The aquatic ecosystem provides a base for the environmental pollutants that have potential to induce the anxiety-like behavioral response in aquatic animals. Benzo[a]pyrene (B[a]P) is a polycyclic aromatic hydrocarbon commonly associated with anxiety-like behavior. Kandhamal haladi (KH) has been used traditionally as anxiolytic drug. The present study is aimed to evaluate the anxiolytic role of Kandhamal haladi following exposure to waterborne B[a]P. Wild-type zebrafish (Danio rerio) were assigned as naive, control (dimethyl sulfoxide), B[a]P, KH, and B[a]P + KH groups. Behavioral studies showed reversal in scototaxis (light and dark preference) behavior in B[a]P group and reinstated by KH cosupplementation in B[a]P + KH group. Video-aided analysis of zebrafish behavior presents an increased range of behavioral endpoints, some of which are not available using manual observations. This protocol describes technique for accurate, consistent and fast video-aided measurements of zebrafish locomotion and anxiety-related behavior. The novel tank diving test and light/dark box experiments showed the anxiety response and allows comparison of anxiety induced behavior in experimental versus control groups. Cosupplementation of B[a]P with KH restored the normal scototaxis behavior of adult zebrafish. The findings confirmed anxiolytic nature of Kandhamal haladi.

Glutamate transmission plays an important role in many behavioral systems, including motor activity, learning, and memory. The noncompetitive NMDA receptor antagonist (+)MK-801 has been shown to increase motor activity and impair learning and memory in a variety of tasks in rats, mice, and other species. In an attempt to characterize the effects of MK-801 on motor activity and cognitive performance in an emerging neurobehavioral model, the zebrafish (Danio rerio), we examined the effects of MK-801 on circling behavior, swimming activity, and latency to enter, as well as preference for, an enriched chamber (EC). In Experiment 1, the effects of a 37-min acute exposure to (+)MK-801 (0, 2.0, and 20.0 μM) on circling behavior were measured in a round observation chamber. (+)MK-801 was observed to increase circling behavior in a dose-dependent manner. In the second experiment, fish were treated with 0, 2, 20, or 200 μM (+)MK-801 for 1 h, and swimming activity was measured in a rectangular observation chamber for 60 min following dosing. The lowest dose of (+)MK-801 decreased swimming activity. In the third experiment, fish were treated with either 0 or 20 μM (+)MK-801 for 1 h each day over four consecutive days. The fish were tested in a modified T-maze to assess both latency to enter, and preference for, an EC 24, 27, and 48 h after the last treatment. The results showed that untreated fish exhibited a preference for the EC at the 27- and 48-h trials, but (+)MK-801-treated fish did not exhibit a preference for the EC at any trial. No significant reduction in latency to enter the chamber was found for either treated or control fish. Together, the results of these experiments suggest that NMDA receptor antagonism (1) increases circling behavior, (2) alters swimming activity, and (3) impairs place preference. These findings lend further support for the usefulness of the zebrafish for assessing the acute and chronic exposure effects of water-soluble compounds on motor and cognitive functions.

Neonatal rat pups exposed to repetitive acute pain show decreases in pain threshold and altered behavior during adulthood. A model using prolonged inflammatory pain in neonatal rats may have greater clinical relevance for investigating the long-term behavioral effects of neonatal pain in ex-preterm neonates. Neonatal rat pups were exposed to repeated formalin injections on postnatal (P) days 1–7 (P1–P7), with or without morphine pretreatment, and were compared with untreated controls. Behavioral testing during adulthood assessed pain thresholds using hot-plate (HP) and tail-flick (TF) tests, alcohol preference, and locomotor activity (baseline and postamphetamine). Adult rats exposed to neonatal inflammatory pain exhibited longer HP latencies than controls and male rats had longer HP thresholds compared to females. Male rats exposed to neonatal morphine alone exhibited longer TF latencies than controls. Both neonatal morphine treatment and neonatal inflammatory pain decreased ethanol preference, but their effects were not additive. During adulthood, male rats exposed to neonatal inflammatory pain exhibited less locomotor activity than untreated controls. We conclude that neonatal formalin and morphine treatment have specific patterns of long-term behavioral effects in adulthood, some of which are attenuated when the two treatments are combined.

