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PubMed1982

Brain stimulation as the reinforcer in alcohol-saline discrimination.

Male Wistar rats were trained to discriminate intraperitoneal injections of 1 g/kg alcohol from saline injections. The reward that reinforced correct choices was an electrical brain stimulation which the animals self-administered according to a FR10 schedule of bar pressing; the stimulation was given in the postero-lateral hypothalamus. Quantitative generalization experiments revealed a mean ED 50 of 0.39 g/kg. The main advantages of this method using direct intracranial stimulation as the reward would seem to be: (1) quantitative and qualitative generalization experiments can be carried out in non-deprived rats having a normal body weight and (2) the possibility of estimating, in addition to the analysis of their discriminative properties, the effects of drugs on self-stimulation rate.

Animals↗
PubMed1985

Naloxone and fluid consumption in rats: dose-response relationships for 15 days.

Rats were given daily intraperitoneal injections of 10.0, 1.0, 0.1, 0.01, 0.001 or 0.0 mg/kg naloxone for 15 days. Each day after the injections, animals were allowed access to a 20% sucrose solution for two hours and to tap water for the subsequent 10 hours. Consumption of the sucrose solution by the group that received 1.0 mg/kg was reliably decreased on Day 1 and 2, reflecting the suppressive effect of naloxone at that dose. By Day 3 until the end of the experiment, however, the suppression was no longer significant, suggesting that tolerance had developed. A similar effect was seen with the group given the highest dose, 10.0 mg/kg; although drinking was significantly less than the control in each of the 15 sessions, this group showed a trend to increase intake over the days of the experiment, thus also indicating possible tolerance to the effect of naloxone. Drinking patterns of the other groups did not differ statistically from the control. Thus, the low doses had no ability to suppress consumption, and the lowest dose that did lower it soon lost that ability; the highest dose continued to suppress drinking throughout the study but with decreasing efficacy. High performance liquid chromatography (HPLC) demonstrated that the naloxone remained intact over the 15 days of the experiment, supporting the suggestion that tolerance to naloxone might have developed.

Animals↗
PubMed1986

Structure-activity relationships of phencyclidine derivatives in rat cerebellum.

The depressant effects of phencyclidine [1-(1-phenylcyclohexyl) piperidine, PCP] and three of its analogs (m-amino-PCP, m-nitro-PCP, and PCP-methyliodide) on the spontaneous action potential discharge of cerebellar Purkinje neurons in urethane-anesthetized rats were examined in this study. Both intraperitoneal injection and micro-pressure ejection were employed as routes of drug administration. The relative potency after parenteral administration corresponded closely with previous findings in behavioral test paradigms. PCP and m-amino-PCP were equipotent, m-nitro PCP was less potent than either PCP or m-amino-PCP, and PCP-methyliodide showed almost no activity. After local administration onto neurons, m-amino-PCP was significantly more potent than PCP, while PCP, m-nitro-PCP, and PCP-methyliodide were equipotent. Tritiated PCP, m-nitro PCP, and m-amino PCP have similar distribution and metabolism in cerebellum. PCP-methyliodide, a quaternary ion, does not cross the blood brain barrier. M-nitro PCP is appreciably less ionized at pH 7.4 than PCP or m-amino-PCP and, therefore, may be more easily sequestered into lipids. Differences between PCP and its analogs found in experiments which employ parenteral administration may reflect differences in drug distribution. These differences are minimized when these drugs are administered directly onto neurons via pressure microejection.

Action Potentials↗
PubMed1989

Opiate control of spontaneous locomotor activity in a urodele amphibian.

An intraperitoneal injection of the preferential opiate receptor agonist (+/-) bremazocine HCl given to male rough-skinned newts acutely and dose-dependently reduced their spontaneous locomotor activity. Inversely, and contrary to the situation generally observed in other vertebrates, administration of the opiate receptor antagonist naloxone HCl dose-dependently and acutely stimulated locomotion. Given at a behaviorally active dosage, naloxone counteracted the inhibitory effect of bremazocine on locomotion. The behavioral influence of the two substances was observed using two different sampling techniques (continuous recording for 3 minutes: repeated instantaneous sampling for 60 minutes). These data are discussed in view of our current knowledge on the opiate regulation of locomotor activity in vertebrates.

Animals↗
PubMed1991

Effects of systemic and intra-amygdaloid diazepam on long-term habituation of acoustic startle in rats.

