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Gender differences in escape-avoidance behavior of mice after haloperidol administration.

Gender differences in the disruptive effects of haloperidol on some reinforced behaviors have been observed in different species. However, the inhibitory action of haloperidol on the acquisition and performance of escape-avoidance behavior has only been investigated in male subjects. The present experiment was designed to investigate possible gender differences in the effects of haloperidol on the initial phase of an escape-avoidance learning task. Male and female mice of the OF1 strain were given a single training session in a shuttle-box. Thirty minutes prior to the behavioral test, mice were injected IP with haloperidol (0.25 mg/kg) or physiological saline (10 ml/kg). Latencies of escape and avoidance responses and the number of nonresponses, escapes, avoidances, pseudoavoidances, crossings during the adaptation period, and crossings during intertrial intervals (ITIs) were evaluated. The disruptive action of haloperidol on the escape-avoidance behavior of the mice was greater in males than in females. The number of nonresponses were higher and the number of escapes lower in treated males than in their female counterparts. These gender differences were not found in control subjects. Activity measures of spontaneous motor behavior (crossings in the adaptation period and during ITIs) did not present gender differences either. Several possible mechanisms responsible for this greater susceptibility of males to the inhibitory effects of haloperidol on escape-avoidance learning are discussed, especially the modulating role of female hormones on dopaminergic activity.

Animals↗

[Application of operant conditioning techniques to forensic toxicology: experimental studies on alcohol and abusable drugs].

This paper describes some experiments that apply the operant conditioning techniques to forensic toxicological research. These techniques may be useful in investigating the mechanisms of action, toxic symptoms, legal competence and drug metabolism associated with substance abuse such as abuse of alcohol, psychotropic drugs, narcotics, stimulants, and organic solvents. 1) Genetic research on alcohol preference in rats. We applied operant conditioning to investigate alcohol preference in rats and constructed an apparatus for the measurement of discriminated operate responses for water or alcohol reinforcement in rat. This apparatus is a modified Skinner box with a one-lever two-liquid system. Fixed ratio-10 (FR-10) schedules of reinforcement are used to increase the work of the rat before it obtains the reinforcement. The voluntary choice of water or 10% ethanol by the rat can be assessed quantitatively by measuring the lever-pushing responses. It is an extremely useful method for measuring the real alcohol preference of rats. A rat was kept in a Skinner box overnight. The numbers of responses and reinforcement for water and ethanol and the volumes of the two liquids consumed were recorded. The ratio of ethanol reinforcement was defined as the number of ethanol reinforcement to the total number of ethanol and water reinforcement. The ratio of ethanol intake was defined as the volume of ethanol consumed to the volume of water and ethanol consumed. Ethanol consumption per g body weight was calculated from the volume of ethanol consumed by the rat. We used this apparatus to investigate alcohol preference of more than 300 Wistar Albino Rats, and divided them into a high alcohol preference (HAP) group and a low alcohol preference (LAP) group. Inbreeding between littermates was conducted in each of the HAP and LAP groups. The liver tissue of each offspring was obtained and the cytosol fraction was collected and subjected to isoelectric focusing using polyacrylamide gel with a pH range of 3.5 to 9.5. Examination of the electrophoretic patterns of the acetaldehyde dehydrogenase (ALDH) revealed polymorphism in cytosolic ALDH 1. We confirmed that the polymorphism follows Mendel's law of inheritance, and is governed by two codominant alleles. Moreover, the polymorphism of ALDH 1 observed in Wistar strain rats correlated closely with the differences in ethanol consumption behavior or alcohol preference. 2) Effects of abusable drugs on learning behavior of rat. In general, animal experiments for assessing drug effects, regardless whether they measure learning or intrinsic motor or physiological function, use behavioral indicators that produce a positive or negative reinforcement. In other words, the behavioral effect of a drug is assessed by whether it enhances the animal's behavior in a positive reinforcement or decreases its response in a negative reinforcement. However, the behavioral indicator of the animal is rarely an independent entity within the body, but is closely associated with other behavioral components. Even when a behavioral indicator is enhanced by a drug, whether the apparent increase is due to the enhancing effect of the drug or a result of decreases of other behavioral components cannot be judged. We therefore devised a multiple active/passive avoidance learning apparatus which is a device for analyzing drug effects in rats using a running-wheel. We used this device to assess the effects of a drug on the animal from three dimensions simultaneously; excitatory, inhibitory and discriminatory behaviors. From these we attempted to clarify the overall effect of the drug on high order learning behavior of animal. This method enables direct examination of the so-called "learning capability" of an animal, which cannot be elucidated by single scheule learning that is strongly influenced by behavioral characteristics such as excitation and inhibition. Therefore, a method which uses avoidance learning as indicator is the best method

