Anticonvulsant effects of magnesium sulfate in hippocampal-kindled rats

The objective of the present study was to determine whether magnesium sulfate has anticonvulsant actions in the hippocampal-kindled rat model of epilepsy. Fully kindled rats received acute intraperitoneal injections of magnesium sulfate (270 mg/kg), phenytoin (20 mg/kg) or saline in random order. Electrical seizure duration, behavioral seizure stage and duration of postictal EEG depression were examined 15, 30 and 60 min after injection. In an additional group of rats, kindled seizures were measured before and after chronic (2 h) intraperitoneal injections of magnesium sulfate versus saline. There was a significant decrease in electrical seizure duration (p<0.01) and behavioral seizure stage (p<0.01) with acute magnesium sulfate injections compared to saline injections. Phenytoin had no statistically significant effects on hippocampal-kindled seizures. Chronic magnesium sulfate treatment significantly reduced behavioral seizure stage at 2, 24, and 48 h postinjection (p<0.05), but did not affect seizure duration. There was a significant time by treatment effect for magnesium sulfate on postictal EEG depression (p<0.01). We conclude that in this model of hippocampal epilepsy-induced (kindled) rats, magnesium sulfate has significant anticonvulsant effects.     

Impaired oxidation of debrisoquine in patients with perhexiline neuropathy.

The use of perhexiline maleate as an antianginal agent is occasionally associated with side effects, particularly neuropathy and liver damage. The reason why some individuals develop these toxic reactions is not clear, though some evidence suggests that they may result from impaired oxidative metabolism, due to genetic or hepatic factors, and consequential accumulation of the drug in toxic concentrations. Drug oxidation was measured with an oxidation phenotyping procedure in 34 patients treated with perhexiline, 20 of whom had developed neuropathy and 14 of whom had not. Most of the 20 patients with neuropathy, but not the unaffected patients, showed an impaired ability to effect metabolic drug oxidation. This impairment was independent of hepatic function, concurrent drug therapy, or tobacco or alcohol consumption. The fact that the ability to oxidise several drugs is genetically controlled points to a genetic susceptibility to developing neuropathy in response to perhexiline. Routine determination of the drug oxidation phenotype might lead to safer use of perhexiline by predicting patients who may be more at risk of developing a neuropathic reaction associated with its long-term use.     

Clinical Evaluation of Perhexiline Maleate in Patients with Angina Pectoris

This paper reports a double-blind trial of a new antianginal drug, perhexiline. Fifty-five patients suffering from angina pectoris were studied for periods of 12 or 24 weeks in a cross-over comparison against a placebo in four centres in the United Kingdom and Ireland. Perhexiline was effective in most patients as judged by reducing the number of anginal attacks in 84% and the consumption of glyceryl trinitrate tablets in 64%. The major side effect, dizziness, noted in one-third of the patients, may be dose/body-weight related. Perhexiline is a valuable new agent for the treatment of patients with angina, especially those who do not respond to other antianginal agents.     

Enantioselective assay for the determination of perhexiline enantiomers in human plasma by liquid chromatography

Effective use of the antianginal agent perhexiline is difficult because saturable metabolism by the polymorphic cytochrome P450 2D6 (CYP2D6) isoform produces elevated plasma perhexiline concentrations that have been associated with serious hepatic and neurological toxicity. Perhexiline is marketed for therapeutic use as a racemate and there is evidence for differences in the disposition of its enantiomers. The current study describes an enantioselective HPLC-fluorescent method utilising pre-column derivatization with (R)-(-)-1-(1-napthyl)ethyl isocyanate. Following derivatization, the enantiomers are resolved on a C18 column with gradient elution using a mobile phase composed of methanol and water. The method described is suitable for the quantification of (+)- and (-)-perhexiline in human plasma following clinical doses and demonstrates sufficient sensitivity, accuracy and precision between 0.01 and 2.00 mg/l for each enantiomer, with intra-assay coefficients of variation and bias <20% at 0.01 mg/l and <10% at 2.00 mg/l, and inter-assay coefficients of variation and biases <15% at 0.03 mg/l and <10% at 0.40 and 0.75 mg/l. The application of this method to plasma samples collected from a patient treated with perhexiline revealed that (+)-perhexiline concentrations were higher than (-)-perhexiline concentrations, confirming the stereoselective disposition of perhexiline. The current study describes an enantioselective method that utilises pre-column formation of fluorescent diastereomers that are resolved on a C18 HPLC column using a gradient of methanol and water.     

