Long-Evans Research Articles

Pubertal Administration of DEHP Delays Puberty, Suppresses Testosterone Production, and Inhibits Reproductive Tract Development in Male Sprague-Dawley and Long-Evans Rats

Although is clear that exposure to high dosage levels of some phthalates delays the onset of puberty in the male rat, it has been hypothesized that low levels of di(2-ethylhexyl) phthalate (DEHP) accelerate puberty by enhancing testicular androgen synthesis. The current study was designed to determine if the dose response to DEHP was nonmonotonic, as hypothesized. Pubertal administration of DEHP delayed the onset of puberty and reduced androgen-dependent tissue weights in both Long-Evans (LE) and Sprague-Dawley (SD) male rats 300 and 900 mg DEHP/kg/day. These effects were generally of greater magnitude in LE than SD rats. By contrast, alterations in testis histopathology (300 and 900 mg/kg/day) were more severe in SD than in LE rats. Taken together, these results suggest that DEHP may be acting on the pubertal male rat testis via two modes of action; one via the Leydig cells and the other via the Sertoli cells. Treatment with DEHP generally reduced serum testosterone and increased serum luteinizing hormone (LH) levels, demonstrating that the reduction in testosterone was due to the effect of DEHP on the testis and not via an inhibition of LH from hypothalamic-pituitary axis. Testosterone production ex vivo (with and without human chorionic gonadotropin stimulation) was consistently reduced in males at the time of puberty and shortly thereafter. DEHP treatment did not accelerate the age at puberty or enhance testosterone levels at 10 or 100 mg/kg/day in either LE or SD rats, as some have hypothesized. Taken together, these results do not provide any evidence of a nonmonotonic dose response to DEHP during puberty.

Strain-Dependent Increases in Retinal Inflammatory Proteins and Photoreceptor FGF-2 Expression in Streptozotocin-Induced Diabetic Rats

Inflammation is thought to play a role in disease progression and vision loss in diabetic retinopathy (DR). However, the level of inflammation and the role of cytokines and growth factors in the early stages of this disease are poorly understood. Streptozotocin (STZ)-induced hyperglycemia in rats is widely used as a model of diabetic retinopathy, and therefore this model was used to better define the inflammatory response and the impact of the genetic background. The expression of a panel of 57 inflammatory proteins and growth factors in the retina of three rat strains was compared by using a highly sensitive flow cytometry-based assay. Hyperglycemia was induced in Brown Norway (BN), Long-Evans (LE), and Sprague-Dawley (SD) rats, and protein expression in the retina was measured 4 weeks and 3 months later. The data revealed a subtle, but reproducible, inflammatory response in the retina of SD, but not in those of BN or LE, rats. Upregulation of fibroblast growth factor (FGF)-2 in the photoreceptor nuclear layer coincided with the inflammatory response in SD rats and may constitute a neuroprotective mechanism. Reduced expression of genes involved in the phototransduction pathway indicates altered photoreceptor function. Taken together, these data show that inflammatory changes in the diabetic rat retina are highly strain dependent, and SD rats exhibit low-level inflammation similar to that observed in diabetic patients. Therefore, SD rats may be a good model for the study of early inflammatory changes in human diabetic retinopathy.

The Brattleboro Rat Displays a Natural Deficit in Social Discrimination That Is Restored by Clozapine and A Neurotensin Analog

Cognitive deficits in schizophrenia are a major source of dysfunction for which more effective treatments are needed. The vasopressin-deficient Brattleboro (BRAT) rat has been shown to have several natural schizophrenia-like deficits, including impairments in prepulse inhibition and memory. We investigated BRAT rats and their parental strain, Long Evans (LE) rats, in a social discrimination paradigm, which is an ethologically-relevant animal test of cognitive deficits of schizophrenia based upon the natural preference of animals to investigate conspecifics. We also investigated the effects of the atypical antipsychotic, clozapine and the putative antipsychotic, PD149163, a brain-penetrating neurotensin-1 analogue, on social discrimination in these rats. Adult rats were administered saline or one of three doses of clozapine (0.1, 1.0 or 10 mg/kg) or PD149163 (0.1, 0.3 or 1.0 mg/kg), subcutaneously. Following drug administration, adult rats were exposed to a juvenile rat for a 4-minute learning period. Animals were then housed individually for 30 minutes and then simultaneously exposed to the previously presented juvenile and a new juvenile for 4 minutes. Saline-treated LE rats, but not BRAT rats, exhibited intact social discrimination as evidenced by greater time spent exploring the new juvenile. The highest dose of clozapine and the two highest doses of PD149163 restored social discrimination in BRAT rats. These results provide further support for the utility of the BRAT rat as a genetic animal model relevant to schizophrenia and drug discovery. The potential of neurotensin agonists as putative treatments for cognitive deficits of schizophrenia was also supported.

