Syndrome In Rodents Research Articles

Intra-cornu ammonis 1 administration of the human immunodeficiency virus-1 protein trans-activator of transcription exacerbates the ethanol withdrawal syndrome in rodents and activates N-methyl- d-aspartate glutamate receptors to produce persisting spatial learning deficits

Human immunodeficiency virus-1 (HIV-1) infection may produce neurological deficits, such as cognitive decline, that may be worsened by concurrent ethanol (EtOH) abuse. Among the many biochemical cascades likely mediating HIV-1-associated neuronal injury is enhancement of N-methyl- d-aspartate (NMDA) receptor function and progression to excitotoxicity, an effect that may be directly or indirectly related to accumulation in brain of the HIV-1 trans-activator of transcription (Tat) factor. The present studies were designed to examine the hypothesis that binge-like EtOH pre-exposure would enhance effects of Tat on NMDA receptor function. These studies employed a modified in vivo binge EtOH exposure regimen designed to produce peak blood EtOH levels (BEL) of <200 mg/dl in adult male rats and were designed to examine effects of intra-hippocampal injection of Tat (0.5 μl/500 pM/2 min) on EtOH withdrawal-related behavior, spatial learning, and histological measures. Unilateral cannulae were implanted into the cornu ammonis 1 (CA1) pyramidal cell layer of animals prior to beginning a 4-day binge EtOH regimen. EtOH was administered via intragastric intubation (∼3.0–5.0 g/kg) with dose determined by behavioral ratings of intoxication daily for 4 days (at 08:00, 16:00, and 24:00 h). EtOH withdrawal behaviors were monitored 12 h after the last administration of EtOH. Morris water maze learning was assessed during the following 4 days, at which times brains were harvested for autoradiographic measurement of NMDA receptor density and neuroinflammation. Maximal BELs of 187.69 mg/dl were observed 60 min after EtOH administration on day 2 of the regimen. In contrast, peak BELs of approximately 100 mg/dl were observed 60 min after EtOH administration on day 4 of the regimen, suggesting development of metabolic tolerance. Significant behavioral abnormalities were observed in EtOH withdrawn animals, including tremor and seizures. Intra-CA1 region injection of Tat significantly potentiated EtOH withdrawal behavioral abnormalities, an effect that was reduced by MK-801 pre-exposure. While EtOH withdrawn animals showed learning similar to control animals, EtOH withdrawn animals that received intra-CA1 Tat injection demonstrated persisting deficits in spatial learning on days 3 and 4 of training, effects that were markedly reduced by administration of the competitive NMDA receptor antagonist MK-801 30 min prior to Tat injection. No changes in [ 3H]MK-801 binding were observed. Binding density of [ 3H]PK11195, a ligand for peripheral benzodiazepine receptors expressed on activated microglia, was elevated proximal to cannula tracks in all animals, but was not altered by EtOH or Tat exposure. These findings suggest that EtOH abuse and/or dependence in HIV-positive individuals may promote HIV-1-associated cognitive deficits by altering NMDA receptor function in the absence of microglial activation or neuroinflammation.

1-Benzyl-1,2,3,4-Tetrahydroisoquinoline, an Endogenous Parkinsonism-Inducing Toxin, Strongly Potentiates MAO-Dependent Dopamine Oxidation and Impairs Dopamine Release: Ex vivo and In vivo Neurochemical Studies

