Activation of CYP3A-mediated testosterone 6β-hydroxylation by tanshinone IIA and midazolam 1-hydroxylation by cryptotanshinone in human liver microsomes

This study evaluated the in vitro activation of CYP3A-mediated midazolam 1-hydroxylation and testosterone 6β-hydroxylation by tanshinone I, tanshinone IIA, and cryptotanshinone. The abilities of tanshinones to activate CYP3A-mediated midazolam 1-hydroxylation and testosterone 6β-hydroxylation in human liver microsomes (HLMs) were tested. Substrate- and effector-dependent activation of CYP3A by tanshinones were both observed. Cryptotanshinone was shown to activate CYP3A-mediated midazolam 1-hydroxylation in a concentration-dependent manner. In contrast, tanshinone IIA and tanshinone I did not activate this hydroxylation reaction. In addition, tanshinone IIA activated CYP3A-mediated testosterone 6β-hydroxylation, whereas cryptotanshinone and tanshinone I did not. The results from our study enhance the understanding of CYP3A activation by tanshinone IIA and cryptotanshinone in HLMs. Additionally, these data allow for an accurate prediction of the magnitude and likelihood of Danshen-drug interactions.     

Activation of CYP3A-mediated testosterone 6β-hydroxylation by tanshinone IIA and midazolam 1-hydroxylation by cryptotanshinone in human liver microsomes

1. This study evaluated the in vitro activation of CYP3A-mediated midazolam 1-hydroxylation and testosterone 6β-hydroxylation by tanshinone I, tanshinone IIA, and cryptotanshinone.

2. The abilities of tanshinones to activate CYP3A-mediated midazolam 1-hydroxylation and testosterone 6β-hydroxylation in human liver microsomes (HLMs) were tested. Substrate- and effector-dependent activation of CYP3A by tanshinones were both observed.

3. Cryptotanshinone was shown to activate CYP3A-mediated midazolam 1-hydroxylation in a concentration-dependent manner. In contrast, tanshinone IIA and tanshinone I did not activate this hydroxylation reaction. In addition, tanshinone IIA activated CYP3A-mediated testosterone 6β-hydroxylation, whereas cryptotanshinone and tanshinone I did not.

4. The results from our study enhance the understanding of CYP3A activation by tanshinone IIA and cryptotanshinone in HLMs. Additionally, these data allow for an accurate prediction of the magnitude and likelihood of Danshen-drug interactions.

     

Strain difference of cadmium-induced testicular toxicity in inbred Wistar–Imamichi and Fischer 344 rats

Previously, we reported that Wistar–Imamichi (WI) rats are highly resistant to cadmium (Cd)-induced lethality and hepatotoxicity compared to Fischer 344 (F344) rats. Since the testes are one of the most sensitive organs to acute Cd toxicity, we examined possible strain-related differences in Cd-induced testicular toxicity between inbred WI and F344 rats. Rats were treated with a single dose of 0.5, 1.0 or 2.0 mg Cd/kg, as CdCl₂, sc and killed 24 h later. Cd at doses of 1.0 and 2.0 mg/kg induced severe testicular hemorrhage, as assessed by pathological and testis hemoglobin content, in F344 rats, but not WI rats. After Cd treatment (2.0 mg/kg), the testicular Cd content was significantly lower in WI rats than in the F344 rats, indicating a toxiokinetic mechanism for the observed strain difference. Thus, the remarkable resistance to Cd-induced testicular toxicity in WI rats is associated, at least in part, with lower testicular accumulation of Cd. When zinc (Zn; 10 mg/kg, sc) was administered in combination with Cd (2.0 mg/kg) to F344 rats, the Cd-induced increase in testicular hemoglobin content, indicative of hemorrhage, was significantly reduced. Similarly, the testicular Cd content was significantly decreased with Zn co-treatment compared to Cd treatment alone. Thus, it can be concluded that the testicular Cd accumulation partly competes with Zn transport systems and that these systems may play an important role in the strain-related differences in Cd-induced testicular toxicity between WI and F344 rats.     