Two experiments were conducted to examine the effects of the anxiolytic drug, diazepam, on long-term habituation of the acoustic startle response. The experiments were based upon the hypothesis that manipulations that reduce fear should enhance long-term response decrements by reducing a fear-like sensitization process. In Experiment 1 rats given intraperitoneal injections of 0.5, 1.2, or 2.5 mg/kg showed larger decrements of startle amplitude than vehicle-injected controls both over trials within sessions and over days. In Experiment 2 rats injected with 35 micrograms of diazepam bilaterally into the amygdala showed larger decrements of startle amplitudes over days than vehicle-injected controls. No within-session startle effects were detected in Experiment 2. Freezing behavior was measured in Experiment 2 as an index of fear, and the amygdala injections of diazepam retarded the development of fear in the startle chamber. This index of fear was not possible in Experiment 1 because of the sedating effects of systemic diazepam. We conclude that diazepam, acting at least in part through the amygdala, attenuates the fear-like sensitization process associated with the acoustic startle stimulus. By attenuating sensitization diazepam produces larger than normal reductions in startle amplitudes over trials and days without significantly affecting initial responsiveness.

Acoustic Stimulation↗
PubMed1992

Parenteral domoic acid impairs spatial learning in mice.

The present study is the first to examine the effect of a single intraperitoneal injection of the neuroexcitotoxin domoic acid on learning in mice. Compared to saline controls, animals exposed to domoic acid (2.0 mg/kg) showed significant impairment on the acquisition of the place task in the Morris water maze. Observation of swim paths taken by mice searching for the underwater platform revealed a failure on the part of the domoic acid-exposed mice to select the appropriate problem solving strategies. The results, along with neuroanatomic work done here and elsewhere, suggest that impairment of acquisition and retention of this spatial navigation task by domoic acid, involves a neuropathology that includes not only the hippocampus, but other limbic, and possibly extralimbic brain regions.

Animals↗
PubMed1992

Behavioral effects of dilazep on cholinergic, dopaminergic, and purinergic systems in the rat.

This study examined the effects of 1,4-bis[3-(3,4,5-trimethoxy benzoyloxy)-propyl] perhydro-1,4-diazepine (dilazep; Comelian) on central dopaminergic, cholinergic, and purinergic neuronal systems in rats. Intraperitoneal injections of dilazep (1-5 mg/kg) produced yawning responses, the most effective dose being 2 mg/kg. Dilazep potentiated physostigmine-induced yawning but not pilocarpine- and bromocriptine-induced yawning. Dilazep-induced yawning was not affected by low doses of haloperidol or sulpiride, but was completely inhibited by atropine, a muscarinic M1 receptor antagonist. Dilazep-induced yawning, as well as physostigmine-induced yawning, were markedly inhibited by pretreatment with SK & F 38393, a dopamine D1 receptor agonist, and were potentiated by SCH23390, a dopamine D1 receptor antagonist that alone does not elicit yawning. Caffeine, an adenosine receptor antagonist, inhibited dilazep- and physostigmine-induced yawning responses but N6-cyclohexyl adenosine (CHA) and N6-(L-phenylisopropyl, adenosine (L-PIA), adenosine A1 receptor agonists, were inactive. These results suggest that because the effects of dilazep on central cholinergic neurons are similar to those of physostigmine dilazep may potentiate indirectly the action of endogenous acetylcholine. Cholinergic neurons activated by dilazep may be modulated by postsynaptic dopamine D1 receptor activity but may not be affected by dopamine D2 receptor activity. Furthermore, the stimulatory effects of dilazep on cholinergic neuron may not be due to an inhibition of dopamine D1 receptors via purinergic (adenosine A1 receptor) stimulation by dilazep.

Animals↗
PubMed1994

The 5-HT2 receptor antagonist ketanserine prevents electroconvulsive shock- and clonidine-induced amnesia.

The 5-HT2-selective antagonist ketanserine was examined for its ability to prevent electroconvulsive shock (ECS)- or clonidine-induced performance deficit in the passive avoidance situation (step-down) in rats. The posttrain intraperitoneal injection of ketanserine at doses of 3 and 10 mg/kg prevented the ECS- or clonidine-provoked amnesia upon retention tests given 3 h, 24 h, and 7 days after training. The present data favor the view that the selective modification of 5-HT2 receptors after training can prevent the performance deficit in step-down-trained rats and suggest a role of the 5-HTergic neurotransmitter system in memory. The results of this study further suggest that 5-HTergic receptor antagonists might be useful in treatment of cognitive disorders.

Amnesia↗
PubMed1983

Cadmium uptake and distribution in sticklebacks related to the concentration and method of exposure.

The uptake of cadmium by sticklebacks and its distribution between the body tissues was compared following two methods of exposure, i.e., natural exposure to the heavy metal in water and direct intraperitoneal injection. In both cases, the greatest concentration of cadmium was detected in the liver. In naturally exposed fish high concentrations were also found in the gut and gills while in injected fish high levels were demonstrated in the gall bladder and kidney.

Animals↗
PubMed1990

The uptake metabolism and biological half-life of benzo[a]pyrene in different tissues of sea bass, Dicentrarchus labrax.