The effects of injections of D,L-5-hydroxytryptophan on the efflux of endogenous serotonin and 5-hydroxyindoleacetic acid from a synaptosomal fraction.

Abstract— The effects of i.p. injections of SO mg/kg d,l-5-hydroxytryptophan (5-HTP) and saline alone on the in uitro release of endogenous serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) were studied using preparations of axon terminals (P₂ isolated from the telencephalon of rats. The level of 5-HT was 2-fold greater and the level of 5-HIAA was 5-fold greater in the P₂ fraction isolated from rats given the d,l-5-HTP injection than from rats given saline injections. At 37°C the in vitro efflux of 5-HT and 5-HIAA from the P₂ fractions of animals injected with 5-HTP 30min before killing was approx 3 times higher than the saline control group. The amount of 5-HT and 5-HIAA released at 37°C was 3–5 times higher than the amount released at 0°C for both the 5-HTP and saline injected rats. Increasing the concentration of potassium ions in the media to 55 mm significantly increased the release of 5-HT but not 5-HIAA in both groups of animals. The amount of 5-HT released by 55mm-K⁺ was about 2-fold higher from the P₂ fraction isolated from rats given 5-HTP injections with respect to those given saline injections. The potassium stimulated release of 5-HT was calcium dependent. The data thus indicate that injection of 50 mg/kg d,l-5-HTP in rats can cause an increase in the level of 5-HT and 5-HIAA in a crude synaptosomal fraction and that as a result of this increase, there is a temperature dependent increased release of 5-HT and 5-HIAA under normal resting membrane conditions. There is also an increased release of 5-HT as a result of membrane depolarizing conditions induced by elevated potassium levels which is calcium dependent.     

A general inhibition kinetics model for ethanol production using a novel carbon source: sodium gluconate

In this study, sodium gluconate was applied as a novel carbon source for the fuel ethanol production using an engineered Escherichia coli strain KO11 in batch fermentations. Ethanol and acetic acid were produced as two major products as well as small amount of lactic acid during the fermentation. Compared to the conventional carbon source glucose, the bioconversion of sodium gluconate possessed two distinct advantages: faster utilization rate of sodium gluconate (1.66 g/L per h) compared to glucose (0.996 g/L per h) and no requirement for pH control during fermentation. A general inhibition model including both substrate and products inhibitory effects was proposed, which adequately simulated batch fermentation kinetics at various concentrations of sodium gluconate. All of the products showed inhibitory effects on cell growth. The order of the inhibitory strength of all products and substrate was for the first time clarified in this study. Acetic acid was the most inhibitory product mitigating the cell growth, followed by ethanol and lactic acid. Sodium gluconate stimulated cell growth when its concentration was below 16 g/L, while it inhibited the cell growth when the concentration was above this concentration. It completely inhibited the cell growth when the concentration was 325 g/L. The high value of both the coefficient of determination (R ²) and the adjusted R ² verified the good fit of the model. This paper provides key insights into further engineering these strains to improve ethanol production.     

