gram-negative bacteriocins produced by and effective against Escherichia coli and related species. Colicin E1 (ColE1) is composed of three functional domains, which collectively have a pore-forming effect on targeted bacteria. ColE1 binding and translocation domains are highly specific in contrast to the pore-forming domain, implying that ColE1 could be broadly effective. In this study, the activity of ColE1 against Listeria monocytogenes was evaluated in broth and on surfaces of ready-to-eat products. Individual strains of L. monocytogenes were examined in broth containing ColE1 at 0, 0.1, 1, or 10 μg/ml. Although strain differences in sensitivity to ColE1 existed, growth was significantly reduced in all strains at doses as low as 0.1 μg/ml. Sterilized ham slices were submerged in a five-strain L. monocytogenes cocktail (either 7 or 4 log CFU/ml) and placed in vacuum packages containing 0, 1, 5, 10, 25, or 50 μg of ColE1. Ham slices were then stored at 4 or 10°C, and samples were removed and examined for L. monocytogenes after 1, 3, 7, and 14 days. Reduction of L. monocytogenes by ColE1 was dependent on initial inoculum concentration and storage temperature. For slices stored at 4°C, treatment with 25 μg reduced Listeria growth below detection limits for the slices inoculated with 4 log CFU/ml for the entire 14 days, whereas for the 7-log CFU/ml slices, growth was detected at 7 days postinoculation. For slices stored at 10°C, 10 μg/ml ColE1 significantly inhibited growth of L. monocytogenes for up to 3 days for both inoculation groups. These data indicate that ColE1 is highly effective against Listeria.

The molecular basis for differential dioxin sensitivity in birds: Role of the aryl hydrocarbon receptor

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) and related halogenated aromatic hydrocarbons (HAHs) are highly toxic to most vertebrate animals, but there are dramatic differences in sensitivity among species and strains. Aquatic birds including the common tern (Sterna hirundo) are highly exposed to HAHs in the environment, but are up to 250-fold less sensitive to these compounds than the typical avian model, the domestic chicken (Gallus gallus). The mechanism of HAH toxicity involves altered gene expression subsequent to activation of the aryl hydrocarbon receptor (AHR), a basic helix-loop-helix-PAS transcription factor. AHR polymorphisms underlie mouse strain differences in sensitivity to HAHs and polynuclear aromatic hydrocarbons, but the role of the AHR in species differences in HAH sensitivity is not well understood. Here, we show that although chicken and tern AHRs both exhibit specific binding of [3H]TCDD, the tern AHR has a lower binding affinity and exhibits a reduced ability to support TCDD-dependent transactivation as compared to AHRs from chicken or mouse. We further show through use of chimeric AHR proteins and site-directed mutagenesis that the difference between the chicken and tern AHRs resides in the ligand-binding domain and that two amino acids (Val-325 and Ala-381) are responsible for the reduced activity of the tern AHR. Other avian species with reduced sensitivity to HAHs also possess these residues. These studies provide a molecular understanding of species differences in sensitivity to dioxin-like compounds and suggest an approach to using the AHR as a marker of dioxin susceptibility in wildlife.

Stress and Strain and Sensorimotor Gating

Strain differences in sensitivity to dopaminergic effects on sensorimotor gating have been used to study the genetic basis of schizophrenia. Corticotropin releasing hormone (CRF), a major mediator of stress effects, also regulates PPI and may be involved in the mechanism by which stress causes onset or relapse of schizophrenia. This study examined whether Sprague Dawley rats from different vendors exhibit equivalent sensitivity to CRF effect on prepulse inhibition of acoustic startle response (PPI). The effect of centrally-administered human/rat CRF (1.0 or 3.0 μg, icv) on percent PPI was assessed in male Sprague Dawley rats from Harlan (San Diego, CA) and from Charles River Laboratories (CR; Wilmington, MA) 40 min and 24 h after CRF infusion. Independent of effect on mean startle, the highest dose of CRF produced a disruption in PPI in Harlan rats 40 min after infusion, while neither dose produced an effect in CR rats. No effect was observed in either sub-strain 24 h after CRF infusion. Next, we tested the effect of a subthrehold dose of quinpirole (0.05 mg/kg), a D2-like receptor agonist, in combination with centrally administered CRF (3.0 μg) on PPI. Neither quinpirole alone nor or in combination with CRF disrupted PPI in CR rats. The results demonstrate that sensitivity to CRF varies across sub-strains of Sprague Dawley rats, with those from Harlan San Diego being most prone to CRF-induced PPI disruption. This sub-strain is known to be more sensitive to dopaminergic disruption of PPI than Long-Evans rats, but enhancing D2-agonist stimulation does not seem to confer CRF sensitivity. Nevertheless, such differences in the sensitivity to PPI-disruptive effects of CRF could be exploited to investigate the neurobiological basis of vulnerability to stress.