The disposition of polycyclic aromatic hydrocarbons in aquatic organisms is of interest from the viewpoint of both animal and human health. The kinetics of uptake and metabolism of benzo[a]pyrene (BaP) were studied in various tissues of the marine fish, sea bass, upon intraperitoneal injection of the compound. A decrease in radioactivity occurred in all tissues and the calculated half-lives were 12.4 days for fat, 6.5 for kidney, 5.1 for intestine, 4.8 for gallbladder, 4.5 for spleen, 2.9 for muscle, 2.4 for whole body, 2.3 for gonads, 2.3 for gills, and 2.2 for liver. The kinetics of distribution of radioactivity between alkali and hexane tissue extracts were determined in order to assess the overall metabolic potential of various organs. The liver, intestine, gills, and kidney displayed a relatively high metabolic potential in comparison with the spleen, muscle, gonads, and fat. The significance of the observations with respect to understanding mechanisms of toxicity is briefly discussed. Attention is specifically drawn to the presence of a fairly active metabolism or metabolite redistribution system in the muscle and the potential for exposure of blood cells to metabolites via hydrocarbon transformation processes in the spleen. This in vivo study, in which hydrocarbon disposition was studied in various tissues, also supports the hypothesis that polycyclic aromatic hydrocarbons should not bioaccumulate to any significant degree in fish and that exposure of humans to such compounds through the consumption of fish products can be expected to be minimal.

Animals↗
PubMed1990

Modulatory effect of metal ions on the immune response of fish: in vivo and in vitro influence of MnCl2 on NK activity of carp pronephros cells.

The in vivo and in vitro influence of MnCl2 on carp pronephros cells was investigated. Increased cytotoxicity against both YAC-1 and P 815 target cells was observed following an intraperitoneal injection of 40, 80, or 120 micrograms MnCl2/g body wt administrated 24 hr prior to the in vitro 51Cr release assay. Similarly, in vitro treatment of carp pronephros cells, at a final concentration of 60 micrograms/culture, resulted in an increase of NK cell activity in both YAC-1 and P 815 target cell lines. However, a significant decrease in this activity was shown with lower doses of MnCl2 (40 and 20 micrograms/culture).

Animals↗
PubMed1996

Biodegradable microparticles as a delivery system for measles virus cytotoxic T cell epitopes.

Cytotoxic T-cell (CTL) responses are likely to be important for the clearance of a measles virus (MV) infection. To induce CTL responses. replicating vectors have generally been used but the use of such vectors in humans mav be problematic, and immunization with synthetic peptides may be more appropriate. We have investigated the potential of poly(lactide-co-glycolide)(PLG) microparticles as a delivery system for a CTL epitope representing residues 51-59 from MV nucleoprotein. After a single intraperitoneal injection in saline of the encapsulated epitope, CTL responses to the homologous peptide and MV were detected over a period of 4 months. Responses reached a maximum 30 days after priming and were maintained at high levels for 120 days. These responses were higher than those observed when the CTL epitope was administered in saline or as an emulsion in Incomplete Freund's Adjuvant. The pronounced immunostimulatory effect of microparticles, combined with their excellent tissue compatibility and biodegradability suggests that they represent a valuable delivery system for synthetic peptide immunogens.

Animals↗
PubMed1992

Scheduled running wheel activity indexes the specificity of pharmacological anorexia.

Nondeprived male Sprague-Dawley rats that were given scheduled access to running wheels for 60 min daily ran immediately and energetically. Intraperitoneal injections of 400 micrograms/kg pancreatic glucagon and 0.15 microgram/kg cholecystokinin octapeptide had no effect on scheduled running, but significantly inhibited feeding when the rats were offered condensed milk instead of access to the running wheels. This is consistent with the hypothesized function of these peptides as postprandial satiety signals. In contrast, 0.5 mg/kg amphetamine and 75 microM/kg LiCl, which produced similar degrees of anorexia, inhibited running by about 50%. Amphetamine, but neither peptide, also inhibited water drinking and disrupted the behavioral sequence of postprandial satiety. The distance run during scheduled running tests was inversely related to body weight, but the patterns of the drugs' effects were not altered by baseline running differences. Scheduled wheel running is a robust consummatory behavior that appears to provide a relatively valid, simple, and sensitive test of the behavioral specificity of pharmacological anorexia.

Amphetamine↗
PubMed1975

Acute cytogenetic effect of 2-(2-furyl)-3-(5-nitro-2-furyl)-acrylamide (AF-2, a food preservative) on rat bone marrow cells in vivo.