Age differences in the spontaneous acquisition of nicotine self-administration in male Wistar and Long–Evans rats

Rationale Epidemiological evidence suggests that adolescents may exhibit a unique susceptibility to the motivational effects of nicotine compared to adults. In contrast to the hypothesis of an enhanced vulnerability to nicotine during adolescence, we have observed that nicotine is less reinforcing in adolescent compared to adult rats using a progressive ratio reinforcement schedule in an operant self-administration procedure, although prior operant conditioning experience may have masked differences in initial sensitivity to nicotine. Objectives This study examined the spontaneous acquisition of nicotine self-administration in adolescent (postnatal day (PD) 31) and adult (PD87) male Wistar and Long–Evans rats. Materials and methods Rats self-administered nicotine (0.015 or 0.03 mg/kg/infusion, i.v.) during 2-h operant conditioning sessions under fixed-ratio-1 (FR1) and FR3 reinforcement schedules for six sessions each. A subset of rats (adolescents: PD42, adults: PD98) underwent extinction of responding and nicotine priming-induced reinstatement (0.15 mg/kg, s.c.). In a separate group of rats, saccharin self-administration (0.1 ml of 0.2% w/v) was tested to determine the specificity of our findings with nicotine. Results A greater proportion of adult compared to adolescent rats acquired self-administration of 0.015 mg/kg/infusion nicotine, but both age groups readily acquired self-administration of 0.03 mg/kg/infusion nicotine and saccharin. Age differences in extinction of responding for nicotine or saccharin depended upon strain, but priming-induced reinstatement was similar across age and strain. Conclusions The current findings are consistent with those obtained under a more demanding progressive ratio reinforcement schedule and suggest that adolescents, compared to adults, may not be as sensitive to the reinforcing effects of nicotine.     

Modulation of serum concentrations and hepatic metabolism of 17β-estradiol and testosterone by amitraz in rats

The present study has investigated the ability of amitraz, a widely used formamidine pesticide, to modulate serum concentrations and liver microsomal metabolism of 17β-estradiol (E2) and testosterone in rats. Amitraz was administered intraperitoneally to male rats for 4 days and to intact female rats or ovariectomized (OVX) and 0.5 mg/kg E2-supplemented female rats for 7 days. E2 and metabolites were analyzed by gas chromatography-electron capture detection and testosterone and metabolites were analyzed by high-pressure liquid chromatography. In OVX and E2-supplemented females, 50 mg/kg amitraz caused an 85% decrease of serum E2 concentration and a marked increase of 2-OH-E2 concentration. Amitraz at 25 and 50 mg/kg produced 9.0-fold or greater increases of serum testosterone and 2β-OH-testosterone levels in males. Amitraz at 25 mg/kg resulted in no or minimal increases of liver microsomal formation of E2 or testosterone metabolites. Amitraz at 50 mg/kg produced 1.4- to 3.6-fold increases of 2-OH-E2; estrone; 2β-, 6β-, and 16α-OH-testosterone; and androstenedione formation in males and intact females. Amitraz at 50 mg/kg preferentially increased intact female 16β-OH-testosterone production by 8.6-fold. In OVX females, E2 supplement alone or cotreatment with E2 and 50 mg/kg amitraz produced 1.3- to several-fold increases of 2- and 4-OH-E2 formation and 2β- and 16α-OH-testosterone production. The cotreatment increased 6β- and 16β-OH-testosterone formation by 1.8- and 1.6-fold, respectively. The present findings show that amitraz induces hepatic E2 and testosterone metabolism in male and female rats, decreases serum E2 concentration in OVX and E2-supplemented females, but increases serum testosterone in males.     

Gender differences in response to chronic treatment with 17β-oestradiol and 17β-aminoestrogen pentolame on hemostasis in rats

Objectives:

This work evaluated chronic treatment with 17β-oestradiol (E₂) and 17β-aminoestrogen pentolame (AEP) on prothrombin time (PT), activated partial thromboplastin time (aPTT), thrombin time (TT), and fibrinogen concentration (FIB). Male (M) and ovariectomized (Ovx) Wistar rats were used to explore gender differences in the pharmacological response.

Materials and Methods:

Rats (n = 12-18) were treated every third day during three months with E₂ (1, 10, 100 μg/kg), AEP (1, 10, 100, 500 μg/kg) or vehicle (propylenglycol 1 ml/ kg). PT, aPTT, TT, and FIB were measured using standardized techniques.

