Ryszard Szkilnik

Serotoninergics attenuate hyperlocomotor activity in rats. Potential new therapeutic strategy for hyperactivity

Hyperactivity is thought to be associated with an alteration of dopamine (DA) neurochemistry in brain. This conventional view became solidified on the basis of observed hyperactivity in DA-lesioned animals and effectiveness of the dopaminomimetics such as amphetamine (AMP) in abating hyperactivity in humans and in animal models of hyperactivity. However, because AMPreleases serotonin (5-HT) as well as DA, we investigated the potential role of 5-HT in an animal model of hyperactivity. We found that a greater intensity of hyperactivity was produced in rats when both DA and 5-HT neurons were damaged at appropriate times in ontogeny. Therefore, previously we proposed this as an animal model of attention deficit hyperactivity disorder (ADHD) — induced by destruction of dopaminergic neurons with 6-hydroxydopamine (6-OHDA (neonatally) and serotoninergic neurons with 5,7-dihydroxytryptamine (5,7-DHT) (in adulthood). In this model effects similar to that of AMP(attenuation of hyperlocomotion) were produced bym-chlorophenylpiperazine (m-CPP) but not by 1-phenylbiguanide (1-PG), respective 5-HT2 and 5-HT3 agonists. The effect ofm-CPP was shown to be replicated by desipramine, and was largely attenuated by the 5-HT2 antagonist mianserin. These findings implicate 5-HT neurochemistry as potentially important therapeutic targets for treating human hyperactivity and possibly childhood ADHD.

Effect of HMG-CoA (3-hydroxy-3-methyl-glutaryl-CoA) reductase inhibitors on the concentration of insulin-like growth factor-1 (IGF-1) in hypercholesterolemic patients

UNLABELLED Studies have shown that HMG-CoA reductase inhibitors (statins) play an important role in the prevention and treatment of atherosclerosis and hyperlipidemia. The aim of this study was to investigate the effect of 3-month treatment with simvastatin on serum levels of Insulin-Like Growth Factor-1 (IGF-1) in patients with diagnosed hypercholesterolemia. In total, 156 patients with hypercholesterolemia were recruited for the study. The inclusion criteria for this study were designed to allow the enrollment of a representative group of patients for cytokine studies. The patients were divided into two groups: (1) patients with a mild-to-moderate risk of heart disease, who had total cholesterol (TC) < 300 mg/dl (7.8 mmol/l), LDL-cholesterol < 210 mg/dl (5.4 mmol/l), and who lacked risk factors for coronary artery disease (CAD) after treatment with a diet for 3 months; (2) patients with a high-to-very high risk of CAD, who had TC > 300 mg/dl (7.8 mmol/l), LDL-cholesterol > 210 mg/dl (5.4 mmol/l), and at least two risk factors for CAD after treatment with a diet and administration of simvastatin (20 mg/day) for a three month period. The control group consisted of ten healthy volunteers who each had a normal lipid profile. Total cholesterol, LDL-cholesterol and IGF-1 concentrations were measured at baseline and either after six months of dietary supplementation (first group) or after three months of dietary supplementation and three months of simvastatin treatment (second group). CONCLUSIONS In patients with mild-to-moderate risk of CAD, a decreased serum concentration of IGF-1 was observed three months after beginning a low-fat diet. However, no changes in the serum concentration of IGF-1 were noted in patients with high-to-very high risk of CAD. Additional three-month treatment with simvastatin decreased the serum concentration of IGF-1.