Further neurochemical and behavioural investigation of Brattleboro rats as a putative model of schizophrenia

Brattleboro (BRAT) rats are a mutant variant of the Long-Evans (LE) strain deficient in the neurohormone vasopressin. BRAT rats show behavioural alterations relevant to schizophrenia. In particular, BRAT rats show deficits in prepulse inhibition (PPI) and alterations in various measures of cognition. The aim of this study was to replicate the reported PPI deficits in BRAT rats and its reversal by antipsychotic drugs and to investigate other behavioural and neurochemical characteristics. Acoustic startle reactivity, PPI, spontaneous and amphetamine-induced locomotor activity (LMA) and ex-vivo steady state neurochemistry were measured in male homozygous BRAT rats and LE rats. The effects of antipsychotics on PPI deficits were also determined. Relative to LE, BRAT rats showed enhanced startle reactivity, hyperactivity to a novel environment, PPI deficits and decreased levels of dopamine and DOPAC (dihydroxyphenylacetic acid) in the frontal cortex. BRAT and LE rats showed similar levels of hyperactivity following amphetamine (0.26 mg/kg s.c.). PPI deficits were attenuated by acute clozapine (5-10 mg/kg s.c.), risperidone (0.1-1 mg/kg i.p.), haloperidol (0.1-0.5 mg/kg p.o.) and less robustly by olanzapine (0.3-3 mg/kg s.c.). Chronic administration of clozapine (5 mg/kg s.c., once daily) attenuated baseline hyperactivity and elevated PPI of both strains. Clozapine concentrations were higher in BRAT brains compared with LE rats. These data confirm the reported PPI deficit in BRAT rats and its reversal by antipsychotic drugs, suggesting BRAT rats may represent a potential model for identifying novel antipsychotic drugs.

Functional and Structural Changes Resulting from Strain Differences in the Rat Model of Oxygen-Induced Retinopathy

Results of studies that compared the racial incidence of retinopathy of prematurity (ROP) suggested that ocular pigmentation might offer protection against the development of severe ROP. The structural and functional consequences of postnatal hyperoxia (oxygen-induced retinopathy; OIR) were compared in albino Sprague-Dawley (SD) and pigmented Long-Evans (LE) rats to verify this finding. Newborn rats were exposed to 80% O(2) during selected postnatal day intervals. The severity of the OIR was determined by examining retinal flatmounts (retinal vasculature assessment), protein level quantification and cellular localization of fibroblast growth factor (FGF)-2 and ciliary neurotrophic factor (CNTF; Western blot analysis and immunohistochemistry, respectively), retinal histology, and photopic and scotopic electroretinograms (ERGs). Irrespective of the parameter considered, structural and functional deficits resulting from postnatal hyperoxia were significantly more pronounced in LE rats. Although FGF-2 levels in LE rats had a tendency to increase after hyperoxia compared with normoxic littermates, it did not reach statistical significance. A similar finding was observed in SD rats. Of interest, however, baseline levels of FGF-2 were approximately four to five times higher in SD rats than in LE rats. There was a similar, hyperoxia-induced increase in CNTF levels between SD and LE rats. The findings suggest an increased susceptibility of newborn LE rats to postnatal hyperoxia in comparison with SD rats. Whether a pro-oxidant rather than antioxidant role of melanin or other genetic factors can explain these differences in oxygen susceptibility of the animal model of this retinopathy, remains to be determined.