Results:

Chronic treatment with E₂ in male rats increased PT (4-7%; P < 0.05), decreased aPTT (9%; 100 μg/kg; P < 0.05) and decreased TT (5% at 100 μg/Kg; P < 0.05). Chronic treatment with E₂ in ovariectomized female rats decreased PT (3-4%; P < 0.05), did not induce significant changes on aPTT and decreased TT in a dose dependent manner (12-27%; P < 0.05). Chronic treatment with AEP in male rats did not alter PT, increased aPTT in a dose dependent manner (5-16%; P < 0.05), and decreased TT (5%; 500 μg/Kg; P < 0.05) while in female ovariectomized rats it decreased PT (5-9%; P < 0.05), increased aPTT (8-13%; P < 0.05) and decreased TT (6-13%; P < 0.05). E₂ and AEP decreased FIB in M and Ovx animals. Decreases in FIB by E₂ were more pronounced in male (15-18% P < 0.05) than in ovariectomized rats (10-14% P < 0.05). E₂ showed more potency than AEP, lowering FIB at 1 and 10 μg/kg doses. Both estrogens decreased FIB in ovariectomized animals (E₂, 10-14%, P < 0.05; AEP, 9% P < 0.05) and were reverted by increasing dosage.

Conclusions:

Gender influenced response to chronic treatment with E₂ and AEP on hemostatic parameters. PT and aPTT were the most affected parameters, demonstrating non-equivalence in the pharmacological response of M and Ovx rats.KEY WORDS: 17β-aminoestrogens, gender, hemostasis, oestradiol, rat     

Plasma concentration and vascular effect of β-endorphin in spontaneously hypertensive and Wistar Kyoto rats

Summary In order to find out whether -endorphin (-E) is involved in the development of hypertension, we performed two series of experiments. Firstly, spontaneously hypertensive rats (SHR) and their normotensive Wistar Kyoto controls (WKY) were submitted to ether stress. Plasma concentrations of -endorphin-like immunoreactivity (-EI), adrenocorticotropin (ACTH) and -melanotropin (-MSH) were measured by radioimmunoassay. The basal concentration of -EI was similar in WKY and SHR, whereas WKY had higher levels of ACTH and lower levels of -MSH than SHR. In both strains acute stress enhanced the plasma concentration of -EI to the same extent and with a similar time-course. The increase of plasma -El coincided with a rise in ACTH but not -MSH. Gel chromatography of -EI revealed that plasma extracts contain similar amounts of -lipotropin- (-LPH) and -E-sized immunoreactive components, and that acute stress elevated both forms of -El. Secondly, isolated tail arteries of SHR and WKY were perfused and field stimulated with two pulses at 1 Hz. -E depressed stimulation-evoked vasconstriction with the same potency in both strains. Thus, basal and stress-induced levels of -EI did not differ in SHR and WKY. Moreover, in the tail artery of both strains the sensitivity of presynaptic opioid receptors towards -E was almost identical. If the -E sensitivity of these receptors in other arteries of WKY and SHR is also similar, a major role of the circulating peptide in the development of hypertension is rather unlikely.This work was partly supported by the Deutsche Forschungsgemeinschaft (SFB 325) Send offprint requests to B. Bucher at the above address     

Sex differences in the neurochemical and functional effects of MDMA in Sprague–Dawley rats

Rationale 3,4-Methylenedioxymethamphetamine (MDMA; “Ecstasy”) use has been associated with acute toxicities and persistent depletion of the neurotransmitter serotonin (5-HT).Objectives This study investigates whether sex differences in the acute and long-term effects of MDMA exist.Methods Male and female rats received saline or 15 mg/kg MDMA, ip, bid for 4 days. Temperature was monitored on days 1 and 4. Locomotor activity was measured in a second cohort of animals on days 1 and 4 and after recovery on day 14. The effects of MDMA on performance in a plus maze task and brain levels of serotonin (5-HT) and the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) were determined in a third cohort of animals 2 weeks after the last MDMA treatment.Results Locomotor activity and temperature increased after MDMA administration on day 1. The drug-induced increases in temperature but not locomotion attenuated with repeated MDMA administration. Male and female MDMA-treated rats spent less time in the open arms of the elevated plus maze and had less 5-HT and 5-HIAA in all brain regions 2 weeks after the end of treatment. Temperature effects of MDMA and persistent effects on plus maze and brain serotonin content were similar in males and females. In contrast, females exhibited markedly greater locomotor stimulation after acute MDMA and also showed sensitization to an acute challenge 2 weeks later.Conclusions MDMA elicits substantially greater locomotor activation in female rats than in males, but persistent effects on anxiety and serotonin content were similar in males and females. Funding: DA 09079. Christina N. Williams was supported by an RJR-Leon Golberg postdoctoral fellowship and ES07031.     