Ontogenetic manganese exposure with perinatal 6-OHDA lesioning alters behavioral responses of rats to dopamine D1 and D2 agonist treatments

The effect of neonatal manganese (Mn) exposure in a 6-hydroxydopamine (6-OHDA) rat model of Parkinsons disease was investigated. Pregnant Wistar rats were given drinking water with 10,000 ppm of Manganese (MnCl₂.4H₂O) from the time of conception until weaning on the 21st day after delivery. Control rats consumed tap water. Three days after the birth, other groups of neonatal rat pups were pretreated with desipramine (20 mg/kg ip 1h) prior to bilateral ICV administration of 6-OHDA or its vehicle, saline-ascorbic (0.1%) (control). Two months after the birth, striatal dopamine and homovanilic acid efflux measured by an in vivo microdialysis method were reduced in rats lesioned with 6-OHDA. Co-exposure to perinatal Mn did not modify neurotransmission alterations. However, there were prominent abnormalities in behavioral testing in rats perinatally exposed to Mn and treated neonatally with 6-OHDA. These findings demonstrate that although Mn did not further damage neurotransmitter activity in the neostriatum, ontogenetic exposure to Mn enhances the behavioral toxicity to 6-OHDA.

Impairment in pain perception in adult rats treated with N-(-2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) as neonates

To examine the impact of a central noradrenergic lesion on antinociceptive effects of morphine, paracetamol and nefopam, we compared intact male rats with rats in which noradrenergic nerve terminals were largely destroyed with the neurotoxin DSP-4 [N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine; 50 mg/kg, sc ×2] shortly after birth, on the 1st and 3rd day of postnatal life. When the rats attained 10 weeks of age, painful reactions were assessed by means of the tail immersion test (thermal stimulus) and the paw pressure test (mechanical stimulus). In addition, monoamine levels in some parts of the brain were estimated using the high pressure liquid chromatography with electrochemical detection (HPLC/ED) method. In the tail immersion test, we showed that there were no differences in the antinociceptive effect evoked by morphine (5.0 mg/kg, sc) and paracetamol (100 mg/kg, ip) between control and DSP-4 rats. Nefopam (20 mg/kg, ip) elicited only slight analgesia in control rats (~17%), and this effect was not observed in the DSP-4 treated group; differences were statistically significant at 90 and 120 min of this test. In the paw pressure test we demonstrated that morphine produced lower analgesia in DSP-4 rats in comparison to the control, and the effect was significant at 60, 90 and 120 min of the test. The antinociceptive effect of paracetamol was also greatly diminished in the DSP-4 group and significant in all tested intervals. Nefopam produced only slight analgesia in both tested groups. In biochemical studies we showed that in DSP-4 treated rats there was a marked decrease in NA level in the prefrontal cortex (to 10.4%, p < 0.005), the thalamus with the hypothalamus (to 54.4%, p < 0.005) and the spinal cord (to 12.3%, p < 0.005) in comparison to the control group. Conversely, in the cerebellum and brain stem of rats with DSP-4 lesions there was a significant increase in the NA content vs. control (to 171.2% and 123.5% of NA, respectively, with p < 0.005 and p < 0.05, respectively). In the striatum we did not observe any changes in NA level between the examined groups. The levels of 5-HT and its metabolite 5-HIAA were also not altered by DSP-4 treatment in all tested structures with the exception of the spinal cord (approx. 40% decrease) and the level of DOPAC (also 40% reduction). In conclusion, obtained results showed that neonatal DSP-4 treatment alters the antinociceptive effects of tested drugs (each of them with a different mechanism of action). These data lead to the proposal that perhaps there is a need to adjust the doses of analgesics applied to patients with noradrenergic system dysfunction (e.g., depression and/or anxiety disorders).

Free Amino Acids in Cytosol of Rat Brain after Intraventricular Administration of 5,6-Dihydroxytryptamine and 6-Hydroxydopamine

Abstract Levels of 24 free amino acids were estimated in the brain after administration of 5,6-dihydroxy-tryptamine and 6-hydroxydopamine into the lateral brain ventricles of male Wistar rats. These neurotransmitters caused serotoninectomy and sympathectomy in the diencephalon, striatum, brain stem and medulla, thalamus and hypothalamus, cerebral cortex and cerebellum. The most abundant amino acids in these brain structures were: glutamic acid, serine, aspartic acid, cystine, gamma-aminobutyric acid, glycine, tryptophan and alanine. We detected and quantified changes in the levels of these and other amino acids in the investigated regions of the rat central nervous system, under the influence of these two neurotransmitters.