Effects of 3,3'-iminodipropionitrile on acquisition and performance of spatial tasks in rats

3,3'-Iminodipropionitrile (IDPN) has been reported to disrupt learning and memory in rats (24). The present work addressed the effects of IDPN on tasks requiring the use of spatial information. Separate groups of male rats were dosed with IDPN (IP, in 1 ml/kg saline) for 3 consecutive days and tested in the following procedures: (a) step-through passive avoidance conditioning (0, 100, 150, and 200 mg/kg/day); (b) Morris water maze (MWM) acquisition and retention (0, 125, 150, 175, and 200 mg/kg/day); (c) radial arm maze (RAM) acquisition (0, 100, 200, and 400 mg/kg/day); (d) RAM steady-state performance (0, 200, and 400 mg/kg/day); (e) repeated acquisition in the RAM (0, and 200 mg/kg/day). The vestibular toxicity of IDPN resulted in alterations in spontaneous behavior or swimming deficits in 5 of 8 rats treated with 175 mg/kg/day and in all the animals dosed with 200 or 400 mg/kg/day. IDPN increased step-through PA latencies at 200 mg/kg/day but not at lower doses. In the MWM, no performance deficits were observed at the dose levels preserving the swimming ability of the animals. In both the acquisition and the steady-state RAM tasks, IDPN (400 mg/kg/day) induced an increase in both choice errors and perseverative errors. In the RAM repeated acquisition paradigm, IDPN (200 mg/kg/day) induced performance deficits that included a decreased rate of within-session reduction in errors. The present data show that IDPN disrupts performance of tasks requiring spatial learning and memory and indicate that these deficits can be in part caused by an acquisition deficit.     

Treatment of unresectable hepatocellular carcinoma with lipiodol chemoembolization: a multicenter randomized trial. Groupe CHC

We investigated the effect of successive administrations of SA4503 (1-(3,4-dimethoxyphenethyl)-4-(3-phenylpropyl)piperazine dihydrochloride), a novel cognitive enhancer with high affinity and selectivity for the sigma1 receptor subtype, on the cortical cholinergic dysfunction-induced impairment of the spatial learning performance in the Morris water maze (MWM) task in rats. The impairment of the spatial learning performance was produced by the ibotenic acid-induced lesion of the basal forebrain (BF) area in rats. Escape latencies to find the platform during the training trials of the MWM task were significantly prolonged in the BF-lesioned rats compared with the sham-operated rats. Daily treatment with SA4503 (0.1-0.5 mg/kg, P.O./day) for 13 days ameliorated this learning deficit. In the probe trial, BF-lesioned rats reduced the number of times each rat crossed the former platform location during the training trials (goal area) in comparison with sham-operated rats. Successive administrations of SA4503 (0.25 mg/kg, P.O./day) also significantly increased the BF lesion-induced reduction of the number of times each rat crossed the goal area. These results suggest that the successive administrations of SA4503 attenuate the impairment of the spatial learning performance in rats with cortical cholinergic dysfunction, and that SA4503 is useful as a therapeutic drug for Alzheimer's disease.     

Effects on open-field behavior of diazepam and buspirone alone and in combination with chronic caffeine

Effects of diazepam (1, 2 mg/kg) and buspirone (1.25, 2.5 mg/kg) on locomotor and rearing activity were observed in rats tested in an open field. Both doses of each drug reduced ambulation. However, for buspirone, this effect was confined to females. Walking and rearing was reduced by the higher dose of diazepam and rearing by both doses of buspirone. In rats that had ingested approximately 26 mg/kg/day of chronic caffeine for seven days prior to and immediately before testing, all effects of diazepam observed earlier failed to achieve significance except for ambulation. However, all earlier buspirone effects (including female-only decreased ambulation) were unaffected by the caffeine treatment. It was concluded that buspirone may be preferable to diazepam as an anxiolytic when in the presence of regular caffeine ingestion.     