Metabolism and disposition of gemfibrozil in Wistar and multidrug resistance-associated protein 2-deficient TR− rats

1. The roles of multidrug resistance-associated protein (Mrp) 2 deficiency and Mrp3 up-regulation were evaluated on the metabolism and disposition of gemfibrozil.

2. Results from in vitro studies in microsomes showed that the hepatic intrinsic clearance (CL_int) for the oxidative metabolism of gemfibrozil was slightly higher (1.5-fold) in male TR^? rats, which are deficient in Mrp2, than in wild-type Wistar rats, whereas CL_int for glucuronidation was similar in both strains.

3. The biliary excretion of intravenously administered [¹⁴C]gemfibrozil was significantly impaired in TR^? rats compared with Wistar rats (22 versus 93% of the dose excreted as the acyl glucuronides over 72?h). Additionally, the extent of urinary excretion of radioactivity was much higher in TR^? than in Wistar rats (78 versus 2.6% of the dose).

4. There were complex time-dependent changes in the total radioactivity levels and metabolite profiles in plasma, liver and kidney, some of which appeared to be related to the up-regulation of Mrp3.

5. Overall, it was demonstrated that alterations in the expression of the transporters Mrp2 and Mrp3 significantly affected the excretion as well as the secondary metabolism and distribution of [¹⁴C]gemfibrozil.     

Comparison of the Pharmacokinetics of Oxycodone and Noroxycodone in Male Dark Agouti and Sprague–Dawley Rats: Influence of Streptozotocin-Induced Diabetes

Purpose The aims of this study are to evaluate whether cytochrome P450 (CYP)2D1/2D2-deficient dark agouti (DA) rats and/or CYP2D1/2D2-replete Sprague–Dawley (SD) rats are suitable preclinical models of the human, with respect to mirroring the very low plasma concentrations of metabolically derived oxymorphone seen in humans following oxycodone administration, and to examine the effects of streptozotocin-induced diabetes on the pharmacokinetics of oxycodone and its metabolites, noroxycodone and oxymorphone, in both rodent strains.Methods High-performance liquid chromatography–electrospray ionization–tandem mass spectrometry was used to quantify the serum concentrations of oxycodone, noroxycodone, and oxymorphone following subcutaneous administration of bolus doses of oxycodone (2 mg/kg) to groups of nondiabetic and diabetic rats.Results The mean (±SEM) areas under the serum concentration vs. time curves for oxycodone and noroxycodone were significantly higher in DA relative to SD rats (diabetic, p < 0.05; nondiabetic, p < 0.005). Serum concentrations of oxymorphone were very low (<6.9 nM).Conclusions Both DA and SD rats are suitable rodent models to study oxycodone’s pharmacology, as their systemic exposure to metabolically derived oxymorphone (potent μ-opioid agonist) is very low, mirroring that seen in humans following oxycodone administration. Systemic exposure to oxycodone and noroxycodone was consistently higher for DA than for SD rats showing that strain differences predominated over diabetes status.     

Dietary calcium supplementation and dopamine-β-hydroxylase in spontaneously hypertensive rats

Spontaneously hypertensive 4-week-old male rats were fed, before and after the onset of hypertension, with either commercial chow (control) or commercial chow combined with different forms of milk proteins with or without calcium supplementation. After 40 weeks, rats were still hypertensive, and dopamine-β-hydroxylase enzyme activity measured simultaneously in serum and adrenal was found to be higher than in the controls. The enzyme activity in rats fed diets with milk proteins was increased significantly in both serum and adrenal compared with the control, and such enhancement was significantly higher than that observed in animals fed the commercial diet supplemented with calcium (1.2%), suggesting that dietary calcium intake associated with dietary protein of high digestibility, such as casein, potentiates the endogenous mechanisms regulating the homeostasis of calcium more than calcium supplementation itself. Moreover, the selective and additive effect of diets supplemented with milk proteins and calcium on adrenal enzyme activity clearly suggests a relationship between cardiovascular diseases involving the genesis of hypertension and stress mechanisms through the hypothalamo-pituitary adreno-sympathetic axis.     

