Zoltan Annau

Evidence that exposure to methyl mercury during gestation induces behavioral and neurochemical changes in offspring of rats

On day 15 of gestation, pregnant Sprague-Dawley rats were orally treated by gavage with 8 mg/kg of methyl mercury (MMC). At day 1 of postnatal life the levels of MMC in whole brain of exposed pups were found to be about 100 times higher than those of saline-exposed rats, while they were near to the control values at 21 days and practically normal at 60 days of age. Behavioral experiments showed that exposure to MMC in late gestation did not affect at any tested time (14, 21 and 60 days) locomotor activity or development of ultrasonic vocalization. An increased response to a challenge dose of amphetamine was, however, detected in MMC-exposed pups at day 14. This phenomenon was no longer evident at day 21 and 60 of age. In parallel, an increased density of dopamine receptors was found in the striatum at 14, but not at 21 and 60, days of age. From these data, we tentatively suggest that a high level of MMC induces a transient phenomenon of disuse-supersensitivity of the dopaminergic system. Moreover, further evidence that acute MMC exposure during prenatal life might induce permanent disturbances in learning and memory which could be partially related to a reduced functional activity of the glutamatergic system is provided.

Behavioral withdrawal following several psychoactive drugs

The chronic administration of several psychoactive drugs has been suggested to produce behavioral withdrawal syndromes in the absence of physical withdrawal. The present study employed four representative psychoactive drugs, amphetamine, chlorpromazine, iproniazid, and desipramine, in a common behavioral paradigm using electrical stimulation of the brain to test for behavioral withdrawal. Behavior differing from both predrug and drug produced behavior occurred following the termination of amphetamine, iproniazid and chlorpromazine administration. The first two drugs produced an increase in self stimulation during administration, followed by a very significant decrease after the drugs were discontinued. Chlorpromazine administration on the other hand, produced a decrease in self stimulation rates, followed by a rebound increase after termination of treatment. No systematic effects were observed with desipramine. The relationship between the behavioral effects of these drugs during and following treatment and possible homeostatic mechanism influencing response tendencies is discussed.

Acetylcholine Receptor-Based Biosensor

Abstract The acetylcholine (ACh) receptor protein isolated from Torpedo electric organ was incorporated into asolectin liposomes and immobilized noncovalently on the surface of a Planar Interdigitated Capacitive sensor to produce an ACh receptor-based biosensor. Capacitance of the biosensor, which was stable in buffered saline, increased rapidly when ACh was added. The response was dosedependent and specific for ACh, and the biosensor did not respond to six other neurotransmitters. Impure receptor preparations containing ACh esterase produced a smaller signal in response to ACh but showed enhanced response after inhibition of ACh esterase with diisopropylfluorophosphate. The competitive antagonist d-tubocurare, and the noncompetitive antagonist amantadine, inhibited the response of the biosensor to ACh, but a time-dependent recovery occurred upon perfusion with ACh. The irreversible antagonist α-neurotoxin inhibited the response and there was no recovery following perfusion with ACh. Thus, the pharmacolog...

Flash evoked potentials from rat superior colliculus

In view of reports that the superior colliculus evoked potential from rats is uniquely sensitive to toxic gases, the present study characterized normal flash evoked potentials from unanesthetized rats. The waveform was complex, with at least 5 positive and 5 negative peaks. The waveform originated in the SGS layer, and some components were stable over time if conditions of light intensity, stimulus frequency and dark adaptation were held constant. The greater complexity of the waveforms reported here compared to those described by others can be attributed to both an intense flash stimulus and unanesthetized preparation.

Evoked potential alterations following prenatal methyl mercury exposure.

Pregnant hooded rats were administered either 5 mg/kg CH3, Hg or 0 mg/kg CH3 Hg by gastric intubation on day seven of gestation. Female offspring were implanted with recording electrodes 60 days after birth and had their cortically recorded visual evoked potentials studied at four different flash intensities. Mercury exposed animals had higher P1-N1 and N1-P2 amplitudes and shorter P2 and N2 latencies than controls. The data provides evidence that a single ingestion of CH3 Hg by pregnant rats is sufficient to produce long term alterations in CNS activity.

Postnatal behavioral effects in mice after prenatal exposure to methylmercury

CFW mice were injected with methylmercury hydroxide (1, 2, 3, 5 or 10 mg/kg as mercury) on Day 8 of gestation. Mice treated with 3, 5 or 10 mg/kg averaged 1/3 fewer pups than controls. Pups from these treated animals weighed less than controls and the weight differences persisted through weaning but were no longer significant at 56 days of age. Mice exposed to methylmercury in utero showed significant differences from controls in their behavior in a 2-way active avoidance shuttle box and in a punishment situation but not when tested in an open field, a water escape runaway or a conditioned suppression paradigm. Neither the mothers nor progeny of the mice exposed prenatally to methylmercury showed bahavioral deficits.