Amphetamine effects on startle gating in normal women and female rats

Dopamine agonists disrupt prepulse inhibition (PPI) of startle in male rodents. In humans, this is observed only in some studies. We reported that PPI was disrupted by D: -amphetamine in men, but only among those with high basal PPI levels. Here, amphetamine effects on PPI were tested in normal women and female rats. Acoustic startle and PPI were tested in normal women after placebo or 20 mg amphetamine, in a double-blind, crossover design, and in female rats after vehicle or 4.5 mg/kg amphetamine. Rats were from Sprague-Dawley (SD) and Long Evans (LE) strains that differ significantly in gene expression in PPI-regulatory circuitry, including levels of nucleus accumbens (NAC) catechol-O-methyl transferase (COMT) mRNA. Amphetamine was bioactive in humans based on quantitative autonomic and self-rating measures, but did not significantly change startle magnitude or PPI across all subjects. Amphetamine's effects on PPI in women correlated significantly (p < 0.0008) with placebo PPI levels (reducing PPI only in women whose basal PPI levels exceeded the sample median) and with measures of novelty and sensation seeking. Amphetamine decreased PPI in SD rats that have relatively low NAC COMT gene expression and increased PPI in LE rats that have relatively high NAC COMT gene expression. The dopaminergic regulation of PPI in humans is related to basal levels of sensorimotor gating and to specific personality traits in normal men and women. In rats, the effects of amphetamine on PPI differ significantly in strains with low vs. high NAC COMT expression.

Possible involvement of arylhydrocarbon receptor variants in TCDD-induced thymic atrophy and XRE-dependent transcriptional activity in Wistar Hannover GALAS rats

Wistar Hannover Global Alliance for Laboratory Animal Standardization (WH GALAS) rats have been distributed for international standardization of preclinical and toxicological research. Han/Wistar (Kuopio) rats are exceptionally resistant to acute toxicities caused by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and mediated by the aryl hydrocarbon receptor (AhR), and they have a mutated AhR, named AhR(hw/hw). We found that the WH GALAS rat has either of the three AhR allele, AhR(wt/wt), AhRwt/hw and AhRhw/hw. We administered TCDD (0, 5 and 10 microg/kg) to Long-Evans (L-E) rats having AhR(wt/wt) and two WH GALAS rat strains having either AhR(wt/wt) or AhR(hw/hw), and examined the weights of their body, liver and thymus 168 hr post-administration. WH GALAS AhR(hw/hw) strain was more resistant to TCDD-induced effects on thymus weight than L-E and WH GALAS AhR(wt/wt) strains. In order to study differences in susceptibility of thymic atrophy among the strains, we examined CYP1A1 mRNA and AhR protein levels between L-E and WH GALAS strains. However, no significant difference was observed in the amount of AhR protein or CYP1A1 mRNA in the thymus. Next, we carried out in vitro assays to examine the transactivation activities of AhR variants and found that the AhR deletion variant (AhRdv) transcribed from AhR(hw/hw) significantly enhanced transactivation activity of the synthesized xenobiotic response element. All AhR variants similarly suppressed the growth of Jurkat T cells upon TCDD exposure. This study suggests that WH GALAS rat having different AhR alleles is an interesting experimental animal model but should be utilized with caution for preclinical research on chemicals having AhR agonistic activities.

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.

Altered pattern of Na,K-ATPase activity and mRNA during chronic alcohol consumption by juvenile and adolescent rats.

The effect of chronic ethanol consumption on cerebral cortical activity of Na,K-ATPase was determined in Long-Evans (LE) rats fed an ethanol-containing diet beginning at different stages of development. Na,K-ATPase activity was operationally resolved into alpha1 and alpha2/3 isozyme activities. There was no significant difference in Na,K-ATPase activities before and after alcohol consumption in the preparations from adult rats. However, for rats beginning alcohol consumption as adolescents, the alpha2/3 activity was significantly elevated following chronic alcohol consumption. Both LE and Sprague-Dawley rats showed this same selective increase in cortical alpha2/3 activity when rats began alcohol consumption as juveniles. The shift in cortical alpha2/3 activity was not observed in cerebellum or subcortical forebrain and was reversible when rats were fed ethanol throughout the normal adolescent period and then withdrawn and tested 2 weeks later (during the adult period). Levels of isoform-specific mRNA were determined in preparations of cerebral cortices of rats showing elevated alpha2/3 isozyme activities. In these preparations, isoform specific alpha2 and alpha3 mRNA was significantly elevated. There was no effect of ethanol feeding on cortical alpha1 mRNA. These findings indicate that the longer term effects of ethanol on the developing brain include elevated Na,K-ATPase activity and a mechanism that is pre-translational and isoform specific.