Gender-related differences in pharmacokinetics of enantiomers of trans-tramadol and its active metabolite, trans-O-demethyltramadol, in rats

AIM: To compare the pharmacokinetics of the enantiomers of trans-tramadol (trans-T) and its active metabolite, trans-O-demethyltramadol (M1), in male and female rats. METHODS: Following a single oral dose of 10 mg/kg trans-T hydrochloride to rats, (+)-trans-T, (-)-trans-T, (+)-M1, and (-)-M1 in plasma were determined by a high performance capillary electrophoresis method. RESULTS: The females showed higher plasma concentrations of (+)-trans-T, (-)-trans-T, and (+)-M1 than the males. The enantiomers of trans-T were absorbed and eliminated more slowly in the females than in the males. (+)-M1 was eliminated more slowly in the females than in the males. All pharmacokinetic parameters but T_(max) of the two enantiomers of trans-T were significantly different in both sex rats. The (+)/(-)-enantiomeric ratios of the pharmacokinetic parameters for trans-T in the males were similar to those in the females. The values of C_(max), AUC_(0-∞) of the two enantiomers of M1 were significantly different in both sex rat     

Effect of age on the prejunctional α-adrenoceptor-mediated feedback in the heart of spontaneously hypertensive rats and normotensive Wistar Kyoto rats

Summary The prejunctional ₂-adrenoceptor-mediated feed-back in the heart of pithed young and adult spontaneously hypertensive rats (SHR) and corresponding normotensive Wistar Kyoto rats (WKY) was studied. After electrical stimulation of the sympathetic outflow from the spinal cord to the heart, B-HT 920 induced an inhibition of the cardiac response, which was significant at stimulation frequencies up to 1 Hz in young SHR and WKY and up to 2 Hz in the adult animals. Rauwolscine produced a potentiation of the cardiac response to electrical stimulation in SHR, which was significant from 0.2–10 Hz in young SHR and from 0.1–10 Hz in adult SHR. In young WKY, rauwolscine did not potentiate the increase in heart rate to sympathetic nerve stimulation, whereas in adult WKY ₂-adrenoceptor blockade by rauwolscine significantly potentiated the cardiac response to electrical stimulation at frequencies in the range of 0.2–10 Hz. In SHR the potentiation of the cardiac response to sympathetic nerve stimulation by rauwolscine was much stronger than in WKY.These results suggest that in adult animals the prejunctional ₂-adrenoceptor mediated feedback is more developed than in young rats. In contrast with young WKY, a significant endogenous feedback can be demonstrated in adult WKY. In SHR, however, the physiological role of prejunctional ₂-adrenoceptors is much more important.     

Effect of 17β-oestradiol and ginsenoside on osteoporosis in ovariectomised rats

To study the anti-osteoporosis effects and mechanism of action of oestradiol (E₂) and ginsenoside (tR), we measured the bone mineral densities (BMD) of lumbar vertebra and tibia and analysed the tibia histological morphological data, as well observed the activity and the number of osteoblasts and the activity of alkaline phosphatase (ALP) and the concentration of cAMP. Results showed that E₂ (400 μg kg^? 1 week^? 1) and tR (10, 20, 30 mg kg^? 1 day^? 1) were able to countervail the decreasing in BMDs of lumbar vertebra and tibia induced by OVX in rats (P < 0.05); E₂ (0.1 μmol l^? 1) and ginsenoside Rg₁ (1 μmol l^? 1 and 10 μmol l^? 1) were able to increase the number of osteoblasts, the activity of ALP and the concentration of intercellular cAMP in cultured osteoblast cells. The present findings suggest that E₂ and tR have an anti-osteoporosis effect in ovariectomised rats.     

Individual differences in cocaine-induced locomotor activity in male Sprague–Dawley rats and their acquisition of and motivation to self-administer cocaine