Aldehyde Oxidoreductases↗

The specific dopamine uptake inhibitor GBR 12783 improves learning of inhibitory avoidance and increases hippocampal acetylcholine release.

The specific dopamine uptake inhibitor, GBR 12783 was tested on the retention performance of a one-trial passive avoidance test. For a moderate electric shock intensity, GBR 12783 (10 mg/kg), injected before acquisition session, improved retention performance. Scopolamine (0.125-0.5 mg/kg) completely blocked the promnesic effect of GBR 12783. Moreover, GBR 12783 increased hippocampal acetylcholine release in vivo. These data suggest that the promnesic effect of GBR 12783 is mediated by an increase in the septo-hippocampal cholinergic transmission.

Acetylcholine↗

[Effects of peri- and postnatal lead administration on learning of high avoider rats].

Effects of administration of lead acetate on Sidman avoidance behavior were assessed in juvenile and adult rats which were obtained by continued selective breeding and which have a high level avoidance ability and small individual differences (THA rat: Tokai high avoider rat). THA rats were administered lead acetate solution at 200-300 mg/kg/day as Pb until 7 wk of age through maternal milk before weaning from mothers which had been administered lead acetate from the 13th day of gestation and per os by gastric tube after weaning. Three series of Sidman avoidance behavior tests were conducted from 49th, 100th and 150th day after birth each for 10 d, 1 h every day. In the first series, a significant delay of shock avoidance acquisition was observed in lead-administered male rats compared with the control subjects, while no acquisition delay was seen in female rats. The lead administered male rats could be divided into two groups with different response patterns; a low susceptible group (LSG) which exhibited as good acquisition rate from the beginning similar to the control rats and a high susceptible group (HSG) which showed a significant delay and individual differences. In the 2nd test series, very high avoidance rates were obtained in all the test groups except in male HSG, but in the 3rd test series, male HSG also attained a final acquisition of high avoidance rate. There was no developmental variation between the groups nor difference in lead contents of the organs of the exposed group. Useful characteristics of THA rats for behavioral toxicology are discussed.

Animals↗

N-Methyl-D-aspartate receptor antagonist MK-801 and radical scavengers protect cholinergic nucleus basalis neurons against beta-amyloid neurotoxicity.

Previous experimental data indicate the involvement of Ca(2+)-related excitotoxic processes, possibly mediated by N-Methyl-D-Aspartate (NMDA) receptors, in beta-amyloid (beta A) neurotoxicity. On the other hand, other lines of evidence support the view that free radical generation is a critical step in the beta A-induced neurodegenerative cascade. In the present study, therefore, a neuroprotective strategy was applied to explore the contributions of each of these pathways in beta A toxicity. beta A(1-42) was injected into the magnocellular nucleus basalis of rats, while neuroprotection was achieved by either single or combined administration of the NMDA receptor antagonist MK-801 (2.5 mg/kg) and/or a vitamin E and C complex (150 mg/kg). The degree of neurodegeneration was determined by testing the animals in consecutive series of behavioral tasks, including elevated plus maze, passive avoidance learning, small open-field and open-field paradigms, followed by acetylcholinesterase (AChE), choline-acetyltransferase (ChAT), and superoxide dismutase (SOD) biochemistry. beta A injected in the nucleus basalis elicited significant anxiety in the elevated plus maze, derangement of passive avoidance learning, and altered spontaneous behaviors in both open-field tasks. A significant decrease in both AChE and ChAT accompanied by a similar decrement of MnSOD, but not of Cu/ZnSOD provided neurochemical substrates for the behavioral changes. Each of the single drug administrations protected against the neurotoxic events, whereas the combined treatment failed to ameliorate beta A toxicity.