Mechanisms of neurotoxicity and their relationship to behavioral changes

In this review some of the evidence relating behavioral alterations induced by 2 neurotoxic chemicals, lead acetate and methyl mercury is presented with an attempt to relate these changes to the underlying neurobiological mechanisms. In the case of neonatal lead poisoning, the results of the early behavioral studies were confounded by excessive lead concentrations resulting in undernutrition of the pups. Subsequent studies in both rodents and monkeys have shown that blood-lead concentrations comparable to those seen in children can induce behavioral alterations that may be related to hippocampal damage. In the case of methyl mercury which is a potent cytotoxic agent, prenatal exposure results in widespread cortical, and cerebellar alterations characterized by reduced myelination, delayed migration and loss of neurons. These morphological alterations are accompanied by permanent alterations in learning and memory as well as altered pharmacological sensitivity in catecholaminergic systems. Recommendations are made for better formulated behavioral and neurobiological assays in neurotoxicology in order to lead to a better understanding of the toxicity of chemicals.

Chunking, sorting, and rule-learning from serial patterns of brain-stimulation reward by rats

Three studies tested the notion that rats would treat brain-stimulation reward (BSR) as a stimulus alphabet from which rules could be abstracted to learn serial patterns. In Experiment 1, rats learned to track a serial pattern of 18-10-6-3-1-0 pulses of BSR, responding fast in anticipation of large quantities of BSR and slowly or not at all in anticipation of small quantities of BSR. In Experiment 2, rats learned to track a formally simple 18-6-1-0 pattern faster than a formally complex 18-1-6-0 pattern in a within-subjects procedure, indicating that rats can learn to discriminate between simple and complex pattern structures. Finally, in Experiment 3 rats learned either a formally simple 25-18-10-3-1-0 or a formally complex 25-3-10-18-1-0 pattern whose successive elements were separated by an embedded three-element 6-6-0 subpattern. Rats learned to “chunk together” the dispersed pattern elements, and rats receiving the simple pattern learned to track their pattern, whereas rats receiving the complex pattern did not. The latter results suggest that when simple pattern structure is available, rats can simultaneously track rule structures in at least two memory locations. The results of these experiments, using a new testing procedure and, presumably, a new stimulus alphabet, generalize and extend the idea that rats can abstract relational rules to learn serial patterns.

Electrical self-stimulation of single and multiple loci: long term observations.

Abstract Rats with chronic hypothalamic electrodes were allowed continuous access to self-stimulation, food and water in a 3 lever chamber. A prolonged burst of self-stimulation, with little food and water intake, was followed by bursts of activity on all 3 levers. A 12 hr light-dark cycle imposed a diurnal periodicity on all behaviors except in animals self-stimulating at the highest daily rates where self-stimulation was equal in dark and light. Under constant light conditions there was a 30 min daily shift in the peak periodicity of all behaviors. Increasing the current by 10 μA led to another continuous self-stimulation session for one day, with a subsequent decline and stabilization after three days. Reduction of the current to its original setting abolished self-stimulation for one day, but within 5 days rates returned to control values. Animals with electrodes in the septal, anterior and posterior hypothalamic areas allowed continuous access to self-stimulation on all 3 electrodes displayed similar behavior in that after a long initial self-stimulation session alternating on all 3 electrodes, periodic bursts of activity occurred on all three electrodes. The diurnal periodicity of self-stimulation seemed to be determined by the current intensity. The similarity of self-stimulation to normal drive mechanisms is discussed.

Serial-pattern-learning processes dissociated by trimethyltin exposure in rats

Trimethyltin (TMT) is a neurotoxic organometal which produces a variety of learning and memory impairments in laboratory animals and humans, including impairments of avoidance learning, maze learning, and problem solving. Two studies investigated the effects of TMT exposure on serial-pattern learning in rats. Rats in both experiments were intubated once with either 0 or 7.0 mg/kg TMT 1 week prior to the pattern-learning procedure. Rats learned serial patterns composed of various quantities of brain-stimulation reward (BSR) pulses; they received BSR quantities in a predetermined order for leverpresses in a discrete-trial operant task. In Experiment 1, all rats received two serial patterns (20-10-0 vs. 1-29-0 pulses of BSR) that alternated within each daily session of 100 patterns. In Experiment 2, all rats received two serial patterns (18-10-6-3-1-0 vs. 18-1-3-6-10-0 pulses of BSR) that alternated within each daily session. In Experiment 1, TMT-exposed rats learned both their patterns more slowly than did controls. In Experiment 2, TMT-exposed rats learned the formally simple 18-10-6-3-1-0 pattern of BSR quantities faster than did controls, but were significantly slower than controls in learning the formally more complex 18-1-3-6-10-0 pattern. In both experiments, however, TMT exposure did not affect either the reinforcing properties of BSR or rats’ asymptotic performance. These results support the notion that TMT exposure impaired some aspects of the rote processes involved in serial-pattern learning in rats, yet spared the rats’ ability to encode some representation of the formal rule-based structure of the pattern. The results thus suggest that the processes involved in learning simple versus complex serial patterns may be mediated by different systems in the brain.