1-Benzyl-1,2,3,4-tetrahydroisoquinoline (1BnTIQ), an endogenous neurotoxin, is known to cause a parkinsonism-like syndrome in rodents and primates. In this study we evaluated the effects of single and multiple 1BnTIQ (50 mg/kg i.p.) administration on the concentrations of dopamine, serotonin, and respective metabolites (homovanillic acid, HVA; 3,4-dihydroxyphenylacetic acid, DOPAC; 3-methoxytyramine, 3-MT; and 5-hydroxyindolacetic acid, 5-HIAA), in substantia nigra, striatum (STR), and nucleus accumbens of Wistar rats. In addition, the effect of 1BnTIQ on locomotor activity and dopamine release in vivo was also estimated in rat STR. In a behavioral study, acute administration of 1BnTIQ (50 mg/kg i.p.) produced a significant decrease in exploratory locomotor activity. A high-performance liquid chromatography with electrochemical detection ex vivo study showed that a single injection of 1BnTIQ produced a dramatic fall in the dopamine concentration in the noted brain regions (approximately 65%; P < 0.01), but not in striatal serotonin. Moreover, 1BnTIQ reduced the content of the extraneuronal dopamine metabolite 3-MT by 70% (P < 0.01). Conversely, levels of DOPAC, HVA, and 5-HIAA were elevated by 220, 320, and 185%, respectively (P < 0.01). Interestingly, multiple 1BnTIQ treatments (50 mg/kg/day i.p. x 10 days) resulted in development of tolerance to its dopamine depressing effect, while the impairment of dopamine synthesis was persisted. An in vivo microdialysis study demonstrated that 1BnTIQ (50 mg/kg i.p.) produced a profound and long-lasting decrease in extraneuronal striatal dopamine. Concurrently, however, DOPAC and HVA were elevated. This comparison between ex vivo and in vivo effects of 1BnTIQ provides greater insight into the neurotoxic actions of 1BnTIQ specific to dopamine neurons. 1BnTIQ neurotoxicity may be related to an impairment of dopamine storage, leading to a fall in intraneuronal dopamine and enhanced dopamine catabolism through a monoamine oxidize-dependent oxidative pathway that results in free radical production and ultimate cell death. Because 1BnTIQ is an endogenous compound, it may be one of the factors responsible for idiopathic Parkinson's disease.

Minocycline reduced craving for cigarettes but did not affect smoking or intravenous nicotine responses in humans

In recent preclinical studies, the role of nitric oxide (NO) in nicotine dependence has become increasingly evident. Inhibition of NO synthesis blocks acquisition of conditioned place preference, and attenuates the nicotine abstinence syndrome in rodents. These findings have not been followed up in human studies. In order to obtain preliminary data on NO inhibition in human smokers, we conducted a randomized, double-blind, crossover study ( N = 12) of minocycline, a tetracycline derivative antibiotic, that inhibits the neuronal nitric oxide (NO) synthase enzyme with resultant inhibition of NO production. Medication effects were assessed through a smoking choice procedure as well as subjective and physiological responses to nicotine administered via the intravenous route (IV). Minocycline treatment did not affect smoking self-administration in our choice procedure and did not affect most of the subjective responses to IV nicotine or sample smoking. Following IV nicotine administration, there was a greater reduction in craving for cigarettes under minocycline, compared to placebo. Similarly, smokers had greater reduction in their craving for cigarettes following sample smoking under minocycline treatment. These findings provide limited support for the potential use of minocycline as a treatment of nicotine dependence.

Prefrontal cortex lesions cause only minor effects on the hyperlocomotion induced by MK-801 and its reversal by clozapine

The non-competitive NMDA receptor antagonist MK-801 elicits a behavioural syndrome in rodents characterized by hyperlocomotion and stereotypies, which is antagonized by antipsychotic drugs. NMDA receptor antagonists increase prefrontal cortex (PFC) activity in rodents, as assessed by electrophysiological and neurochemical measures. The increase in glutamate outflow induced by systemic MK-801 administration in the medial PFC (mPFC) is prevented by the local administration of clozapine (Clz). In the present study, we examine whether a PFC lesion alters the behavioural syndrome induced by MK-801 in rats and the Clz-induced antagonism of MK-801 actions. We evaluated the hyperlocomotion, stereotypies and other behavioural changes induced by MK-801 in the open field and the effect of electrolytic lesions of the mPFC, and of cortical transection on the behavioural syndrome induced by MK-801 and its reversal by Clz. MK-801 (0.1-0.2 mg/kg i.p.) reduced rearings but only the higher dose induced hyperlocomotion. At this dose, MK-801 also increased disorganized movements, head weavings, and induced ataxia signs. An electrolytic lesion of the mPFC markedly reduced the number of rearings pre-treatment but caused a very slight attenuation of MK-801-induced hyperlocomotion. Cortical transection did not significantly alter MK-801 effects. Clz administration (1 mg/kg s.c.) significantly attenuated hyperlocomotion, head weavings and ataxia signs induced by MK-801 but did not prevent the decrease in rearings. The effect of Clz was essentially unaffected by electrolytic lesions of the mPFC. These results show that MK-801-induced motor syndrome and its reversal by Clz are mostly independent on PFC integrity.