μ opioid receptor agonist DAMGO-induced suppression of saccharin intake in Lewis and Fischer rats

Rats suppress intake of a saccharin cue when paired with a drug of abuse such as morphine or cocaine. Relative to Lewis rats, Fischer rats exhibit greater avoidance of a saccharin cue following saccharin–morphine pairings. The present study used the μ agonist, [ d-Ala 2, N-MePhe 4,Gly-ol 5]enkephalin (DAMGO), to test whether strain differences in sensitivity of the μ receptor contribute to this effect. Water-deprived Lewis and Fischer rats were given 5 min access to 0.15% saccharin followed by an icv injection of either DAMGO (0.5 microg/1 microl/rat) or an equal volume of saline. There were six taste–drug pairings occurring at 48 h intervals. The results showed that, relative to the saline treated controls, all rats reduced intake of the saccharin cue following saccharin–DAMGO pairings. No differences occurred between strains. These data suggest that greater morphine-induced suppression of saccharin intake by the Fischer rats is not likely mediated by differences in sensitivity of the μ receptor. Other mechanisms are implicated.

Genetic differences in startle gating-disruptive effects of apomorphine: evidence for central mediation.

Strain differences in sensitivity to dopamine agonist-induced disruption of prepulse inhibition (PPI) may be a useful model for the genetics of PPI deficits in neuropsychiatric disorders. Compared with Long-Evans (LE) rats, Sprague-Dawley (SD) rats are more sensitive to the PPI-disruptive effects of the DA agonist apomorphine. The authors tested the hypothesis that this strain difference reflects brain function rather than peripheral physiology. Significant SD > LE PPI-disruptive effects of apomorphine were observed despite equal apomorphine levels in SD and LE rats in forebrain regions that regulate PPI. SD > LE PPI-disruptive effects of apomorphine were also independent of peripheral versus central route of administration. This model for PPI genetics is sensitive to differences in central rather than peripheral substrates.

Toward Understanding the Biology of a Complex Phenotype: Rat Strain and Substrain Differences in the Sensorimotor Gating-Disruptive Effects of Dopamine Agonists

Sensorimotor gating, measured by prepulse inhibition (PPI) of the startle reflex, is reduced in schizophrenia patients and in rats treated with dopamine agonists. Strain differences in the sensitivity to the PPI-disruptive effects of dopamine agonists may provide insight into the genetic basis for human population differences in sensorimotor gating. We reported strain differences in the sensitivity to the PPI-disruptive effects of the D1/D2 agonist apomorphine in adult rats, with greater sensitivity in Harlan Sprague Dawley (SDH) versus Wistar (WH) rats. However, Kinney et al. (1999) recently reported opposite findings, using Bantin-Kingman Sprague Dawley (SDBK) and Wistar (WBK) rats; in fact, SDBK rats did not exhibit clear apomorphine-induced reductions in sensorimotor gating. These new findings of Kinney et al. (1999) directly conflict with over 15 years of results from our laboratories and challenge interpretations from a large body of literature. The present studies carefully assessed drug effects on sensorimotor gating in SD versus W strains, across rat suppliers (H vs BK). Significantly greater SDH than WH apomorphine sensitivity in PPI measures was observed in both adult and 18 d pups, confirming that these strain differences are both robust and innate. These strain differences in apomorphine sensitivity were not found in adult BK rats. Supplier differences in sensitivity (SDH > SDBK) were also evident in the PPI-disruptive effects of D1 but not D2-family agonists; PPI was clearly disrupted by quinpirole in both SDH and SDBK rats. These findings demonstrate robust, innate, neurochemically specific, and apparently heritable phenotypic differences in an animal model of sensorimotor gating deficits in human neuropsychiatric disorders.