The cytogenetic effects of 2(2-furyl)-3-(5-nitro-2-furyl)-acrylamide (AF-2), a food preservative used in Japan, on rat bone marrow cells in vivo were studied. The aberrant metaphase cells in the bone marrow increased and reached the peak level 6 h after intraperitoneal injection of 240 mg/kg body weight of AF-2 and returned to the normal level within 24 h. A dose-response relationship was obtained using 4-240 mg/kg of AF-2. Chromosome aberrations were also induced after oral administration of 30-240 mg/kg. The aberrations were mostly chromatid breaks and the distribution among and within chromosomes was similar to those induced by a carcinogen, 7, 12-dimethylbenz(a)anthracene (DMBA). The present results provide the first evidence of in vivo cytogenetic effects of AF-2 on mammalian cells and, together with the evidence of mutagenicity already proved in other organisms, warn of the possible genetic hazards to cells exposed to this compounds.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1979

Detection of mutagens in the urine of rats following topical application of hair dyes.

Mutagens were detected in the urine of rats following topical application of two commercial oxidative-type hair dye preparations. The test system used was induction of back mutation with the bacterial tester strain TA1538, a histidine-dependent mutant of Salmonella typhimurium. Various quantities of dye were applied to the shortened hair on the backs of the test animals. The dye was allowed to remain on the hair for 20 min after application and was then removed by shampooing and thorough rinsing. Maximal levels of mutagenic activity occurred with urine collected during first 24 h following dye application, and a dose--response was observed when increasing volumes of mutagenic urine were tested. Mutagens were detected in rat urine after intraperitoneal injection, and also after topical application of 4-nitro-o-phenylenediamine, one of the constituents of the hair-dye preparations.

Administration, Topical↗
PubMedDate not supplied

In vivo cytogenetic studies on mice exposed to ethylene dibromide.

The pesticide, ethylene dibromide (EDB), was evaluated with in vivo cytogenetic assays to determine its genotoxicity. CD1 male mice were exposed to EDB through intraperitoneal injections. Bone marrow cells isolated from femora were analyzed for sister-chromatid exchange (SCE), chromosome aberration and micronucleus formation. The results showed that only certain concentrations of EDB tested caused a slight but significant increase in SCEs and chromosome aberrations. However, these increases were not dose-related. No increase in the polychromatic erythrocytes with micronuclei was observed following EDB exposure. Also, EDB did not cause cell-cycle delay in comparison with controls. Thus, it appears that EDB is not an effective genotoxic agent in vivo in mice.

Animals↗
PubMed1986

Mouse specific-locus test for the induction of heritable gene mutations by dibromochloropropane (DBCP).

The nematocide DBCP (1,2-dibromo-3-chloropropane) produced negative results in a specific-locus test for gene-mutation induction in the germline of male (101 X C3H)F1 mice, most of which were treated with 5 daily intraperitoneal injections of 80 mg/kg (total exposure, 400 mg/kg); a few received lower exposures. For treated spermatogonial stem cells, the finding of 2 mutations among 39519 offspring--a rate almost identical to the control rate--rules out (at the 5% significance level) an induced mutation frequency greater than 2.0 times the historical control rate. From treated poststem-cell stages, no mutants were found among 6240 offspring, ruling out (at the 5% significance level) a multiple of 8.0 times the control for these cell types. A multiple rearrangement (7 chromosomes involved in 3 translocations) found in one of the mutants probably arose as a postmeiotic event not associated with the DBCP treatment. The fertility of DBCP-treated males was not disturbed, in keeping with the absence of germ-cell toxicity and dominant lethals found by other investigators in these mice, and in contrast to results in certain other species. While the treated (101 X C3H)F1 mice are Ah-responsive, other findings make it questionable whether biotransformation of DBCP to reactive intermediates is accomplished via the Ah-receptor system.

Animals↗
PubMed1989

Administration-route-related difference in the micronucleus test with 7,12-dimethylbenz[a]anthracene.

The effect of route of administration on the outcome of the mouse micronucleus test was evaluated in 2 laboratories by administering a model chemical, 7,12-dimethylbenz[a]anthracene (DMBA) by intraperitoneal injection (i.p.) and oral gavage administration (p.o.) to males of 2 mouse strains, MS/Ae and CD-1. On the basis of a small-scale acute toxicity study and a pilot micronucleus test, a full-scale micronucleus test was performed with a 48-h sampling time at doses of 25, 50, 100, and 200 mg/kg by both administration routes in the 2 strains. At each dose level and in both strains, higher frequencies of micronucleated polychromatic erythrocytes (MNPCEs) were found after use of the i.p. route. In the MS/Ae strain, a linear, positive dose response was obtained by both routes. In the CD-1 strain, the maximum response was reached at 100 mg/kg and a downturn occurred at 200 mg/kg by both routes. The comparison of maximum responses indicated that MS/Ae was the higher responder for both routes of application. Although DMBA induced micronuclei more efficiently by the i.p. route than after oral administration on a mg/kg base, this route-related difference was reversed in both strains when the comparison was made on the basis of LD50 values and when the maximum responses were neglected.

9,10-Dimethyl-1,2-benzanthracene↗