Receptor mediation of exaggerated responses to serotonin-enhancing drugs in serotonin transporter (SERT)-deficient mice

Administration of serotonin-enhancing drugs induces a distinctive behavioral syndrome in rodents. We previously reported that mice with a targeted disruption of the serotonin transporter (SERT) display some of these behaviors spontaneously, in the absence of drug. In the current studies, we assessed the drug-induced serotonin syndrome in SERT wildtype (+/+), heterozygous (+/−) and knockout (−/−) mice. In SERT −/− mice, the monoamine oxidase inhibitor (MAOI) tranylcypromine (1 mg/kg) or the serotonin precursor 5-hydroxy- l-tryptophan (5-HTP; 80 mg/kg) led to markedly exaggerated serotonin syndrome behaviors relative to SERT +/+ mice, with an intermediate phenotype in SERT +/− mice. SERT +/+ mice developed significant serotonin syndrome behaviors only with the combination of the MAO-A/B inhibitor tranylcypromine (0.5 or 1 mg/kg) or the MAO-A-selective inhibitor clorgyline (1.2 mg/kg) plus 5-HTP. In evaluations of underlying mechanisms, pretreatment with the Htr1a receptor antagonist WAY 100635 (1 mg/kg), but not the Htr7 antagonist SB 269970 (3 mg/kg) or the Htr2a antagonist MDL 11,939 (5 mg/kg), markedly decreased the exaggerated 5-HTP-induced behaviors in SERT −/− mice. Subsequent experiments showed that the Htr1a agonist 8-OH-DPAT (1 or 2 mg/kg) elicited serotonin syndrome behaviors in a dose-dependent manner, blocked by WAY 100635 (1 mg/kg), in mice of all three genotypes, confirming the role of Htr1a receptors. The current data document markedly enhanced behavioral sensitivity to serotonin-enhancing drugs in SERT-deficient mice. These studies also show that the exaggerated behavioral responses observed in SERT +/− and −/− mice are mediated by postsynaptic Htr1a receptors, and suggest intact postsynaptic Htr1a function in SERT −/− mice.

Protective Effect of Hydrocortisone on Iminodipropionitrile‐Induced Neurotoxicity in Rats

Occupational and environmental exposure of synthetic nitriles is of potential relevance to human health. Iminodipropionitrile (IDPN), a prototype nitrile toxin, has been shown to produce dyskinetic syndrome in rodents. This study reports the effect of concomitant exposure of rats to hydrocortisone and IDPN on behavioural abnormalities namely excitation, circling and chorea (ECC) syndrome. Four groups of female Wistar rats were given hydrocortisone (0, 10, 30 and 60 mg/kg, gavage, for 10 days) 30 min. before IDPN (100 mg/kg, intraperitoneally for 8 days). Two additional groups of rats were treated with either saline (control group) or 60 mg/kg of hydrocortisone (drug alone group). The animals were observed for neurobehavioural abnormalities including dyskinetic head movement, circling, tail hanging, air righting reflex and contact inhibition of righting reflex. After behavioural studies, the animals were killed, and the discrete brain regions and temporal bones were collected for biochemistry and inner ear histopathology, respectively. Hydrocortisone significantly and dose dependently attenuated the incidence and severity of IDPN-induced behavioural syndrome. Administration of hydrocortisone (60 mg/kg) alone significantly increased glutathione (GSH) levels in olfactory bulb and striatum, whereas IDPN alone significantly reduced GSH levels in olfactory bulb, striatum and hippocampus. Hydrocortisone (60 mg/kg) significantly compensated IDPN-induced depletions of GSH in different brain regions. Hydrocortisone also protected the animals against IDPN-induced vestibular hair cell degeneration. The protective effect of hydrocortisone may be attributed to its anti-inflammatory and antioxidant properties.