POST-MITOTIC AGE OF MONONUCLEAR CELLS MIGRATING INTO TA-3(St) SOLID TUMORS

Subcutaneous transplantation of 5 × 10⁶ TA-3(St) mammary carcinoma cells into A/J mice produced rapidly growing tumors that showed a substantial accumulation of lymphocytes, monocytes and macrophages. This must have resulted primarily from an influx of circulating cells, since none of the cell types exhibited any significant local proliferation as indicated by 1 hr ³H-TdR uptake. The post mitotic age of the various leukocyte types in circulation of normal and tumor bearing animals, and those appearing within the tumors, was evaluated by a repeated ³H-TdR labeling protocol designed to label newly formed leukocytes. Tumor transplantation (or injection of an equivalent volume of saline in control animals) was preceded by thirteen ³H-TdR injections (12.5 μCi every 8 hr) and followed by eight more injections at equivalent intervals. Animals were serially sacrificed at 5-14 days after tumor transplantation or saline injection. Total lymphocyte labeling in the blood during these intervals was higher in tumor bearing mice (approximately 25% between 5 and 12 days) than in the saline injected controls (approximately 20%), indicating that tumor transplantation resulted in an increase in the proportion of young lymphocytes in circulation. More significantly, a much higher labeling (57-60% at 5-12 days) was exhibited by lymphocytes isolated from the tumors, indicating selective migration (and/or retention) of newly formed lymphocytes within the tumor. This finding applied to lymphocytes in all size categories. Although blood monocyte labeling in the control and experimental animals was similar (e.g. 83% at day 5 and 52% at day 14), significantly higher labeling (e.g. 93% and 70% at the respective intervals) was exhibited by monocytes isolated from tumors. This suggested a preferential accumulation of young monocytes at the tumor site. An identical macrophage labeling pattern compared to that shown by monocytes within the tumor indicated a rapid monocyte-macrophage transition. Since these findings in the present strain-specific solid tumor are similar to those previously obtained in this laboratory in the strain-nonspecific Ehrlich ascites tumor, the phenomenon of selective localization of newly formed mono-nuclear leukocytes appears to be a general occurrence in transplanted murine tumors.     

Effects of intense exercise training on plasma catecholamines in coronary patients

This paper reports the effect of 12 mo of intense endurance exercise training on the plasma catecholamine response to exercise in 11 male patients [aged 50 +/- 8 yr (mean +/- SD)] with coronary artery disease. A substantial adaptation to training was attained as evidenced by a 42% increase in maximum O2 uptake capacity. At rest, heart rate was lower after training, but resting blood pressure and plasma catecholamines were unchanged. At the same absolute work rate, plasma norepinephrine and epinephrine levels, rate pressure product, and ischemic S-T segment depression were all significantly lower after training. A higher plasma norepinephrine level was attained at maximal exercise after training (2,049 +/- 654 before vs. 3,408 +/- 1,454 pg/ml after, P less than 0.025); this was associated with a higher systolic blood pressure (175 +/- 25 before vs. 188 +/- 22 mmHg after, P less than 0.025) and a higher rate-pressure product (25.3 X 10(3) +/- 4.5 X 10(3) before vs. 27.6 X 10(3) +/- 5.2 X 10(3) after, P less than 0.025). Despite the higher plasma norepinephrine level and rate pressure product, S-T segment depression at maximal exercise was unchanged. These findings suggest that some patients with coronary arterial disease can attain a higher myocardial O2 requirement, without electrocardiographic evidence of increased ischemia, after prolonged strenuous exercise training.     

Ion transport in liver mitochondria from normal and thyroxine-treated rats

Liver mitochondria isolated from rats 24 h after a single subcutaneous injection of 8 mg thyroxine per kilogram body weight were compared with those isolated from control rats that received injections of isotonic saline at the same time. The mitochondria isolated from the thyroxine-treated rats show higher rates of energy-dependent K⁺ and phosphate accumulation than those from control animals. It was also found that mitochondria from the hormone-treated animals required a larger addition of Ca²⁺/mg mitochondrial protein in order to uncouple oxidative phosphorylation, and showed smaller tendency to swellin vitro under energizing conditions. The data obtained on ion movements support previous observations that the stimulation of the basal rate of mitochondrial respiration by thyroxine is associated with an increase in the transmembrane protonic electrochemical potential difference, and indicate thatin vivo the hormone raises the intramitochondrial concentration of K⁺ and phosphate.     