The long-lasting neurobehavioral effects of developmental exposure to NMDA antagonists (e.g., phencyclidine (PCP) and MK-801) are poorly understood. Exposure to these agents in adults produces a characteristic neuropathology that is associated with neuronal excitotoxicity and presumed behavioral consequences. The present studies were designed to determine if developmental PCP exposure results in alterations in the regulation of locomotor activity. Rats were dosed with saline or 7.5 mg/kg PCP on postnatal days (PNDs) 4-17 or 24-37. Ten and 20 days post-dosing, locomotor activity was measured for one hr following a challenge with either saline, 2.5 or 5.0 mg/kg PCP, 0.1 mg/kg MK-801 or 1.0 mg/kg d-amphetamine. In rats dosed on PNDs 24-37, PCP treatment resulted in decreased locomotor responses to both PCP and MK-801 challenges. PCP treatment on PNDs 4-17 did not result in any consistent effects. These results suggest that subchronic post-weaning exposure to PCP results in long-lasting decreases in the locomotor response to both PCP and MK-801. The mechanism(s) mediating these effects are unclear but might involve alterations in the regulation of NMDA systems that mediate locomotor activity.

We have previously reported that exposure to 10 mg/kg of all-trans-retinoic acid (RA) daily on the 11th, 12th, and 13th days of rat gestation is lethal to all fetuses so exposed, due to an inability to suckle [R.R. Holson et al., Neurotoxicol Teratol 19 (1997) 347-353]. Because this lethal RA effect could be due to any of a variety of causes, from olfactory problems in locating the nipple to a motor problem in sucking or swallowing, we performed the following experiment. Albino dams were exposed to 10-mg/kg RA or vehicle daily over gestational days (GDs) 11 to 13. On the afternoon of GD 21 all pups were delivered by c-section. Tongue cannulae were inserted into the oral cavity of these offspring, and used to infuse a solution of condensed milk directly into the mouth. During and after each of four infusions, the behavioral response to the infusion (typically rolling and curling) was recorded. Controls responded well to this procedure, typically swallowing all milk so infused. In contrast, almost no RA-exposed neonates were able to swallow milk infused into the oral cavity. In such cases the milk simply dribbled out of the mouth, while the stomach was found to be empty at autopsy. However, the RA-treated animals did seem aware that milk was entering their mouths, because they showed a normal behavioral response to milk infusion. We conclude that GD 11-13 retinoid lethality is due to motor not sensory problems in the control of swallowing.

Self-destructive behavior in current society promotes a search for psychobiological factors underlying this epidemic. Perinatal brain plasticity increases the vulnerability to early adverse experiences, thus leading to abnormal development and behavior. Although several epidemiological investigations have correlated perinatal and neonatal complications with abnormal adult behavior, our understanding of the underlying mechanisms remains rudimentary. Models of early experience, such as repetitive pain, sepsis, or maternal separation in rodents and other species have noted multiple alterations in the adult brain, correlated with specific behavioral phenotypes depending on the timing and nature of the insult. The mechanisms mediating such changes in the neonatal brain have remained largely unexplored. We propose that lack of N-methyl-D-aspartate (NMDA) receptor activity from maternal separation and sensory isolation leads to increased apoptosis in multiple areas of the immature brain. On the other hand, exposure to repetitive pain may cause excessive NMDA/excitatory amino acid activation resulting in excitotoxic damage to developing neurons. These changes promote two distinct behavioral phenotypes characterized by increased anxiety, altered pain sensitivity, stress disorders, hyperactivity/attention deficit disorder, leading to impaired social skills and patterns of self-destructive behavior. The clinical important of these mechanisms lies in the prevention of early insults, effective treatment of neonatal pain and stress, and perhaps the discovery of novel therapeutic approaches that limit neuronal excitotoxicity or apoptosis.