Metabolic effects of fructose

Fructose is consumed in significant amounts in Western diets. An increase in fructose consumption over the past 10-20 years has been linked with a rise in obesity and metabolic disorders. Fructose/sucrose produces deleterious metabolic effects in animal models. This raises concern regarding the short-term and long-term effects of fructose and its risk in humans. In rodents, fructose stimulates lipogenesis and leads to hepatic and extrahepatic insulin resistance, dyslipidaemia and high blood pressure. Insulin resistance appears to be related to ectopic lipid deposition. In humans, short-term fructose feeding increases de-novo lipogenesis and blood triglycerides and causes hepatic insulin resistance. There is presently no evidence for fructose-induced muscle insulin resistance in humans. The cellular mechanisms underlying the metabolic effects of fructose involve production of reactive oxygen species, activation of cellular stress pathways and possibly an increase in uric acid synthesis. Consuming large amounts of fructose can lead to the development of a complete metabolic syndrome in rodents. In humans, fructose consumed in moderate to high quantities in the diet increases plasma triglycerides and alters hepatic glucose homeostasis, but does not appear to cause muscle insulin resistance or high blood pressure in the short term. Further human studies are required to delineate the effects of fructose in humans.

Metoclopramide attenuates iminodipropionitrile-induced oxidative stress and neurobehavioral toxicity in rats

Metoclopramide (MET) has long been used as a neuroleptic and antiemetic drug in clinical practice. Motor impairment and dyskinesia have been reported in some patients following chronic treatment with MET. Occasionally, the adverse symptoms may appear even after acute exposure to MET in more susceptible population (such as elderly individual) or due to concomitant exposure to MET and certain neurotoxins. Iminodipropionitrile (IDPN), a prototype nitrile toxin, has been shown to produce dyskinetic syndrome in rodents. This study reports the effect of concomitant exposure of rats to MET and IDPN on behavioral abnormalities in rats namely excitation, circling and chorea (ECC) syndrome. Four groups of female Wistar rats (aged 3 months) were given MET (0, 10, 40 and 80 mg/kg, i.p., for 11 days) 30 min before IDPN (100 mg/kg, i.p. for 8 days). Two additional groups of rats were treated with either saline (control group) or 80 mg/kg of MET (drug alone group). The animals were observed for neurobehavioral abnormalities including dyskinetic head movement, circling, tail hanging, air righting reflex and contact inhibition of righting reflex. Horizontal and vertical locomotor activities and fore limbs grip strength were also measured. On day 12, the animals were sacrificed and brains were collected for biochemical analysis. MET significantly and dose-dependently protected the animals against IDPN-induced ECC syndrome, motor impairment and deficiency in grip strength. MET also protected the animals against IDPN-induced oxidative stress.

Sex differences in behavioral, neurochemical and neuroendocrine effects induced by the forced swim test in rats