Drug-environment interaction: Context dependency of cocaine-induced behavioral sensitization

The effect of the environmental context in which rats received cocaine upon subsequent cocaine-induced hyperactivity and stereotypy was explored. “Cocaine test cage” animals were injected with cocaine in the test cage and then received saline upon leaving it 40 minutes later, while in the “saline test cage” group the injections, were in the reverse order. Thus, all animals had identical injections, handling, and environmental exposure, differing only in whether they received cocaine during or after their test cage experience. The cocaine test cage animals displayed increasing response (p < .001) to the 10 daily cocaine injections, i.e., behavioral sensitization. However, in contrast, the “saline-test cage” animals had significantly less cocaine-induced activation upon 2 of 3 challenges with cocaine and showed no significant evidence of behavioral sensitization even though they had received the same dose and number of previous cocaine injections in a different environment. Thus, this study reveals environment- specific drug effects and suggests that environmental context plays a role in the development and manifestation of behavioral sensitization to cocaine.     

Effects of a long-acting LHRH agonist preparation on plasma gonadotropin and prolactin levels in castrated male rats and on the release of prolactin from ectopic pituitaries

We have examined the effects of a single subcutaneous injection of an LHRH agonist, D-Trp-6-LHRH, in biodegradable microcapsules of poly(DL-lactide-co-glycolide) on plasma gonadotropin and prolactin (PRL) levels in castrated and in castrated-hypophysectomized-pituitary grafted (CAST-APX-GRAFT) male rats. The results were compared to the effects of daily injections of the same LHRH agonist dissolved in saline. In castrated rats, there were no significant alterations in plasma LH or PRL levels during the 10 days following the injection of LHRH agonist microcapsules, while FSH levels were generally reduced. In castrated males given daily injections of 6 micrograms of LHRH agonist in saline, plasma LH levels were significantly reduced while plasma PRL levels were not changed. In CAST-APX-GRAFT rats, both D-Trp-6-LHRH microcapsules and daily LHRH agonist injections appeared to increase plasma PRL levels. The pattern of changes in PRL release in both groups was similar, with levels on day 6 being significantly higher than those measured on days 1, 3 and 10 after onset of treatment. As expected, LH and FSH levels in these animals were extremely low. Immunoreactive D-Trp-6-LHRH was consistently detectable in the plasma of CAST-APX-GRAFT animals after microcapsule administration, whereas in animals given daily injections of this agonist in saline, its plasma concentrations were often below the detectability limit of the employed assay. These findings suggest that the LHRH agonist, D-Trp-6-LHRH, is capable of causing a short term stimulation of PRL release from ectopic pituitaries. Elevation of plasma LH levels is apparently not required for this effect.     

Abatement of bleomycin-induced pulmonary injury by cell-impermeable inhibitor of phospholipase A2

The mechanism of bleomycin (Bleo)-induced pulmonary injury is not fully understood. Elevated levels of lung phospholipase A₂ (PLA₂) have been previously reported following intratracheal (IT) instillation of Bleo, but the role of this enzyme in the pathogenesis of lung injury is not clear.In this pilot study, we have evaluated the effect of a cell impermeable inhibitor of PLA₂ (CME) on Bleo-induced pulmonary inflammation in hamsters. Pulmonary injury was induced by a single IT instillation of Bleo (1 unit/0.5 ml saline). Three groups of male Syrian hamsters were evaluated: 1) BLEO-CME animals received IT Bleo and daily intraperitoneal (IP) injections of CME (1 μmole/kg), starting 1 day before IT instillation; 2) BLEO-SAL animals-received IT Bleo and IP injections of saline and 3) SAL-SAL animals — treated with IT and IP administrations of saline. Animals were sacrificed 14 days after IT treatment and lung injury was evaluated histologically by a semiquantitative morphologic index and by a differential cell count of bronchoalveolar lavage fluid. CME treatment significantly ameliorated Bleo-induced lung injury compared to BLEO-SAL animals (P < 0.05). The percentage of neutrophiles in bronchoalveolar lavage fluid was reduced from 17.7 ± 3.2% (mean ± S.E.) in BLEO-SAL group to 7.3 ± 1.7% in BLEO-CME group (P < 0.05), achieving levels comparable to SAL-SAL control animals. These results suggest that treatment with an extracellular PLA₂ inhibitor-CME abates Bleo-induced pulmonary injury. This may indicate an active role of PLA₂ in the pathogenesis of interstitial pulmonary fibrosis.     