The orl Rat with Inherited Cryptorchidism Has Increased Susceptibility to the Testicular Effects of In Utero Dibutyl Phthalate Exposure

Phenotype results from interactions between genetics and environment, but for most environmental chemical exposures, such interactions are theoretical. The phenotypic response of the testis to in utero dibutyl phthalate (DBP) exposure was compared between two strains of Long-Evans (LE) rats, the orl substrain with inherited cryptorchidism and an outbred (wt) strain. orl and wt LE rats were exposed daily between gestational day (GD) 12 and GD21 to DBP dose levels ranging from 50 to 200 mg/kg by oral gavage and sensitive phthalate testicular end points examined at either GD19, GD21, or postnatal day (PND) 21. At 50 mg/kg DBP, GD19 expression of Cyp17a1, Insl3, and Scarb1 was significantly reduced in orl but not wt testis. At GD21, statistically significant differential strain effects (orl more sensitive than wt) were observed for testicular expression of Scarb1 at 50 and 200 mg/kg DBP and Star at 200 mg/kg DBP. Similarly, DBP exposure disproportionately increased GD21 seminiferous cord diameters and numbers of multinucleated germ cells in the orl strain. At PND21, body weight-corrected testis weights were lowered significantly by DBP exposure at all dose levels in the orl strain but not in wt rats. While the frequency of undescended testes after 200 mg/kg DBP exposure in the orl strain appeared increased, these data were not statistically significant. These results demonstrated enhanced sensitivity of the orl rat to phthalate exposure as compared to its parent strain, a potentially important model of the effects of gene-environment interaction on development of male reproductive malformations.

Changes in parvalbumin immunoreactivity with aging in the central auditory system of the rat

Changes in the levels of calcium binding proteins are known to occur in different parts of the brain during aging. In our study we attempted to define the effect that aging has on the parvalbumin-expressing system of neurons in the higher parts of the central auditory system. Age-related changes in parvalbumin immunoreactivity were investigated in the inferior colliculus (IC), medial geniculate body (MGB) and auditory cortex (AC) in two rat strains, normally aging Long–Evans (LE) and fast aging Fischer 344 (F344). The results demonstrate that the changes in PV-immunoreactivity are strain-dependent with an increase in the number of PV-immunoreactive (PV-ir) neurons occurring in the inferior colliculus of old LE rats and a pronounced decline in the number of PV-ir neurons appearing in the auditory cortex of aged F344 animals. In some parts of the AC of old F344 animals no PV-ir neurons were present at all. The number of PV-ir neurons in the MGB in all examined animals was very low independent of the strain and age. The loss of PV-ir neurons in the auditory cortex of Fischer 344 rats with aging may contribute to the substantial deterioration of hearing function in this strain.

Strain Differences in the Gating-Disruptive Effects of Apomorphine: Relationship to Gene Expression in Nucleus Accumbens Signaling Pathways

Prepulse inhibition (PPI) of startle is a measure of sensorimotor gating that is deficient in certain psychiatric disorders, including schizophrenia. Sprague Dawley (SD) rats are more sensitive to PPI-disruptive effects of apomorphine (APO) at long interstimulus intervals (ISIs) (60-120 msec) and less sensitive to PPI-enhancing effects of APO at short ISIs (10-30 msec) compared with Long Evans (LE) rats. Prepulse inhibition was tested in SD and LE rats after APO (.5 mg/kg) or vehicle in a within- subject design and sacrificed 14 days later. Total RNA was extracted from the nucleus accumbens (NAC). Approximately 700 dopamine-relevant transcripts on the Affymetrix 230 2.0 microarray were analyzed. As previously reported, SD rats exhibited greater APO-induced PPI deficits at long intervals and less APO-induced PPI enhancement at short intervals compared with LE rats. One hundred four genes exhibited significantly different NAC expression levels in these two strains. Pathway analysis revealed that many of these genes contribute to dopamine receptor signaling, synaptic long-term potentiation, or inositol phosphate metabolism. The expression of some genes significantly correlated with measures of APO-induced PPI sensitivity in either SD or LE rats. The expression of select genes was validated by real-time reverse transcription polymerase chain reaction (RT-PCR). Differences in PPI APO sensitivity in SD versus LE rats are robust and reproducible and may be related to strain differences in the expression of genes that regulate signal transduction in the NAC. These genes could facilitate the identification of targets for ameliorating heritable gating deficits in brain disorders such as schizophrenia.