The forced swim test (FST) has been considered as a pharmacologically valid test of the depressive syndrome in rodents. However, few studies have focused on neurochemical and behavioral responses during FST in both male and female rats. Thus, we investigated certain behavioral and neuroendocrine responses as well as the serotonergic activity after the application of FST in both sexes. Our data show that the duration of immobility was increased in both male and female rats during the 2nd session of the FST. Sex differences are observed in some behavioral responses, such as head swinging that is mostly present in male rats. In female rats FST induced a decrease in serotonergic activity in hippocampus and hypothalamus while in male rats it induced an increase in serotonergic activity in hypothalamus. Corticosterone serum levels were elevated in both sexes. However, hippocampal GR mRNA levels tended to be increased in males and females respectively. Moreover, hypothalamic serotonin (5-HT) 1A mRNA levels were decreased in female rats while in male rats hippocampal 5-HT 1A mRNA levels were increased. These data have shown that FST induces “depressive like symptoms” in both sexes and provide evidence that sex differences characterize certain behavioral aspects in the FST. Notably, hippocampal and hypothalamic serotonergic activity has been differentially modified in male rats compared with female rats and these neurochemical findings could be relevant to the differentiated expression of 5-HT 1A receptor. Hypothalamic–pituitary–adrenal axis activity was also affected by FST application in a sex specific manner. The present results support that FST induced behavioral, neurochemical and neurobiological alterations, which are sex dependent.

Pyrethroid stimulation of ion transport across frog skin

Pyrethroids are grouped into two classes (types I and II) because of the absence or presence of an alpha-cyano substituent and the production of a different intoxication syndrome in rodents. In this study, we investigated the effect of pyrethroids on the ion transport across frog skin (Rana esculenta). The short-circuit current value (estimate of ion transport) was increased by each of the eight pyrethroids tested, with the following order of potency: lambda-cyhalothrin > deltamethrin > alpha-cypermethrin = beta-cyfluthrin > bioallethrin > permethrin > bioresmethrin > phenothrin. The first four compounds are type II pyrethroids. Therefore, ion transport is stimulated more by type II pyrethroids than by type I. Experiments performed in the presence of amiloride support the conclusion that pyrethroids mainly increase Na+ absorption and to a lesser extent Cl- secretion. In these experiments, no systematic difference between type I and II pyrethroids was found. Finally, the stimulation by pyrethroids was inhibited by indomethacin and W7 (inhibitors of cyclooxygenases and the Ca2+/calmodulin system, respectively). These observations suggest that pyrethroids do not directly affect the epithelial Na+ channel (ENaC) but indirectly influence an intracellular event involved in ENaC modulation and linked to the Ca2+ signaling cascade.

Influence of age on iminodipropionitrile-induced vestibular and neurobehavioral toxicities in rats

A direct association between aging and drug-induced dyskinesia has been reported by several investigators. Iminiodipropionitrile (IDPN), a prototype nitrile compound produces a motor syndrome in rodents, which resembles neuroleptic drug induced dyskinesia. In this investigation attempt has been made to study the effect of age on IDPN induced vestibular hair cell degeneration and resulting dyskinetic syndrome. Male Wistar rats aged 3, 6 and 12 weeks received IDPN in the doses of 0, 200 and 400 mg/kg, intraperitoneally for 3 consecutive days. IDPN-induced dyskinesia was assessed using a behavioral testing battery on days 3, 4, 5, 6, 7, 14, 21 and 28. The rats were sacrificed on day 28; temporal bones were excised for vestibular histopathology and sera were collected for measuring the indices of oxidative stress (glutathione and conjugated dienes). IDPN in the dose of 200 mg/kg produced dyskinesia in 12 weeks old rats, but failed to do so in 3 and 6 weeks old rats. The high dose of IDPN (400 mg/kg) caused dyskinesia in all age groups, however, its onset and severity were age-dependent. Older rats showed an early onset and significantly high incidence of dyskinesia as compared to younger rats. The susceptibility of rats to IDPN-induced behavioral deficits was proportional to oxidative stress and degeneration of sensory hair cells in the crista ampullaris.