Rationale  Factors that increase an individual’s susceptibility to cocaine dependence remain largely unknown. We have previously shown that adult outbred male Sprague–Dawley rats can be classified as either low or high cocaine responders (LCRs or HCRs, respectively) based on their locomotor activity following the administration of a single dose of cocaine (10 mg/kg, i.p.). Furthermore, LCR/HCR classification predicts dopamine transporter function/inhibition, cocaine-induced locomotor sensitization, and cocaine-conditioned place preference. Objectives  The present study assessed LCR/HCR classification and the development of locomotor sensitization on the latency to acquire cocaine self-administration and motivation to self-administer cocaine. Results  LCRs and HCRs did not differ in their latency to acquire low-dose cocaine self-administration (0.25 mg/kg/infusion over 12 s, fixed ratio 1 schedule of reinforcement). In a follow-up experiment, repeated experimenter-administered injections of cocaine (10 mg/kg, i.p.) resulted in locomotor sensitization for LCRs, but not HCRs; nonetheless, all rats exhibited decreased latency to acquire cocaine self-administration compared to the first experiment. Repeated cocaine preexposure and LCR/HCR classification predicted break point when rats responded for cocaine under a progressive ratio schedule of reinforcement (0.25, 0.5, and 1.0 mg/kg/infusion; multiple exposure>single exposure, LCR>HCR), but there was no interaction between these variables. Conclusions  Although LCR/HCR classification did not predict the rate of acquisition of cocaine self-administration under these conditions, LCR rats demonstrated greater responding for cocaine after acquisition (PR). Thus, these findings demonstrate the relevance of using the LCR/HCR model when studying susceptibility to cocaine dependence.     

Orthostatic hypotensive effect of antipsychotic drugs in Wistar rats by in vivo and in vitro studies of α1-adrenoceptor function

Rationale It has been suggested that the increase in serotonin transmission induced by indirect agonists such as fenfluramine and fluoxetine attenuates cue-elicited reinstatement of cocaine-seeking in rats through a 5-HT_2C receptor-dependent mechanism. Objective We investigated whether Ro 60-0175, a nonselective 5-HT_2B–2C agonist, influences cue-elicited reinstatement of cocaine-seeking behavior. We evaluated the 5-HT_2C receptor’s role in Ro 60-0175 by studying its interaction with SB-242,084, a selective 5-HT_2C antagonist. The study also explored whether Ro 60-0175 influences cue-elicited seeking behavior associated with sucrose, a highly palatable nutritive reinforcer. Materials and methods Different groups of free-feeding rats were trained to associate discriminative stimuli (S^Ds) with the availability of cocaine or a sucrose pellet or no-reward in two-lever operant cages. Cocaine and sucrose pellets were available under an FR1 schedule of reinforcement, and each reinforcer was followed by a 20-s timeout signaled by a cue light coming above the active lever. After extinction of reinforced responding in the absence of cue, the reinforcer-associated stimuli were reintroduced in reinstatement sessions in which reinforcers were withheld. Results Ro 60-0175, at IP doses from 0.1 to 1 mg/kg, dose-dependently reduced cocaine-seeking behavior, while 1 mg/kg had no such effect for the sucrose pellet. Pretreatment with 1 mg/kg SC SB-242,084 completely prevented the effect on cocaine-seeking behavior. Conclusions These findings, provided they can be extrapolated to abstinent human addicts, suggest therapeutic potential for the selective 5-HT_2C agonist in preventing cue-controlled cocaine-seeking and relapse. An erratum to this article can be found at     

Alcohol and “bursts” of aggressive behavior: ethological analysis of individual differences in rats

A quantitative ethological analysis of rodent aggression was performed in order to characterize the aggression-heightening effects of alcohol in certain individuals. In dyadic confrontations, a resident rat pursues, threatens and attacks an intruder, who reacts with defensive, flight and submissive behaviors. The behavioral data from five series of experiments conducted from 1984 through 1989 were subjected to a lag sequential analysis that identified highly predictable sequences of aggressive behavior, and to interval analysis that delineated a burst pattern of aggressive behavior. These analyses revealed a distinct behavioral sequence of pursuit sideways threat attack bite aggressive posture that occurs in bursts with an inter-event interval of less than 6.6 s. In the total population, alcohol heightened attack behavior at low acute doses (0.1, 0.3, 1.0 g/kg) in 47% of the animals (n=44), suppressed reliably attack behavior in another 25% (0.1–3.0 g/kg;n=23) and had unreliable effects in the remaining 28% (n=24). The peak enhancement of aggressive behavior was seen over more than a log cycle of alcohol doses (0.1, 0.3 or 1.0 g/kg) in different individuals. In an additional group of rats (n=20), individuals were identified according to whether or not acute low alcohol doses enhanced or suppressed the frequency of attack bites. In the subgroup of five rats who doubled their attack frequency upon acute alcohol challenge, this aggression-heightening effect was confirmed on repeated occasions. The aggression-heightening effects of alcohol were seen during the high-rate interactions in the initial phase of the confrontation and particularly during the lower level of fighting later on. Regardless of alcohol dose and subgroup, the highly predictable sequence of pursuit sideways threat attack bite aggressive posture remained intact as long as the individual was able to fight. The present analysis identifies those individuals in whom low alcohol doses increase the frequency of attack behavior, the number of aggressive elements in bursts and particularly the time in burst. Alcohol produces these changes without altering the latency to initiate aggressive behavior, the rate of aggressive behavior within a burst or the number of bursts in an encounter. Alcohol may lengthen aggressive bursts by preventing termination of longer aggressive sequences rather than by altering the initiation of this behavior.We dedicate this paper to our friend Dr. Milos Krsiak, Professor of Pharmacology, Charles University, Prague, Czechoslovakia     