Acetylcholinesterase↗

Passive avoidance training decreases synapse density in the hippocampus of the domestic chick.

The bird hippocampus (Hp), although lacking the cellular lamination of the mammalian Hp, possesses comparable roles in spatial orientation and is implicated in passive avoidance learning. As in rodents it can be divided into dorsal and ventral regions based on immunocytochemical, tracing and electrophysiological studies. To study the effects of passive avoidance learning on synapse morphometry in the Hp, spine and shaft synapse densities of 1-day-old domestic chicks were determined in dorsal and ventral Hp of each hemisphere by electron microscopy, 6 and 24 h following training to avoid pecking at a bead coated with a bitter-tasting substance, methyl anthranilate (MeA). The density of asymmetric spine and shaft synapses in MeA-trained birds at 6 h post-training was significantly lower in the dorsal and ventral Hp of the right hemisphere relative to control (untrained) chicks, but by 24 h this difference was absent. A hemispheric asymmetry was apparent in the ventral Hp where the water-trained group showed enhanced shaft and spine synapse density in the left hemisphere, whilst in the MeA-trained group only asymmetric shaft synapses follow the same pattern in relation to the right hemisphere. There were no differences in asymmetric shaft synapses in the dorsal Hp at 6 h post-training, but at 24 h post-training there was a reduction in the density of shaft synapses in the right hemisphere in MeA compared with control birds. These data are discussed in relation to the pruning effects of stress and learning on synapse density in chick Hp.

Analysis of Variance↗

Taste avoidance, but not aversion, learning in rats lacking gustatory cortex.

Control rats rapidly learned to avoid drinking either a sucrose solution (Experiment 1) or a NaCl solution (Experiment 2) when the taste was paired with illness. These rats also produced aversive reactivity to each of these solutions in a taste reactivity test. Rats that lacked gustatory cortex (GC) learned to avoid drinking sucrose and NaCl, albeit at a slower rate than control rats. GC rats failed to display aversive reactivity to these tastes. The GC rats did show normal aversive reactivity to a strong quinine HCl solution during additional tests. It is suggested that the avoidance developed by GC rats did not entail a palatability shift of the conditional stimulus as it did in control rats. This altered learning strategy may account for the consistent learning deficits found in GC rats trained to avoid tastes.

Animals↗

Parafascicular electrical stimulation attenuates nucleus basalis magnocellularis lesion-induced active avoidance retention deficit.

Previous experiments from our laboratory showed that retention of two-way active avoidance learning is improved by post-training intracranial electrical stimulation (ICS) of the parafascicular nucleus (PF) and impaired by pre-training electrolytic lesions of the nucleus basalis magnocellularis (NBM). The question investigated here was whether post-training PF ICS is able to attenuate the active avoidance retention deficit observed in rats lesioned pre-training in the NBM. To this goal, the following experimental design was used: rats bilaterally lesioned in the NBM and stimulated in the PF, rats lesioned in the NBM, rats stimulated in the PF, control rats implanted in the PF, and sham-operated rats were first trained in a shuttle-box for a single 30-trial session and tested again following two successive retention intervals (24 h and 11 days). The results showed that: (1) NBM lesions impaired the 11-day performance without affecting either the acquisition or the 24-h retention of the avoidance learning; (2) PF ICS treatment in unlesioned rats improved performance in both retention sessions only when the stimulation was applied in the posterior region of the nucleus; and (3) stimulation of the posterior PF compensated the 11-day retention impairment induced by NBM lesions. These results are discussed in relation to the interaction of arousal systems in the modulation of cognitive processes.

Animals↗