Modeling the Toxicokinetics of Inhaled Toluene in Rats: Influence of Physical Activity and Feeding Status

Toluene is found in petroleum-based fuels and used as a solvent in consumer products and industrial applications. The critical effects following inhalation exposure involve the brain and nervous system in both humans and experimental animals, whether exposure duration is acute or chronic. The goals of this physiologically based pharmacokinetic (PBPK) model development effort were twofold: (1) to evaluate and explain the influence of feeding status and activity level on toluene pharmacokinetics utilizing our own data from toluene-exposed Long Evans (LE) rats, and (2) to evaluate the ability of the model to simulate data from the published literature and explain differing toluene kinetics. Compartments in the model were lung, slowly and rapidly perfused tissue groups, fat, liver, gut, and brain; tissue transport was blood-flow limited and metabolism occurred in the liver. Chemical-specific parameters and initial organ volumes and blood flow rates were obtained from the literature. Sensitivity analysis revealed that the single most influential parameter for our experimental conditions was alveolar ventilation; other moderately influential parameters (depending upon concentration) included cardiac output, rate of metabolism, and blood flow to fat. Based on both literature review and sensitivity analysis, other parameters (e.g., partition coefficients and metabolic rate parameters) were either well defined (multiple consistent experimental results with low variability) or relatively noninfluential (e.g. organ volumes). Rats that were weight-maintained compared to free-fed rats in our studies could be modeled with a single set of parameters because feeding status did not have a significant impact on toluene pharmacokinetics. Heart rate (HR) measurements in rats performing a lever-pressing task indicated that the HR increased in proportion to task intensity. For rats acclimated to eating in the lab during the day, both sedentary rats and rats performing the lever-pressing task required different alveolar ventilation rates to successfully predict the data. Model evaluation using data from diverse sources together with statistical evaluation of the resulting fits revealed that the model appropriately predicted blood and brain toluene concentrations with some minor exceptions. These results (1) emphasize the importance of experimental conditions and physiological status in explaining differing kinetic data, and (2) demonstrate the need to consider simulation conditions when estimating internal dose metrics for toxicity studies in which kinetic data were not collected.

Evidence for impulsivity in the Spontaneously Hypertensive Rat drawn from complementary response-withholding tasks

BackgroundThe inability to inhibit reinforced responses is a defining feature of ADHD associated with impulsivity. The Spontaneously Hypertensive Rat (SHR) has been extolled as an animal model of ADHD, but there is no clear experimental evidence of inhibition deficits in SHR. Attempts to demonstrate these deficits may have suffered from methodological and analytical limitations.MethodsWe provide a rationale for using two complementary response-withholding tasks to doubly dissociate impulsivity from motivational and motor processes. In the lever-holding task (LHT), continual lever depression was required for a minimum interval. Under a differential reinforcement of low rates schedule (DRL), a minimum interval was required between lever presses. Both tasks were studied using SHR and two normotensive control strains, Wistar-Kyoto (WKY) and Long Evans (LE), over an overlapping range of intervals (1 – 5 s for LHT and 5 – 60 s for DRL). Lever-holding and DRL performance was characterized as the output of a mixture of two processes, timing and iterative random responding; we call this account of response inhibition the Temporal Regulation (TR) model. In the context of TR, impulsivity was defined as a bias toward premature termination of the timed intervals.ResultsThe TR model provided an accurate description of LHT and DRL performance. On the basis of TR parameter estimates, SHRs were more impulsive than LE rats across tasks and target times. WKY rats produced substantially shorter timed responses in the lever-holding task than in DRL, suggesting a motivational or motor deficit. The precision of timing by SHR, as measured by the variance of their timed intervals, was excellent, flouting expectations from ADHD research.ConclusionThis research validates the TR model of response inhibition and supports SHR as an animal model of ADHD-related impulsivity. It indicates, however, that SHR's impulse-control deficit is not caused by imprecise timing. The use of ad hoc impulsivity metrics and of WKY as control strain for SHR impulsivity are called into question.