Effects of isolation rearing on startle reactivity, habituation, and prepulse inhibition in male Lewis, Sprague-Dawley, and Fischer F344 rats

This study compared the interaction of strain with isolation rearing on startle reactivity, habituation, and prepulse inhibition (PPI) in male Lewis, Sprague-Dawley, and Fischer F344 rats tested as adults. Lewis and Fischer rats exhibited lower startle reactivity than Sprague-Dawley rats. Lewis rats displayed more rapid habituation than the other strains. Most important, isolation rearing produced deficits in PPI in both Sprague-Dawley and Fischer rats but had no effect in Lewis rats. By contrast, isolation rearing had no effect on startle reactivity or habituation. In a separate study, 0.5 mg/kg apomorphine disrupted PPI in Fischer but not in Lewis rats. Thus, PPI in Lewis rats is relatively unaffected by either a pharmacological or a developmental manipulation, both of which disrupt PPI in Sprague-Dawley and Fischer F344 rats.     

Evaluating parameters of osseointegrated dental implants using finite element analysis--a two-dimensional comparative study examining the effects of implant diameter, implant shape, and load direction

The hexachlorophene-induced cytotoxic brain oedema is an experimental model of brain damage, suitable for testing cerebroprotective substances (Andreas 1993). In order to examine whether glutamate receptors are involved in mediating functional disorders due to neurotoxic brain damage, we have studied the protective effects of several competitive and non-competitive antagonists using adult male Wistar rats in a simple "ladder-test" for assessing coordinative motor behaviour. Hexachlorophene-induced brain damage was verified by histological examination of the cerebellum with vacuolation of white matter, astrocyte hypertrophy and astrocyte proliferation taken as signs of neurotoxic injury. The non-competitive N-methyl-D-aspartate (NMDA) antagonist dizocilpine maleate (MK-801) decreased the motor disturbance on the first and second day of the "ladder-test" when applied in the doses 0.1 mg/kg and 0.2 mg/kg intraperitoneally for 3 weeks during the hexachlorophene treatment. Acute MK-801 administration (0.1 mg/kg intraperitoneally) after 3 weeks hexachlorophene exposure improved the coordinative motor response only on the first day. When testing the competitive NMDA receptor antagonist 2-amino-5-phosphonopentanoic acid (AP-5) in the dose 1.0 mg/kg intraperitoneally the motor disturbance was lowered significantly earlier than in spontaneous remission. Similar effects were observed with 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) in the dose of 0.8 mg/kg intraperitoneally, an antagonist interacting both with the strychnine-insensitive binding site for glycine within the NMDA receptor complex and with the kainate(+/-)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor complex. Concurrent MK-801 administration decreased the vacuolation of white matter. The results suggest that NMDA receptors and non-NMDA receptors are involved in development of functional disorders induced by hexachlorophene.     

FOS is induced by singing in distinct neuronal populations in a motor network

The acute and subacute effects of intracerebroventricularly (ICV) administered nerve growth factor (NGF) or brain-derived neurotrophic factor (BDNF) on locomotor activity were evaluated in awake adult rats. Immediately after ICV injection through an implanted cannula, locomotor activity was measured by a computerized system using infrared photocells, which allowed us to record locomotion, motility, and rearing simultaneously. A single dose of 5 microg mouse beta-NGF produced significant increases in horizontal ambulatory components of locomotor activity (locomotion and motility), but not vertical movement (rearing) 30-45 min after ICV administration. These increases lasted for at least 3-4 h. Systemic injection of 2.0 mg/kg mecamylamine, a central nicotinic receptor antagonist, inhibited the hyperactivity induced by NGF. Systemic injection of 0.5 mg/kg scopolamine, a muscarinic receptor antagonist, did not interfere with the NGF effects. Thus, while scopolamine induced marked increases in all three measures of behavior in both NGF and cytochrome-c-treated animals, locomotion and motility remained significantly higher in the NGF group. Immunohistochemistry demonstrated that NGF diffused readily from the ventricular space into brain parenchyma on the injected side and could be visualized 1 h after ICV injection. These results suggest that ICV administration of NGF increases locomotor activity by inducing acetylcholine release, and that nicotinic receptors are involved in the hyperactivity induced by NGF. ICV administration of 5 microg recombinant human BDNF had no significant effect on locomotor activity during the 0- to 4-h period after ICV injection. However, it produced significant decreases in locomotion, motility, and rearing 24-26 h later. Hence ICV administration of BDNF has entirely different effects on animal behavior from those evoked by NGF. While NGF elicits increases in ambulatory behavior within hours, BDNF causes delayed decreases in ambulatory behavior.     