Attenuation of iminodipropionitrile induced behavioral syndrome by sodium salicylate in rats

Iminodipropionitrile (IDPN) produces irreversible behavioral abnormalities characterized by excitation with choreiform and circling movements (ECC) syndrome in rodents. Concomitant exposure to drugs or environmental chemicals has been shown to alter IDPN-induced neurobehavioral toxicity. This investigation was undertaken to study the effect of sodium salicylate (SS) on IDPN-induced behavioral abnormalities in rats. The animals were exposed to IDPN (100 mg/kg ip) daily for 8 days. SS was administered daily 30 min before IDPN in the doses of 50, 100 and 200 mg/kg ip for 12 days. The animals were observed for neurobehavioral abnormalities including dyskinetic head movements, circling, tail hanging, air righting reflex and contact inhibition of the righting reflex. Horizontal and vertical locomotor activities and forelimbs grip strength were also measured. After behavioral studies, the animals were sacrificed, and the cerebrum and temporal bones were collected for glutathione analysis and inner ear histopathology, respectively. The onset of ECC syndrome was observed on Day 9 in the IDPN-alone group with 100% incidence on Day 12. Cotreatment with salicylate dose-dependently delayed the onset time and significantly attenuated the incidence and severity of IDPN-induced neurobehavioral signs. IDPN alone significantly increased horizontal motor activity and reduced vertical motor activity and forelimbs grip strength; these effect were significantly reversed by salicylate treatment. Treatment with salicylate also attenuated IDPN-induced depletion of GSH in the cerebrum, suggesting its free radical scavenging property.

Iris hypoplasia in mice that lack the alternatively spliced Pax6(5a) isoform.

PAX6 is an evolutionarily conserved transcription factor that plays a critical role in vertebrate and invertebrate eye formation. Heterozygous null mutations in the PAX6 gene result in aniridia in humans and a distinct small eye syndrome in rodents. Vertebrates primarily express two alternatively spliced isoforms of Pax6 that differ by the presence or absence of exon 5a (e5A) that encodes an additional 14 aa residues within the paired domain. The e5a-containing isoform, PAX6(5a), is specific to and conserved in vertebrates. To determine the role of PAX6(5a), we have generated mice that lack e5a of the Pax6 gene. Unlike Pax6 null mice that exhibit anopthalmia with central nervous system defects and lethality, 5a isoform-null mice have iris hypoplasia and defects in the cornea, lens, and retina. Although invertebrates have structures that respond to light intensity and act to restrict light exposure of the eyes, a significant and distinct feature of the vertebrate eye is its ability to regulate the amount of incoming light through contractile pupils. This feature of the eye not only allows vertebrates to see in various light conditions but also enhances image resolution. The requirement of the 5a isoform in iris formation suggests that the evolution of this isoform contributed to advanced features of the vertebrate eye.

Control of irritable bowel syndrome with polyamine analogs: a structure-activity study.

The evaluation of a group of polyamine analogs as agents to ameliorate diarrhea-predominant irritable bowel syndrome is described. Each compound was assessed when administered subcutaneously in a psychological stress-induced model of irritable bowel syndrome in rodents for its ability to reduce stool output in a dose-dependent manner. The spermine pharmacophore is shown to be an excellent platform from which to construct compounds to treat irritable bowel syndrome. The activity of the compounds is very dependent on both the nature of the terminal alkyl groups and the geometry of the methylene spacers separating the nitrogens. In addition to the subcutaneous studies, several compounds, N1,N11-diethylnorspermine, N1,N12-diethylspermine, N1,N12-diisopropylspermine, N1,N14-diethylhomospermine, N,N'-bis[5-(ethylamino)pentyl]-1,4-butanediamine, N,N'-bis[2-(4-piperidinyl)ethyl]-1,4-diaminobutane, and N,N'-bis[3-(ethylamino)propyl]-trans-1,4-cyclohexanediamine, were subsequently evaluated for oral efficacy. The remarkable activity of N,N'-bis[3-(ethylamino)propyl]-trans-1,4-cyclohexanediamine underscores the need to explore this framework further as a pharmacophore for the construction of other analogues to relieve the symptoms of diarrhea-predominant IBS.

Induction of obesity and hyperleptinemia by central glucocorticoid infusion in the rat.