Severity of alcohol withdrawal symptoms depends on developmental stage of Long–Evans rats

To investigate alcohol dependency and the potential role of age of initial alcohol consumption, Long–Evans (LE) rats were fed an ethanol-containing liquid diet starting at postnatal (P) ages (days): P23–27 (juvenile), P35–45 (adolescent) or P65–97 (young adult). Severity of subsequent withdrawal symptoms was dependent on age when consumption began and on duration of alcohol consumption. Frequency of withdrawal seizures was highest for rats starting consumption as juveniles, intermediate for adolescents and lowest for adults. Normalized to body weight, alcohol consumption was significantly higher for adolescent and juvenile rats than for adults. Sprague–Dawley rats that began alcohol consumption as adolescents (P35) had a level of alcohol consumption identical to that of the adolescent LE rats but showed much lower frequency of withdrawal seizures when tested after 2, 3 and 5 weeks of alcohol consumption. Based on several indicators, the capacity of the juveniles to metabolize ethanol is equal to or exceeds that of adults. Recoveries from a single dose of ethanol (2.5 g ethanol/kg body weight) were faster for juvenile LE rats than adults. The rate of decline in blood ethanol concentration was identical for juvenile and adult rats while the corrected ethanol elimination rate was higher for juveniles. The primary isozyme of alcohol dehydrogenase (ADH) in rat liver, ADH-3, had a similar Km and higher activity in liver preparations from juveniles. In conclusion, LE rats beginning alcohol consumption as juveniles or adolescents develop a severe alcohol withdrawal syndrome that may not be attributed entirely to higher levels of consumption and was not explained by any obvious deficiencies in metabolism.

Cannabinoid self‐administration in rats: sex differences and the influence of ovarian function

We recently demonstrated the existence of strain differences in self-administration of the cannabinoid CB1 receptor agonist WIN55,212-2 (WIN) by Long Evans (LE) and Lister Hooded (LH) but not Sprague-Dawley (SD) male rats. This follow-up study is aimed at verifying whether sex and ovarian hormones might also be critical factors in the initiation, retention and extinction of WIN self-administration. LE, LH and SD male and female rats, the latter either intact or bilaterally ovariectomized (OVX), were trained to self-administer WIN (12.5 microg kg(-1) per infusion) under a FR1 reinforcement schedule, using lever-pressing. Data showed that contrary to the findings in SD rats, LE and LH rats developed robust cannabinoid intake, with rates of responding for WIN being constantly higher in intact females than in males (+45 and +42% for LE and LH strains, respectively). In comparison with intact females, OVX females of both strains acquired self-administration at lower rates, displaying slower acquisition, lower drug intake (-42 and -52% for LE and LH, respectively) and longer extinction. These findings provide the first evidence of significant sex differences in cannabinoid self-administration, females acquiring stable WIN intake at higher rates and more rapidly than males. Moreover, when compared to intact females, a lower percentage of LE and LH OVX rats acquired and maintained stable drug intake, suggesting that ovarian hormones might represent a critical factor in modulating the reinforcing effect of cannabinoids.

Cannabis reward: biased towards the fairer sex?

In contrast to drugs such as alcohol, amphetamine and cocaine, cannabis use in humans has proven difficult to model in laboratory animals. Recent breakthrough discoveries of intravenous THC self-administration in rhesus monkeys and self-administration of the synthetic cannabinoid agonist WIN 55,212-2 in rats have allowed new studies of the genetic, neural and environmental determinants of cannabis use. In the present issue of BJP, Fattore and colleagues further demonstrate genetic (strain) differences in WIN 55,212-2 self-administration in rats, with Long Evans (LE) and Lister Hooded (LH), but not Sprague-Dawley, rats self-administering this drug. They then show that female LE and LH rats self-administer more WIN 55,212-2 than male rats. Ovariectomy abolished this sex difference, suggesting a permissive role for oestrogen in cannabis reward. This accompanying Commentary reviews recent progress in animal models of cannabis use and highlights the role of genetic, developmental and endocrine factors in driving cannabis use and dependence.