Multi-Ion Mechanism for Ion Permeation and Block in the Cystic Fibrosis Transmembrane Conductance Regulator Chloride Channel

The mechanism of Cl⁻ ion permeation through single cystic fibrosis transmembrane conductance regulator (CFTR) channels was studied using the channel-blocking ion gluconate. High concentrations of intracellular gluconate ions cause a rapid, voltage-dependent block of CFTR Cl⁻ channels by binding to a site ∼40% of the way through the transmembrane electric field. The affinity of gluconate block was influenced by both intracellular and extracellular Cl⁻ concentration. Increasing extracellular Cl⁻ concentration reduced intracellular gluconate affinity, suggesting that a repulsive interaction occurs between Cl⁻ and gluconate ions within the channel pore, an effect that would require the pore to be capable of holding more than one ion simultaneously. This effect of extracellular Cl⁻ is not shared by extracellular gluconate ions, suggesting that gluconate is unable to enter the pore from the outside. Increasing the intracellular Cl⁻ concentration also reduced the affinity of intracellular gluconate block, consistent with competition between intracellular Cl⁻ and gluconate ions for a common binding site in the pore. Based on this evidence that CFTR is a multi-ion pore, we have analyzed Cl⁻ permeation and gluconate block using discrete-state models with multiple occupancy. Both two- and three-site models were able to reproduce all of the experimental data with similar accuracy, including the dependence of blocker affinity on external Cl⁻ (but not gluconate) ions and the dependence of channel conductance on Cl⁻ concentration. The three-site model was also able to predict block by internal and external thiocyanate (SCN⁻) ions and anomalous mole fraction behavior seen in Cl⁻/SCN⁻ mixtures.     

Bleomycin-induced lung injury is enhanced by interferon-α

We have evaluated the effect of intraperitoneal (IP) injection of human recombinant interferon-2α (IFN-α) on Bleomycin-induced pulmonary injury in hamsters. Pulmonary injury was induced by a single intratracheal (IT) instillation of Bleomycin (Bleo). Six groups of male Syrian hamsters were treated as follows: 1) IT Bleo and daily IP injections of low-dose interferon-α (2 × 10⁴ U), 2) IT Bleo and daily IP injections of high-dose interferon-α (10⁵ U), 3) IT Bleo and IP injections of saline, 4) IT saline and IP low-dose IFN-α, 5) IT saline and IP high-dose IFN-α, 6) IT saline and IP saline. Animals were sacrificed 28 days after IT treatment. Lung injury was evaluated histologically and biochemically. Treatment of hamsters with low-dose but not high-dose IFN-α significantly augmented the Bleo-induced lung injury, as determined by a semiquantitative morphological index. Lung hydroxyproline measurements were highest in Bleo-low-dose-IFN-α followed by Bleo-high-dose-IFN-α and Bleo-Sal as compared to Sal-Sal and Sal-IFN-α controls. These results suggest that IFN-α augments Bleo-induced lung injury but that this effect is complex and does not follow a simple-dose-response pattern.     

Stimulation of either cholecystokinin receptor subtype reduces while antagonists potentiate or sensitize a morphine-induced excitatory response.