It has been claimed that factors favoring the development or maintenance of animal or human obesity may include increases in glucocorticoid production or hyperresponsiveness of the hypothalamic-pituitary-adrenal axis. In normal rats, glucocorticoids have been shown to be necessary for chronic intracerebroventricular infusion of neuropeptide Y to produce obesity and related abnormalities. Conversely, glucocorticoids inhibited the body weight-lowering effect of leptin. Such dual action of glucocorticoids may occur within the central nervous system, since both neuropeptide Y and leptin act within the hypothalamus. The aim of this study was to determine the effects of glucocorticoids (dexamethasone) given intracerebroventricularly to normal rats on body weight homeostasis and hypothalamic levels of neuropeptide Y and corticotropin-releasing hormone. Continuous central glucocorticoid infusion for 3 days resulted in marked sustained increases in food intake and body weight relative to saline-infused controls. The infusion abolished endogenous corticosterone output and produced hyperinsulinemia, hypertriglyceridemia, and hyperleptinemia, three salient abnormalities of obesity syndromes. Central glucocorticoid infusion also produced a marked decrease in the expression of uncoupling protein (UCP)-1 and UCP-3 in brown adipose tissue and UCP-3 in muscle. Finally, chronic central glucocorticoid administration increased the hypothalamic levels of neuropeptide Y and decreased those of corticotropin-releasing hormone. When the same dose of glucocorticoids was administered peripherally, it resulted in decreases in food intake and body weight, in keeping with the decrease in hypothalamic neuropeptide Y levels. These results suggest that glucocorticoids induce an obesity syndrome in rodents by acting centrally and not peripherally.

Effect of bimoclomol (N-[2-hydroxy-3-(1-piperidinyl) propoxy]-3 pyridine-carboximidoyl-chloride) on iminodipropionitrile-induced central effects

Dyskinesia is frequently seen in neurological disorders affecting the basal ganglia. Iminodipropionitrile (IDPN) produces a somewhat similar motor syndrome in rodents, one that is a possible model for dyskinesia. Because in previous studies the compound (N- 2-hydroxy-3-(1-piperidinyl) propoxy -3 pyridine-carboximidoyl-chloride) (Bimoclomol, BRLP-42) was shown to provide pro- tection against IDPN-induced retinopathy; we investigated the effect of BRLP-42 on IDPN-induced motor changes and on IDPN- induced cerebral amino acid level changes in rats and mice. IDPN had a biphasic effect on motor activity in C57BL/6 mice: it was a depressant for 24 days and a stimulant after 30 days. Bimoclomol inhibited the motor depressant effect and enhanced the stimulatory effect of IDPN in this mouse strain. In BALB/cBy mice and Sprague Dawley rats IDPN produced persistent vertical head movements and changes in the level of glutamic acid in brain. Bimoclomol reduced the effect of IDPN on head movements and blocked the effect on cerebral glutamate; by itself it had no effect on motor activity in either species. Bimoclomol inhibited ischemia-induced [ 3H] norepinephrine release from rat hippocampal slices. Our findings indicate that Bimoclomol could have a beneficial effect on some dyskinesias, and on drug-induced vertical head movements.

Neuropeptide Y-Induced Feeding and Its Control

Publisher Summary This chapter critically reviews evidence of physiologically relevant appetite stimulation by neuropeptide Y (NPY) and to forecast how this knowledge might be applied in the context of eating disorders. Recently, a novel receptor for NPY, termed “Y5”, has been cloned from rat hypothalamus and appears to meet all the criteria necessary to be designated the “feeding” receptor distinct from previously cloned Y-type receptors. Striking appetite stimulation by NPY receptor agonists under pharmacological conditions can only elucidate the true physiological role of this neuropeptide if NPY receptor antagonists are found to be equally effective in blunting feeding produced under naturalistic conditions. Evidence for insulin actions on NPY gene expression was provided by studies that demonstrated that central infusion of insulin could depress elevated preproNPY mRNA levels induced by food deprivation of lean Zucker rats but was without effect on preproNPY mRNA content in fed or fasted obese Zucker rats. The extrapolation of the NPY-induced overeating and overweight syndrome in rodents to human obesity must await knowledge about the role of NPY in the human brain.