What are the differences in decisional balance and self-efficacy between Turkish smokers in different stages of change?

This paper reports the results of an examination of decisional balance (pros and cons of smoking), and self-efficacy constructs, sociodemographic and smoking-related variables among smokers from different stages of change as proposed by the transtheoretical model. A convenience sample of 398 smokers completed the research instrument. Almost 60% of the sample were in the precontemplation stage. The results indicated that pros of smoking dropped significantly from precontemplation to contemplation and preparation but then increased again for the action stage smokers. Cons of smoking increased almost linearly from precontemplation to preparation stages and they were the highest for the action stage. Self-efficacy also increased in a linear fashion and preparation and action stages were significantly higher than the precontemplation and contemplation stages. There were also significant differences among stages of change of groups on age, years of education, and smoking duration and number of quit attempts. Results underlined the importance of finding alternatives that may substitute for the pros of smoking and interventions for changing the cognitive evaluations related to cons of smoking. Additionally, smokers may gain from approaches that focus on encouraging and reinforcing self-efficacy during the action and maintenance stages to ensure a long-term positive outcome.     

Buccal absorption of propofol when dosed in 1-perfluorobutylpentane to anaesthetised and conscious Wistar rats and Göttingen mini-pigs

The purpose of this study was to evaluate whether propofol could be absorbed buccally when administered in semifluorinated alkanes (SFAs), here specifically perfluorobutylpentane (F4H5). This was evaluated in anesthetised and conscious rats and mini-pigs, to measure the relative bioavailability of propofol following buccal administration, but also partly to evaluate the animal models used for this investigation. The absolute bioavailability in the conscious animals was approximately 10% for both species and approximately 50% and 30% in the anesthetised rats and mini-pigs, respectively. This clearly demonstrates that propofol can be absorbed buccally, and F4H5 appears to be a relevant excipient for buccal administration of lipophilic drugs like propofol. The lower absorption in the conscious animals clearly indicates the need for an optimisation of the formulation.     

Dissociation between sex differences in the immunological, behavioral, and physiological effects of κ- and δ-opioids in Fischer rats

Rationale The sex of the individual can have a profound effect on sensitivity to the effects of opioids. Recently, our laboratory provided the first evidence that females may be more sensitive to the immune-altering effects of μ-opioids than males. However, it remains unknown whether κ- and δ-opioids produce sexually dimorphic effects on immune responses. Objective The present study sought to determine whether κ- and δ-opioids produce differential immunological effects in males and females using the memory-T-cell-dependent in vivo inflammatory response contact hypersensitivity (CHS). As sex differences in the magnitude of opioid effects can be outcome-specific, additional experiments were conducted to compare the immunological effects of κ- and δ-opioids with other behavioral and physiological effects. Materials and methods Contact hypersensitivity was induced in male and female Fischer rats. Prior to elicitation of CHS, animals were administered selected doses of the κ-opioid spiradoline (0.2–20 mg/kg), δ-opioid SNC80 (1–10 mg/kg), or vehicle. The antinociceptive and diuretic effects of spiradoline were also assessed in males and females, as were the locomotor effects of SNC80. Results Spiradoline produced significantly greater enhancement of CHS in females than males, but produced comparable antinociceptive and diuretic effects in both sexes. By contrast, SNC80 did not significantly affect the course of CHS in either sex, but females were significantly more sensitive to its locomotor stimulatory effects. Conclusions These results demonstrate that females are more sensitive than males to the CHS-altering effects of spiradoline and that sex differences in the magnitude and direction of opioid-induced sex differences are outcome dependent.