Rat strain differences in startle gating-disruptive effects of apomorphine occur with both acoustic and visual prepulses

Prepulse inhibition of startle (PPI) is an operational measure of sensorimotor gating that is impaired in schizophrenia and is disrupted in rats by dopamine (DA) agonists like apomorphine (APO). Using acoustic prepulses and acoustic startle pulses, previous studies have demonstrated heritable strain differences between Sprague Dawley (SD) and Long Evans (LE) rats in the sensitivity to the PPI-disruptive effects of APO. As PPI deficits in schizophrenia are evident with both uni- and cross-modal stimuli, we tested whether strain differences in the gating-disruptive effects of APO occur with a cross-modal visual and acoustic stimulus combination. APO caused a dose-dependent disruption of both acoustic and visual PPI in SD rats. Compared to LE rats, SD rats were more sensitive to the PPI-disruptive effects of APO with both acoustic and visual PPI. These findings suggest that SD vs. LE strain differences in PPI APO sensitivity are mediated outside of the auditory system, within higher circuitry that regulates or processes multi-modal information. The present findings provide further validation for this heritable model of impaired sensorimotor gating in schizophrenia, which can be detected across multiple sensory modalities.

The effect of caffeine to increase reaction time in the rat during a test of attention is mediated through antagonism of adenosine A 2A receptors

Caffeine produces effects on cognitive function particularly relating to aspects of attention such as reaction time. Considering the plasma exposure levels following regular caffeine intake, and the affinity of caffeine for known protein targets, these effects are likely mediated by either the adenosine A 1 or A 2A receptor. In the present studies, two rat strains [Long-Evans (LE) and CD] were trained to asymptote performance in a test of selective attention, the 5-choice serial reaction time task (5-CSRTT). Next, the effects of caffeine were compared to the selective A 2A antagonists, SCH 412348 and KW-6002 (Istradefylline), and the A 1 antagonist, DPCPX. Further studies compared the psychostimulant effects of each drug. Finally, we tested the A 2A agonist, CGS-21680, on 5-CSRTT performance and given the antipsychotic potential of this drug class, studied the interaction between CGS-21680 and amphetamine in this task. Caffeine (3–10 mg/kg IP) increased reaction time in both LE and CD rats, with no effect on accuracy, an effect replicated by SCH 412348 (0.1–1 mg/kg PO) and KW-6002 (1–3 mg/kg PO), but not DPCPX (3–30 mg/kg PO). At least with SCH 412348, these effects were at doses that were not overtly psychostimulant. In contrast, CGS-21680 (0.03–0.3 mg/kg IP) slowed reaction speed and increased omissions. Interestingly, at a comparatively low dose of 0.03 mg/kg, CGS-21680 attenuated the increased premature responding produced by amphetamine (1 mg/kg IP). The present results suggest that the attention-enhancing effects of caffeine are mediated through A 2A receptor blockade, and selective A 2A receptor antagonists may have potential as therapies for attention-related disorders. Furthermore, the improvement in response control in amphetamine-treated rats following CGS-21680 pretreatment supports the view that A 2A agonists have potential as novel antipsychotics.

Altered cerebral glucose metabolism in an animal model of diabetes insipidus: A micro-PET study

The Brattleboro rat is an animal model of genetically induced central diabetes insipidus. These rats show cognitive and behavioral disorders, but no neurodegenerative disease has been observed. We studied brain glucose uptake, a marker of neuronal activity, in 6 Brattleboro rats, in comparison with 6 matched Long–Evans (LE) control rats. A group of 3 Brattleboro rats and 3 Long–Evans rats was studied in vivo and another group of animals was studied ex vivo. In vivo studies were performed using fluorodeoxyglucose labeled with fluorine 18 ( 18F-FDG) and a dedicated small-animal PET device. At 30 min and 60 min p.i., 18F-FDG uptake was significantly higher in the frontal cortex, striatum, thalamus and cerebellum of Brattleboro rats than in LE rats when measured by PET in vivo ( p < 0.05), but only a trend towards higher values was found ex vivo. Our results show for the first time that brain glucose metabolism is modified in Brattleboro rats. This altered brain glucose metabolism in Brattleboro rats may be related to the observed cognitive and behavioral disorders. Functional analyses of brain metabolism are promising to investigate cognitive behavioral disturbances observed in Brattleboro rats and their link to diabetes insipidus.