II. αN-acetyl human β-endorphin-(1–31) alleviates the morphine withdrawal syndrome in rodents: A comparative study with clonidine

The potential effect of intracerebroventricular (icv) αN-acetyl human β-endorphin-(1–31) on morphine dependence was examined in mice and rats. Animals were rendered tolerant-dependent by subcutaneous (sc) implantation of an oily suspension (10 ml/Kg mouse and 3 ml/Kg rat) containing 0.1 g/ml of morphine. After 72 h of chronic morphine, 1 mg/Kg sc naloxone precipitated in both species a withdrawal syndrome that was moderate in animals pretreated with the acetylated derivative of β-endorphin. Doses of 28 fmols/rat or 80 fmols/mouse αN-acetyl human β-endorphin-(1–31) reduced the number of animals presenting the jumping behaviour, as well as the number of jumps recorded. Moreover, less than half of the rats presented the other withdrawal signs evaluated: squeak on touch, diarrhoea, chattering, chewing, ptosis and body shakes. This activity could be observed when αN-acetyl human β-endorphin was injected 1 h to 24 h before naloxone; longer intervals resulted in a significant loss of this activity. The α 2 agonist clonidine given icv at pmol-nmol doses decreased the incidence of morphine withdrawal syndrome. Combinations of these two substances generally did not produce any further enhancement of the effects of clonidine and αN-acetyl β-endorphin when used alone. Icv injections of the antagonist of α 2-adrenoceptors yohimbine prevented both clonidine and αN-acetyl β-endorphin-(1–31) from reducing the jumping behaviour displayed by morphine-abstinent mice. It is suggested that αN-acetyl β-endorphin produces this alleviation of the morphine withdrawal syndrome by improving the efficiency of α 2-mediated agonist effects after acting on a neural substrate that is distinct from the μ opioid receptor binding site.

The receptor antagonist MK-801 induces increases in dopamine and serotonin metabolism in several brain regions of rats

MK-801 (dizocilpine maleate), a non-competitive, N-methyl-D-aspartate receptor antagonist which induces a characteristic phencyclidine-like motor syndrome in rodents, was administered to rats after handling habituation to examine the effects of this drug on concentrations of monoamines and their metabolites in 14 brain regions. MK-801 increased dopamine and serotonin metabolism in several regions, the most marked effects being determined in frontal and piriform cortex, nucleus accumbens and striatum. The data indicate that not only effects on dopaminergic transmission but also on serotonergic transmission may be involved in the pharmacological actions of MK-801.

Tumour Necrosis Factor Alpha (TNF‐α) and Interleukin 6 in a Zymosan‐Induced Shock Model

TNF plays a central role in septic shock induced by endotoxin or Gram-negative bacteria. Zymosan can elicit a septic shock-like syndrome in rodents in the absence of endotoxin. TNF and IL-6 release in mice treated with zymosan was investigated. One hour after intraperitoneal zymosan injection, maximal TNF levels were measured in serum, followed by IL-6 peak levels 1 h later. Treatment with a monoclonal antibody against TNF lowered zymosan-induced mortality from 63 to 11.6%, while maximal IL-6 levels were lowered by about 40%. Mechanisms triggering zymosan-induced cytokine release in murine macrophages were analysed in vitro. Cytokine release was only slightly triggered by uncoated zymosan particles. Thirty-nine per cent of TNF release by macrophages appeared to be triggered by zymosan-bound activated complement. Maximal TNF release also required the presence of natural antibodies against zymosan and zymosan-activated serum. In contrast, maximal IL-6 release was reached upon stimulation with zymosan-activated serum only, while the presence of zymosan particles lowered this response. We conclude that TNF is a crucial mediator in zymosan-induced shock. TNF release can be induced by different immunological pathways, without the need for the direct presence of endotoxins. Although IL-6 release during septic shock is partly dependent on TNF, in vitro trigger mechanisms for IL-6 and TNF differ remarkably.