The nonlinearity and complexity of compartment pharmacokinetic models which are unavoidable in modern pharmacokinetic studies, indicate the possibility of fuzzy modelling approach also in this area. The latter, however, completely cancels the structural transparency of compartment models which is frequently of crucial importance. The work deals with the idea of partial fuzzification of compartment models, thus enabling the model to include advantages of both modelling methods. The concrete pharmacokinetic study of Phencyclidine, being potential drug of abuse, illustrates the sucessfiilness of the approach. It came out that the proposed fuzzification contributes to the more natural course of nonlinearities and parameter variabilities as well as to the interpretability of some mechanisms in the investigated process.

Gestational cocaine (COC) exposure has been reported to alter behavior and possibly dopamine (DA) receptors. In this paper, we further examined the effects of prenatal COC (40 mg/kg, s.c.) on DA receptor binding and the behavioral response to quinpirole, a DA D-2 receptor agonist. In an attempt to elucidate possible mechanisms of such effects, we exposed pregnant dams to specific reuptake blockers; fluoxetine 12.5 mg/kg, a serotonin reuptake blocker; desipramine 10 mg/kg, a norepinephrine reuptake blocker; GBR-12909 10 mg/kg, a DA reuptake blocker; or to a local anesthetic, lidocaine 40 mg/kg. Drugs were administered once daily over gestational days 8-20. Control dams were injected with saline (SAL) or pair-fed to the COC group. Quinpirole challenge was performed in the offspring on post natal day 19. Two pups per litter were injected (s.c.) with 0.03 or 0.09 mg/kg quinpirole-HCl on post-natal day 19. The remaining pups in each litter were sacrificed for analysis of-striatal DA receptors. Results showed that only COC exposure altered the behavioral response to the quinpirole challenge by increasing quinpirole-induced stereotypy and motor activity relative to SAL controls. DA receptor analysis showed no alteration in K-D or B-MAX for striatal D-1 or D-2 sites in any group. These results suggest that prenatal COC exposure produces alterations in function of the D-2 receptor complex which are not reflected in K-D or B-MAX and that these effects are not fully mimicked by exposure to specific monoamine reuptake blockers or a local anesthetic.

Leptin is a hormone produced by adipocytes that regulates body weight and has been found to correlate with the percentage of body fat in children and adults. In addition, leptin is also produced by the placenta and a positive correlation between cord blood leptin levels and birthweight suggests a role for leptin as a fetal growth factor. In the premature infant several studies have demonstrated a higher accretion of body fat when compared to fetuses of the same post-conceptual age and accurate measures of body fat might be useful in guiding nutritional decisions in this population. In this initial study we therefore set out to examine leptin levels in the very low birthweight infant and correlate with other measures of body fat including skinfold measurements and dual energy x-ray absorptiometry (DEXA). Four infants with a mean birthweight of 890 grams and gestational age of 27.7 weeks were studied. Infants were greater than 1 week of age and initiating feeds at enrollment and underwent weekly anthropometric measurements in addition to serum leptin levels until discharge or back transport. All infants manifested adequate weight gain and linear growth as well as increases in skinfold thickness suggesting deposition of subcutaneous fat. In addition, one infant underwent DEXA evaluation revealing 7.3% body fat at one month of age which increased to 9.3% at seven weeks of age. However, no serum leptin was detected in this infant at the time of the DEXA measurements. Suprisingly only one of the four infants had detectable serum leptin with a mean level of.19 ng/ml utilizing an ultrasensitive RIA. We conclude that serum leptin as it is currently measured is not useful to predict body fat mass in the very low birthweight infant. We further speculate that the lack of detectable leptin may be important in altering the extrauterine accretion of body fat in the prematurely born infant.

Development exposure to drugs of abuse can produce adverse neurobehaviouraI and cardiovascular effects. The acute and residual motor and cardiovascular effects of animal models of human neonatal exposure to phencyclidine and cocaine are poorly understood. Therefore the pharmacokinetical models of both drugs were developed to elucidate mechanisms influencing mentioned drugs kinetic behaviour. Several model structures were validated by the aid of measured and simulated data using different simulation tools. It came out that increased blood pressure and hean rate following i.v. administration of both drugs is the consequence of high blood levels in distribution phase while prolonged locomotor increases are associated with the elimination phase.