Cholecystokinin peptides (CCK) have been shown to antagonize many opioid-mediated effects. The present study was undertaken to determine whether peripheral injections of cholecystokinin sulphated octapeptide (CCK8), cholecystokinin tetrapeptide (CCK4), the CCK(1) (lorglumide) and the CCK(2) (PD-135,158 and LY-225910) receptor antagonists can influence a classic morphine excitatory effect, i.e. the display of Straub tail reaction in mice (STR). A total of 570 female Balb/C mice were tested. Experiment 1 was undertaken to determine whether i.p. injections of CCK8 or CCK4 can influence STR. Each animal was treated with i.p. injections of saline or CCK8 (10 and 20 nmol/kg) or CCK4 (20 and 40 nmol/kg). After 30 min all animals received an i.p. injection of morphine hydrochloride (10.0 mg/kg). The highest doses of both CCK8 (35% STR) and CCK4 (40% STR) significantly reduced STR as compared to saline (85% STR) treated mice (Fisher test; P < 0.01). In experiment 2 each animal was treated with ip injections of saline or 1.0 mg/kg lorglumide or PD-135,158 fifteen minutes before an injection of morphine at doses ranging from 1.0 to 50.0 mg/kg. In experiment 3 animals were treated with injections of saline, 0.1 or 10.0 mg/kg lorglumide or LY-225910 before an injection of a fixed MC dose (2.0 mg/kg). Both lorglumide and PD-135,158 induced a significant shift to the left in the morphine dose-response curves as well as a significant decrease in ED50 of the STR. ED50 for lorglumide was significantly lower than ED50 for PD-135,158. Both doses of lorglumide and the highest dose of LY-225910 significantly increased the percent of animals displaying STR. Experiment 4 was undertaken to determine whether repeated peripheral injections of morphine or the morphine-potentiating agents CCK(1) (lorglumide) and the CCK(2) (LY-225910) receptor antagonists can induce morphine sensitization. Each animal was treated with 5 daily i.p. injections of saline (control group), 1.5 mg/Kg morphine hydrochloride (group morphine), and 1.0 mg/Kg lorglumide (group LOR) or LY-225910 (group LY). One, two, three and four weeks after the last treatment day, all animals were challenged with one i.p. injection of morphine (1.5 mg/Kg). The morphine, LOR groups and group LY showed a significant increase in percentage of animals displaying STR. These data demonstrate that the blockade of endogenous CCK actions leads to morphine sensitization probably through both CCK receptors. The present data are consistent with the antagonistic effects of CCK and opioids in the control of morphine-induced STR. In addition, these results suggest that both CCK receptors are involved in the modulatory effects of CCK on this morphine effect.     

Intake of individual macronutrients following IP injections of BBS and CCK in rats

The effects of injections of either bombesin (BBS) or cholecystokinin octapeptide (CCK-8) on patterns of food intake of macronutrients were examined in adult male rats, and compared to the effects following saline injections. The animals were food deprived for 18 hours and then offered one of three isocaloric dietary components (protein, carbohydrate or fat). During the first 30 minutes following injections of BBS, protein intake was decreased. Suppression of carbohydrate intake, significant between 30 and 60 minutes, was sustained up to two hours following injections. During the first 30 minutes following injections of CCK, animals reduced their intake of each macronutrient. Reductions in the consumption of fat and protein were sustained up to one and six hours, respectively. The availability of particular macronutrients is proposed as a possible factor accounting for differences among studies with respect to self-selection profiles and duration effects.     

Effects of nitric oxide synthesis inhibition with or without nitric oxide inhalation on responses to systemic cocaine administration in rats

The effects of N^ω-nitro-L-arginine methyl ester (L-NAME) i.v. and nitric oxide (NO) inhalation on integrated systemic responses to cocaine were studied in lightly anesthetized, paralyzed, and mechanically ventilated rats. Cocaine (4 mg/kg/min i.v.) produced seizures then isoelectric electrocephalographic (isoEEG) activity as well as an initial increase in systolic blood pressure and heart rate, then progressive cardiovascular system depression culminating in asystole. Pretreatment with L-NAME (2 mg/kg/min i.v.) for 30 min significantly reduced the incidence of seizure as compared to saline treated animals (saline 7/8; L-NAME 3/8). Doses of cocaine that produced arrhythmias, isoEEG and asystole were significantly lower in the L-NAME treated animals as compared to the saline group. L-NAME did not affect peak systolic blood pressure and heart rate responses to cocaine. NO inhalation (80 ppm) did not affect CNS and cardiovascular responses to cocaine in control animals but enhanced the effects of L-NAME on cocaine toxicity. The results show that pretreatment with L-NAME reduces the central nervous system stimulatory effect of cocaine (reduced seizure incidence) and enhances its depressant effect on both the central nervous system (lower does for isoEEG) and the cardiovascular system (lower dose for arrhythmias and asystole), but does not affect the cardiovascular stimulatory action of cocaine. NO inhalation does not protect against any of the systemic effects of cocaine in animals with normal or suppressed NO production.     