Rat strain differences in response to galanin on the Morris water task

Galanin acts as an inhibitory modulator of cholinergic transmission in the septohippocampal pathway of the rat. Centrally administered galanin induces performance deficits on rodent learning and memory tasks, including delayed non-matching to position, T-maze delayed alternation, passive avoidance, starbust radial maze acquisition, and the Morris water task. The present study investigates differences in responsiveness to intraventricularly administered galanin across three strains of laboratory rat on acquisition of spatial learning in the Morris water task. Sprague–Dawley rats showed normal performance during training, but lack of selective quadrant search on the probe trial in response to galanin treatment. Long–Evans rats showed no effects of galanin on performance during training or probe trial. Wistar rats showed longer latencies to reach the hidden platform during training, and lack of selective quadrant search on the probe trial in response to galanin. Performance on the visible platform task and on locomotor activity in the open field was normal in rats treated with galanin. These results are consistent with an interpretation of strain differences in sensitivity to the inhibitory actions of galanin on learning and memory.

Multiple pathways of prostate carcinogenesis analyzed by using cultured cells isolated from rats treated withN-methyl-N-nitrosourea and testosterone

Treatment of rats with N-methyl-N-nitrosourea (MNU) and testosterone results in a high incidence of metastasizing dorsolateral prostate tumors. In previous studies, a high frequency (> or = 70%) of a G35 --> A transition mutation at the second position of codon 12 of the Ki-ras oncogene was found in these tumors. This was confirmed in the study reported here, and the frequency of this mutation appeared similar in tumors induced in four different rat strains, regardless of differences in sensitivity among these strains to the induction of prostate cancers by MNU and testosterone: Wistar Furth (62% incidence of grossly visible prostate tumors) > Lobund Wistar (55%) > Fisher 344 (40%) > Copenhagen (37%). A method was developed to isolate and separately culture epithelial and stromal cells from these rat prostate carcinomas. Of 20 primary cell cultures established from histologically confirmed rat prostate carcinomas, 19 (95%) displayed one or more of the following characteristics: the Ki-ras mutation (17 of 20; 85%), anchorage-independent growth in soft agar at early passage (12 of 20; 60%), or tumorigenicity at later passage (eight of eight; 100%). One epithelial cell culture and all five stromal cell cultures established from prostate tumors had none of these characteristics. Epithelial cultures that had the Ki-ras mutation and grew in soft agar constitute the predominant genotype/phenotype (55%), cultures with the mutation that did not grow in soft agar were less frequent (30%), 10% of the cultures had neither characteristic, and only one grew in soft agar but did not have the mutation. These findings suggest that there are at least two and perhaps more different molecular pathways of prostate carcinogenesis in rats treated with MNU plus testosterone. Furthermore, these data suggest that these pathways and the mechanisms determining strain differences in sensitivity to prostate cancer induction are unrelated.

Discrimination and self-administration of nicotine by inbred strains of mice

These studies aim to characterize the discriminative stimulus effects of nicotine in two inbred strains of mice that differ in many pharmacological responses, and to investigate the feasibility of IV self-administration studies with nicotine in one of the strains. For discrimination studies, three groups of C57BL/6 and one group of DBA/2 mice were trained in a two-lever operant conditioning paradigm with a tandem VI-30" FR-10 schedule of food reinforcement. After 40 training sessions, accuracy reached 57.5, 77.5 and 90.0% in C57BL/6 mice trained with (-)-nicotine (SC) in doses of 0.4, 0.8 and 1.6 mg/kg, respectively (n = 8). DBA/2 mice trained with 0.8 mg/kg nicotine attained similar (73.3 %) accuracy (n = 9). Results from extinction tests showed that all groups of mice yielded orderly dose-response curves for nicotine (0.03-1.6 mg/kg), but stimulus control remained notably weaker for the mice trained with 0.4 mg/kg nicotine than for any other group. Overall rates of responding in the undrugged state were lower for DBA/2 than for C57BL/6 mice; DBA/2 mice were also slightly less sensitive than C57BL/6 mice to the response rate-reducing effect of nicotine. The nicotine antagonist mecamylamine (1.5 mg/kg SC) blocked the discriminative stimulus effect of the training dose of nicotine in all groups. The results of the IV self-administration study suggest that nicotine (0.1 mg/kg) can serve as a positive reinforcer in drug-naive C57BL/6J mice (n = 13). Behaviour maintained by 0.1 mg/kg nicotine injections was significantly greater than behaviour maintained by vehicle injections, and it was maintained under an intermittent schedule of reinforcement (FR4). The methods described provide possible approaches for genetic analyses of strain differences in sensitivity to the discriminative and reinforcing stimulus properties of nicotine.