Pilocarpine and physostigmine attenuate spatial memory impairments produced by lesions of the nucleus basalis magnocellularis.

Three experiments, with 63 male Long-Evans rats, investigated the effects of bilateral ibotenic acid-induced lesions of the nucleus basalis magnocellularis (NBM) on the acquisition and retention of several spatial memory tasks. Maintenance of spatial memory in a food-search task was impaired following NBM lesions. Acquisition of spontaneous alternation and reinforced alternation in a T-maze, but not the acquisition of a position habit, was also significantly impaired in Ss with these lesions. In several of the tasks, there was evidence of some learning in the lesioned Ss after substantial training, although they were significantly deficient when compared with controls. Intraperitoneal administration of the cholinergic agonists physostigmine sulfate (0.5 mg/kg) or pilocarpine nitrate (3 mg/kg) prior to behavioral testing resulted in a rapid and significant improvement in the performance of the lesioned Ss. Lesions significantly reduced the activity of choline acetyltransferase in the anterior and the posterior neocortex but not the hippocampus. Results indicate that the cholinergic projections originating in the NBM are involved in the learning and memory of spatial tasks. (48 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Restoration of sympathetic noradrenergic nerve fibers in the spleen by low doses of L-deprenyl treatment in young sympathectomized and old Fischer 344 rats

It is well-established that noradrenergic (NA) nerve fibers in spleen and lymph nodes influence cell-mediated immune responses. Such responses are diminished in young animals following chemical sympathectomy and in older animals accompanying an age-related decline in NA nerve fibers in spleen and lymph nodes. The purpose of this study was to determine whether treatment with deprenyl, an irreversible monoamine oxidase-B (MAO-B) inhibitor, would hasten the process of splenic NA reinnervation following chemical sympathectomy in young rats and would reverse the age-related loss of sympathetic NA fibers in the spleen of old rats. To examine the effects of deprenyl in young sympathectomized rats, 3-month-old male Fischer 344 (F344) rats were treated with 6-hydroxydopamine (6-OHDA) and administered 0, 0.25, 1.0, 2.5, or 5.0 mg deprenyl/kg body weight (BW)/day intraperitoneally (i.p.) for 1, 15, or 30 days. In another study, 21-month-old male F344 rats were treated with 0, 0.25, or 1.0 mg deprenyl/kg BW/day i.p. for 9 weeks. At the end of the treatment period, spleens were removed and NA innervation was assessed by fluorescence histochemistry, immunocytochemistry, and quantitation of norepinephrine (NE) by high performance liquid chromatography with electrochemical detection (HPLC-EC). In the spleens of young sympathectomized rats, there was faint fluorescence or absence of fluorescence and tyrosine hydroxylase-positive (TH+) fibers around the central arteriole and in the periarteriolar lymphatic sheath of the white pulp one day after administration of 6-OHDA, indicating a severe loss of NA innervation compared with unlesioned control animals. Treatment of sympathectomized rats with 1.0 mg, 2.5 mg, and 5.0 mg/kg deprenyl for 30 days increased the density of NA innervation estimated by both fluorescence histochemistry and immunocytochemistry compared with vehicle-treated controls recovering spontaneously from 6-OHDA. Splenic NE concentration was increased in the hilar region of sympathectomized rats treated with 2.5 mg and 1.0 mg/kg deprenyl after 15 and 30 days, respectively, compared with untreated and vehicle-treated sympathectomized rats. The spleens of untreated and saline-treated old rats showed a reduction in the density of NA innervation in the white pulp compared with young animals. Treatment of old rats for 9 weeks with 1.0 mg/kg deprenyl induced moderate to intense fluorescent fibers and linear TH+ nerve fibers around the central arteriole and in other compartments of the white pulp, and increased splenic NE concentration in the hilar region and NE content in the whole spleen. Taken together, these results provide strong evidence for a neurorestorative property of deprenyl on sympathetic NA innervation of the spleen, which may lead to an improvement in cell-mediated immune responses.     