EFFECT OF A SPERMATOGONIAL CHALONE ON THE GROWING RAT TESTIS

Immature rats were used in an experiment to test the possible influence of a spermatogonial chalone on the expanding spermatogonial population in their developing testes. An extract from adult rat testes was injected intraperitoneally into 33-day-old rats and control animals were injected with an equal amount of saline. Two groups of normal adult rats similarly injected with the testicular extract and saline solutions served as additional controls. Following these injections, all animals were administered a dose of ³H-thymidine 10 hr before sacrifice. An analysis of the labeling indices of the various types of spermatogonia revealed that in young rats injected with testicular extract the percentage of labeled type A spermatogonia was significantly lower than in control animals. In contrast, the labeling indices of Intermediate and type B spermatogonia were similar in the two groups of young rats. In the two groups of adult animals, there was no difference in the labeling indices of type A or of other types of spermatogonia. These data indicated that the saline extract of adult testes contained a substance, a spermatogonial chalone, inhibiting specifically the proliferation of some type A spermatogonia. The results also support the concept that a spermatogonial chalone may intervene, through its action on the spermatogonial stem cell population, to arrest the growth of the seminiferous tubules as the animal reaches maturity.     

Serotonin and Dopamine Sensitization in the Nucleus Accumbens, Ventral Tegmental Area, and Dorsal Raphe Nucleus Following Repeated Cocaine Administration

Abstract— The present study was designed to examine the effects of chronic cocaine administration on the extracellular response of serotonin (5-HT) and dopamine (DA) to a peripheral cocaine injection using in vivo brain microdialysis in awake rats. Two different dual probe preparations were used: One group of animals had guide cannulae aimed at the ventral tegmental area (VTA) and nucleus accumbens (N ACC) and a second group of animals had guide cannulae aimed at the dorsal raphe nucleus (DRN) and N ACC. Rats from both groups were given daily injections of either cocaine (20 mg/kg i.p.) or saline (0.9%; 0.05 ml/kg i.p.) for 10 consecutive days. On day 11, baseline dialysate levels of DA, 5-HT, dihydroxyphenylacetic acid, and 5-hydroxyindoleacetic acid were obtained from either the N ACC and VTA or the N ACC and DRN, followed by a 10 mg/kg i.p. cocaine injection and an additional 150 min of dialysate sampling. The percent baseline increases of both 5-HT and DA were significantly higher in the N ACC, VTA, and DRN of animals that received daily injections of cocaine compared with saline controls ( p < 0.05, in each region). Maximum dialysate 5-HT concentrations after cocaine challenge were significantly higher in the N ACC and VTA ( p < 0.05) and DRN ( p < 0.01) of chronically treated animals compared with saline controls. Maximum dialysate DA concentrations were significantly higher in the N ACC and DRN ( p < 0.05) of chronically treated animals compared with saline controls. There was no significant difference between acute and chronic animals in the maximum dialysate DA concentration from the VTA after cocaine challenge. 5-HT was significantly more sensitized in the 5-HT cell body region (DRN) than the N ACC terminal field ( p < 0.05), whereas DA was significantly more sensitized in the N ACC terminal field than the DA cell bodies of the VTA ( p < 0.05).     

Intratumoral BCG and Corynebacterium parvum therapy of canine mammary tumours before radical mastectomy

Summary In two parallel studies, bitches with mammary tumour received single intralesional injections of BCG (1 mg: 10⁷ living bacteria) and Corybacterium parvum (10⁹ killed bacteria) (53 bitches) or C. parvum alone (129 bitches) at the same dosage. Control groups received injections, following the same protocol, of 1 ml BCG suspension medium diluted in saline in the first study (51 bitches) or no injections at all (120 bitches in the second study).A block dissection, including mammary tumours, adjacent mammary glands, and regional lymph nodes, was performed 2 weeks later in all animals. On the basis of histologically confirmed malignant tumours, 48 bitches (25 treated by immunotherapy and 23 controls) in the first study and 67 bitches (30 treated by immunotherapy and 37 controls) in the second study remained for postsurgical follow-up.The clinical tolerance of the treatment was generally good. No significant differences were found in cumulative survival rates between treated and control group in either studies.