Differential metabolite accumulation may be the cause of strain differences in sensitivity to streptozotocin-induced beta cell death in inbred mice.

Inbred strains of mice vary in their sensitivity to the diabetogenic effects of streptozotocin (STZ). To investigate the basis for this strain difference we exposed islet cells from two strains of mice that differ in sensitivity to the drug. We examined them morphologically and measured islet NAD + NADH content, streptozotocin metabolite accumulation, glucose transport capacity, Glut2 levels and medium nitrite accumulation. C57bl/6J mice were more sensitive to STZ than Balb/c mice as judged by the extent of pancreatic insulin depletion and beta cell death, in vivo and in vitro. The mode of cell death was necrosis. After a 30-min in vitro exposure to the drug the more sensitive C57bl/6J islets contained higher levels of streptozotocin metabolites and less NAD + NADH than the more resistant Balb/c islets. The lack of any strain differences in 3-O-methyl glucose transport, Glut2 levels and medium nitrite accumulation suggested that STZ transport and nitric oxide metabolism were not responsible for differences in STZ sensitivity and metabolite accumulation. Thus the strain differences in STZ sensitivity appears to be due to intracellular events within the beta cell occurring after STZ transport and before NAD + NADH depletion. STZ metabolite accumulation appears to be associated with STZ sensitivity. Further studies are warranted to determine if differential STZ metabolite accumulation is responsible for STZ sensitivity.

Differential Metabolite Accumulation May Be the Cause of Strain Differences in Sensitivity to Streptozotocin-Induced Cell Death in Inbred Mice

Differential Metabolite Accumulation May Be the Cause of Strain Differences in Sensitivity to Streptozotocin-Induced Cell Death in Inbred Mice

Strain differences in sensitivity to the promoting effect of sodium L-ascorbate in a two-stage rat urinary bladder carcinogenesis model.

Rat strain differences in sensitivity to the promoting effect of sodium L‐ascorbate (SA) on the development of urinary bladder tumors were investigated. In experiment 1, WS/Shi (WS), ODS/Shi‐od/od (ODS), and LEW/Crj (LEW) rats were initiated with 0.05%N‐butyl‐N‐(4‐hydroxybutyl)‐nitrosamine (BBN) in their drinking water and subsequently given basal Oriental MF diet (M) with or without a 5% SA supplement. In LEW rats the SA treatment increased the induction of neoplastic lesions in the urinary bladder, whereas WS and ODS animals proved unresponsive to its promoting effects. In experiment 2, WS and F344 rats were maintained on two kinds of commercial basal diets, M and CLEA CA‐1 (C), during administration of SA, since dietary factors can influence promoting effects. Feeding M during the promotion period in F344 rats yielded significantly more neoplastic lesions than feeding C, but in WS rats no such dietary influence was apparent. In experiment 3, strain differences in biosynthesis of α‐2u‐globulin (α2u‐g) were assessed because both α2u‐g in the urine and administration of sodium salts of organic acids such as SA have been reported to be involved in tumor promotion. Immunohistochemical analysis of renal tubules and Western blotting analysis of urine revealed the presence of α2u‐g in all three strains examined. These data suggest that differences in susceptibility to promotion are due to genetic factors rather than dietary factors and the ability to synthesize . α2u‐g.

Discriminative stimulus properties of nicotine: Approaches to evaluating potential nicotinic receptor agonists and antagonists

The prototypic nicotinic acetylcholinergic receptor (nAChR) agonist, nicotine, is one of the primary psychoactive ingredients of tobacco. This review examines the effects of nicotine and similar compounds in nicotine discrimination procedures, a paradigm in which the subjective effects of nicotine can be modeled in animals. Results of these studies have shown that the discriminative stimulus effects of nicotine are shared by nicotine analogues and by the novel nicotinic agonists, epibatidine and ABT-418, and can be antagonized by the nAChR channel blocker, mecamylamine. Individual and strain differences in sensitivity to the discriminative stimulus effects of nicotine have been noted, suggesting the possibility of genetic differences in the functioning of nACh receptors or related processes. In human smokers, individual variability is also observed ; however, the degree of within smoker (but between situation) variability far exceeds between smoker variability. Further research into the ways in which situational factors affect the discriminative stimulus effects of nicotine is needed.