Shift work, nitrous oxide exposure and subfertility among Swedish midwives

High-dose nicotinamide (1000 mg/kg) leads to a minor increase of plasma choline but to a major increase of the choline concentrations in the intra- and extracellular spaces of the brain. In the hippocampus, the nicotinamide-induced increase in choline was associated with an increase in the release of acetylcholine under stimulated conditions. In young rats, nicotinamide in doses between 10 and 1000 mg/kg did not influence spatial learning, as tested in the Morris water maze. In old rats, low doses of nicotinamide were ineffective whereas the high dose of 1000 mg/kg even impaired spatial learning. The combined administration of choline and nicotinamide had a synergistic effect on brain choline levels but had similar effects as nicotinamide given alone in the behavioral experiments. Additional tests for spontaneous behaviour and locomotion revealed procholinergic and sedative effects of the compound. We conclude that the ineffectiveness of the putative cognition enhancer nicotinamide in the learning task may be due to the observed sedative effect. Therefore, the development of nonsedative nicotinamide derivatives is recommended.     

Toxicity of fumonisin B1 to B6C3F1 mice: a 14-day gavage study

Fumonisin B1 (FB1) is a fungal toxin produced by members of the genus Fusarium. Ingestion of FB1 causes species-specific neurotoxic, nephrotoxic, hepatotoxic and pulmonary effects. The clinical, haematological and pathological responses of adult male and female B6C3F1 mice to FB1 were assessed following 14 daily gavage doses ranging from 1 to 75 mg FB1/kg body weight/day. There were no consistent sex-related changes. Although all responses were modest, the most notable effects of FB1 were on the liver, bone marrow, adrenals and kidneys. In the liver, hepatocellular single cell necrosis, mitosis and anisokaryosis were observed, accompanied by elevated serum ALT. In the kidneys, minor histopathological changes were confined to female mice, while mild decreases in ion transport and increases in blood urea nitrogen were seen only in males. Small changes in glutathione levels were observed in the kidneys and livers of male mice. Adrenal cortical cell vacuolation was observed at 15 mg FB1/kg and higher in females and from 35 mg FB1/kg in males. Serum cholesterol was elevated in both male and female mice, possibly due to FB1-induced changes in lipid metabolism in the liver and adrenals. Although bone marrow cell numbers were unchanged, increases in vacuolated myeloid cells and lymphocytes were observed in female mice. In general, the degree of changes observed indicate that mice are not as sensitive a model of FB1 toxicity as rats.     

Effects of prenatal exposure to low concentrations of carbon monoxide on sexual behaviour and mesolimbic dopaminergic function in rat offspring

1. Inhalation of low concentrations of carbon monoxide (CO) by pregnant rats (75 and 150 p.p.m. from day 0 to day 20 of gestation) leads to changes in mesolimbic dopaminergic transmission associated with an impairment of sexual behaviour in male offspring. 2. Eighty day old males exposed in utero to CO (150 p.p.m.) exhibited a significant increase in mount/ intromission latency as well as a significant decrease in mount/intromission frequency. A significant decrease in ejaculation frequency was also found in CO (150 p.p.m.)-exposed animals. 3. The acute administration of amphetamine, at a dose (0.5 mg kg(-1) s.c.) stimulating copulatory activity in control rats, failed to reduce mount/intromission latency and did not increase mount frequency in 80-day offspring exposed to CO (150 p.p.m.) during gestation. 4. These behavioural alterations were paralleled by neurochemical changes (in vivo microdialysis) showing that prenatal CO exposure, at concentrations (150 p.p.m.) that did not affect basal extracellular levels of dopamine in the nucleus accumbens, blunted the amphetamine (0.5 mg kg(-1) s.c.)-induced increase in dopamine release in 80-day old male rats. 5. No significant changes in either behavioural or neurochemical parameters were observed in 10-month old rats exposed prenatally to CO. 6. Since the alterations in sexual behaviour and dopaminergic transmission have been produced by prenatal exposure to CO levels resulting in maternal blood carboxyhaemoglobin concentrations equivalent to those maintained by human cigarette smokers, the present data further point out the large risk that the smoking mother poses for her offspring.     

Importance of metabolism in pharmacological studies: possible in vitro predictability

Groups of 20 male and 20 female Sprague-Dawley rats were administered undiluted Aquacoat ECD ethylcellulose aqueous dispersion by oral gavage at doses of 903, 2709 or 4515 mg/kg body weight/day (dry weight basis) for 90 days. Control animals received water at the same dosage volume as the high-dose group. Body weights and food consumption were recorded weekly. Blood was collected prior to study termination for haematology and clinical chemistry measurements. Survivors underwent complete necropsies on days 91 94. Selected organs were weighed and histologically examined. The only treatment-related clinical sign observed was pale faeces which was noted among males and females receiving 2709 and 4515 mg/kg/day Aquacoat ECD. No statistically significant differences in body weights, body weight gains, food consumption and organ weights were noted among males and females when compared with controls. No treatment-related effects in haematology parameters were noted. Significantly decreased total protein and globulin levels and increases in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in male rats receiving 2709 and 4515 mg Aquacoat ECD/kg/day were considered to be treatment related. No gross or microscopic lesions were attributed to Aquacoat ECD treatment. Under the conditions of this study, the no-observed-adverse-effect level (NOAEL) for female rats is in excess of 4515 mg/kg/day: the NOAEL for male rats is 903 mg/kg/day.     

Strain differences in the isolation-induced effects on prepulse inhibition of the acoustic startle response and on locomotor activity.

The authors investigated the effects of isolation rearing on acoustic startle response, prepulse inhibition (PPI), its modification by apomorphine, and locomotor activity in 3 rat strains: Wistar (WS), Sprague-Dawley (SD), and Lister hooded (ListH). SD and ListH, but not WS, showed isolation-induced PPI deficits. In 2 consecutive PPI tests, only SD isolates showed significant PPI deficits. An isolation rearing effect in ListH was significant only in the 1st PPI test. Apomorphine dose-dependently (0.0–0.5 mg/kg) disrupted PPI, but sensitivity to the drug differed, with WS and SD rats being more sensitive to lower doses (0.01–0.05 mg/kg) than ListH rats (0.5 mg/kg). Isolates, irrespective of strain, did not differ from grouped rats in their response to the apomorphine challenge. Only WS and ListH isolates demonstrated significantly increased locomotor activity. Strain differences in the different parameters measured did not predict isolation-induced effects on PPI. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Arrhythmogenic right ventricular cardiomyopathy underlies syndrome of right bundle branch block, ST-segment elevation, and sudden death

In all experimental mammals tested (rats, dogs, primates), intramuscular injections of the oil-soluble antimalarial artemisinin derivatives artemether and arteether have produced an unusual pattern of selective damage to brain stem centers predominantly involved in auditory processing and vestibular reflexes. Artesunate, the most widely used of these compounds, is a water soluble hemisuccinate derivative given parenterally either by intravenous or intramuscular injection. The neurotoxic potential of parenteral artesunate and artemether was compared in a murine model. Adult Swiss albino mice were assigned randomly to 28-day regimens of intramuscular artemether or artesunate in doses ranging from 30 to 100 mg/kg/day. At 30 mg/kg/day, no abnormalities were detected with either drug. At 50 mg/kg/day, abnormalities were observed in six of 12 artemether recipients and two of 12 artesunate recipients. These were reversible in all but one (artemether) mouse. At 100 mg/kg/day, eight of 36 artemether recipients, two of 36 artesunate recipients, and one of 18 control mice died. All but four surviving mice in the artemether group (86%) showed obvious and usually irreversible abnormalities of balance and equilibrium, whereas only four artesunate recipients (11%) exhibited abnormalities, and these were reversible in each case (P < 0.001). At this dose the relative risk (95% confidence interval) for death or disability was 5.3 (2.6-11.2) for artemether recipients. Intramuscular artemether is significantly more neurotoxic than intramuscular artesunate in this murine model.     

Diazepam eliminates the anxious state induced by amputation of the vibrissae (a model for assessing anxious behavior)

Diazepam (0.5 mg/kg) prevented reduction of motor activity of rats (both vertical and horizontal components) induced by vibrissae amputation. It is suggested that the observed decrease in motility is related to development of a pathologic reaction of anxiety. The method is recommended as a test for anxious behaviour in experiment.     

Evaluation of the developmental toxicity of methacrylonitrile in Sprague-Dawley rats and New Zealand white rabbits

Timed-pregnant Sprague-Dawley (CD) outbred rats and New Zealand White rabbits were dosed by gavage with methacrylonitrile (MACR) in distilled water during major organogenesis. Rats were dosed on Gestational Days (GD) 6 through 15 (0, 5, 25, or 50 mg MACR/kg/day) and rabbits on GD 6 through 19 (0, 1, 3, or 5 mg MACR/kg/day). Maternal clinical status was monitored daily during treatment. At termination (GD 20, rats; GD 30, rabbits), confirmed-pregnant females (25-26 per group, rats; 17-22 per group, rabbits) were evaluated for clinical status and gestational outcome; each live fetus was examined for external, visceral, and skeletal malformations. In rats, no treatment-related maternal clinical signs or mortality were observed, nor was there any adverse effect on maternal body weight or food or water consumption. At necropsy, absolute, relative, and adjusted maternal liver weight was increased at the mid- and high-dose groups, an effect that may be indicative of induction of hepatic enzymes rather than toxicity. In the absence of any indication of maternal toxicity, the no-observed-adverse-effect level (NOAEL) for maternal toxicity in this study was >/=50 mg MACR/kg/day. The NOAEL for developmental toxicity in rats was also >/=50 mg MACR/kg/day. There was no effect of treatment on postimplantation loss, mean fetal body weight per litter, or morphological development. In rabbits, maternal mortality and clinical signs were not dose related. Maternal food consumption, body weight, and liver weight were not adversely affected by treatment. Thus, the maternal NOAEL was >/=5 mg MACR/kg/day. Maternal toxicity, including death, was observed >/=7.5 mg/kg/day in preliminary studies. The developmental NOAEL was also >/=5 mg MACR/kg/day. There was no adverse effect of treatment on postimplantation loss or fetal body weight. A significant decrease in the percentage male fetuses per litter was observed, although there was no effect on total live litter size, suggesting that the reduction in the ratio of live male fetuses in the high-dose group was not biologically significant. MACR had no adverse effect on morphological development. In summary, oral administration of MACR to rats and rabbits during organogenesis, at doses that did not cause persistent maternal toxicity (50 mg MACR/kg/day, rats; 5 mg MACR/kg/day, rabbits), also did not cause any adverse developmental effects.     

Effects of chronic nicotine treatment and withdrawal on hypothalamic proopiomelanocortin gene expression and neuroendocrine regulation

Considerable evidence suggest that some responses to smoking and nicotine are mediated by forebrain beta-endorphinergic opioid mechanisms. It has also been demonstrated that nicotine stimulates rat tuberoinfundibular dopaminergic activity. Since we have proposed that interactions between mediobasohypothalamic (MBH) dopaminergic and beta-endorphinergic mechanisms have a key role in neuroendocrine integration, we investigated the effects of chronic nicotine treatment and withdrawal on: (1) MBH concentrations of proopiomelanocortin (POMC, precursor for beta-endorphin biosynthesis) mRNA; (2) MBH concentrations of tyrosine hydroxylase (TH, rate limiting enzyme in catecholamine biosynthesis) mRNA; (3) corresponding serum prolacin, corticosterone, luteinizing hormone (LH), and testosterone concentrations. POMC and TH mRNA levels were measured by RNase protection/solution hybridization assay; serum hormone levels were measured by radioimmunoassay. Adult male rats received subcutaneous injections of either nicotine or saline during the dark period of each day on an increasing frequency (1-3 injections/day) and dosage (0.4-0.5 mg nicotine/kg body weight) schedule over 4 weeks. The rats were sacrificed after 4 weeks treatment and at 1, 3, 7, 14 and 21 days withdrawal. Chronic daily nicotine administration induced significant changes in serum corticosterone, serum prolactin, MBH TH mRNA, and MBH POMC mRNA concentrations that tended to persist through day 3 of withdrawal; serum prolactin and MBH POMC mRNA concentrations were suppressed whereas serum corticosterone and MBH TH mRNA concentrations were stimulated. None of the parameters were significantly different from control levels following 7 or more days of withdrawal from nicotine, except for a significant decrease of MBH POMC mRNA concentrations on day 21. Chronic daily nicotine or withdrawal did not significantly alter serum LH or testosterone concentrations. These results suggest that chronic nicotine inhibited POMC gene expression and thus, probably, biosynthesis of beta-endorphin and other opiomelanocortins. We hypothesize that suppression of forebrain beta-endorphin synthesis in response to long-term nicotine exposure produces a chronically opioid deficient condition which may play an important role in maintaining nicotine self-administration and in mediating some changes during the nicotine withdrawal syndrome.     

Monoamine oxidase inhibitor sensitive site implicated in sensitization to quinpirole

Clorgyline (1.0 mg/kg/day) administered via osmotic minipumps blocked the development of locomotor sensitization to the dopamine receptor agonist quinpirole (0.5 mg/kg every 3 days for 8 injections). In male rats already well sensitized to quinpirole, the continuous infusion of clorgyline (1.0 mg/kg/day for 28 days) produced a progressive decline in locomotor activity, despite a continued regimen of quinpirole injections (0.5 mg/kg every 3 days). It is suggested that the development, as well as the maintenance, of locomotor sensitization to quinpirole is modulated by the activation of an monoamine oxidase inhibitor-sensitive site. This site may be a dopamine D2 receptor-linked monoamine oxidase inhibitor-displaceable quinpirole binding site, the enzyme monoamine oxidase-A, or other clorgyline binding sites.     

Male fertility in rats treated with etretinate for 4 weeks

The toxicity of Etretinate, a retinoid compound, on the male reproductive system was studied in male rats. The drug was administered for four weeks at the dose levels of 0 (control: Vehicle, Peanut oil), 5 and 25 mg/kg/day. The animals were then allowed to mate, and their male reproductive functions and organs were examined in detail. No significant changes due to toxicity were observed in male reproductive functions and organs in the 5 mg/kg/day group after the 4-week treatment. In contrast, males in the 25 mg/kg/day group showed drug-related changes in their reproductive performance (decrease of mating ability and fertility rate), testosterone blood level, sperm head counts, sperm viability and number in the caudal epididymis, organ weight and in the histopathology of their reproductive organs (atrophy of seminiferous tubules, necrosis of spermatocytes and spermatids, vacuolation of nuclei of spermatocytes and spermatids). Even though Etretinate belong to the retinoid group of compounds, the changes seen in the 25 mg/kg/day group were almost the same as those observed in Vitamin A-deficient animals. In conclusion, there is a correlation between changes due to toxicity observed for parameters of male fertility and for histopathological evaluation of the testis of rats that receiving high dose, treatment with Etretinate for 4 weeks.     

Correlates of change in depressive symptomatology among gay men with AIDS

The present experiment investigated the ability of the opiate receptor antagonist naltrexone to block the increased locomotion and rearing produced acutely by amphetamine as well as the sensitization of these responses produced when this drug is administered repeatedly. Rats in different groups received an injection of amphetamine (1.5 mg/kg, i.p.) or saline preceded 30 min earlier by an injection of naltrexone (0, 0.5, 1.0, 5.0 or 10.0 mg/kg, i.p.). Naltrexone dose-dependently reduced the rearing but had no effect on the locomotion produced by this dose of amphetamine. The locomotion and rearing observed following saline were not affected. This pattern of results was observed following each of six additional pairs of injections, one pair of injections given every third day. Once, soon (2-4 days) and once, long (9-12 days) after the last injection, all animals were injected with amphetamine (0.75 mg/kg, i.p.) in the absence of naltrexone (tests for sensitization). Animals having been pre-exposed to amphetamine preceded by naltrexone showed no evidence of sensitized rearing on either test, indicating that naltrexone blocked sensitization of this response to amphetamine. These animals, however, exhibited sensitized locomotion on both tests. These results suggest an important but complex role for dopamine-opioid interactions not only in the production of acute locomotor responding to amphetamine but also in the sensitization of locomotor responding when this drug is administered repeatedly. The present findings also suggest that amphetamine-induced rearing is more dependent than locomotion on neuronal mechanisms involving dopamine-opioid interactions.