Neonatal 6-hydroxydopamine-induced dopamine depletions: motor activity and performance in maze learning.

Three experiments were performed to study the effect of dopamine (DA) depletions, induced by neonatal intracerebroventricular (ICV) treatment with 6-hydroxydopamine (6-OHDA), upon measures of spontaneous motor activity. Instrumental learning for food reward in an Olton radial arm maze and escape learning from a large, circular water maze were studied also. Motor activity was measured by direct observation of rats in a modified radial arm maze and by use of automated test cages equipped with photocell devices. 6-OHDA-treated rats demonstrated considerable and long-lasting locomotor (ambulation) activity and total activity increases. 6-OHDA-treated rats showed notably less rearing activity than the vehicle-treated rats during the initial 20 min of each 60-min test period. However, over the second half of these 60-min test periods, the 6-OHDA-treated rats demonstrated significantly more rearing activity than the vehicle-treated rats. In the acquisition of the running response, to obtain the 8 food pellets placed in each of the 8 arms of the radial arm maze, 6-OHDA rats showed a retarded acquisition, as measured by the latency and number of arms visited to acquire all eight pellets. 6-OHDA-treated rats failed completely to acquire the Morris-type swim maze task by which they were required to locate a platform just under the water surface in a circular water tank. The neurochemical assays indicated severe DA depletion in several forebrain regions. The present findings add to existing indications of the potential of this DA depletion condition as an animal model of the minimal brain dysfunction syndrome.

Hyperactivity and instrumental learning deficits in methylazoxymethanol-treated rat offspring.

Several changes of spontaneous motor and learned behaviours were obtained in the male offspring of pregnant rats that were treated on gestation day 15 with the antimitotic agent methylazoxymethanol (MAM, 25 mg/kg). MAM-treated offspring, when tested at adult ages, showed notable increases in motor activity parameters as measured by direct observation or in automated photocell test cages. This hyperactive state was accompanied by clear impairments by MAM offspring in the acquisition of instrumental learning in a radial arm maze and in a circular swim maze. In Skinner boxes, MAM offspring made fewer responses during the Fixed Ratio (FR) 1 schedule but did not differ from the saline offspring in the acquisition of the difficult differential-reinforcement-of-low-rates (DRL) 72 sec task. Neurochemical assays indicated that the MAM rats had elevated noradrenaline and dopamine levels in several brain regions. These findings are discussed with regard to possible alterations of habituation processes in MAM rats.

Lack of effects of prenatal exposure to lidocaine on development of behavior in rats.

The objective of this investigation was to study the effects of lidocaine upon postnatal development of the rat. Lidocaine, 6 mg/kg (21 mumol/kg), was given to a group of 12 rats. Injections were administered intramuscularly, bilaterally in the masseter muscles, once a day on days 10 and 11 of pregnancy. Twelve control rats were given physiologic saline. Clinical signs, mortality, body weight, and food consumption were recorded during pregnancy and lactation. The duration of gestation was also recorded. The development of the offspring was monitored by tests of spontaneous activity, nociception, learning ability, and physical development. No clinical signs of adverse reactions were seen in any of the groups. In the majority of the learning ability tests, the control and lidocaine-treated groups showed similar results. However, in the schedule of differential reinforcement of low rates of responding (DRL 20), the lidocaine-exposed males received more reinforcements than the controls and made fewer responses. In the tests of nociception, a significant difference between sexes was recorded, in that the females were more sensitive than the males in the shock-titration test. Physical development, as monitored by swimming ability and spontaneous activity, showed no inter-group difference. The present results indicate that prenatal exposure to lidocaine fails to result in postnatal impairment of the development of behavioral performance of a wide range of tasks.

LD50 - its value for the pharmaceutical industry in safety evaluation of drugs.

Does the pharmaceutical industry perform LD50-determinations in animals just because it is required by the authorities or are there any scientific benefits from counting dead animals and calculating and index of lethal toxicity? This is an important question when discussing LD50 and possible alternatives. We will try to answer this question by presenting data and some views collected during almost ten years at a Swedish pharmaceutical company. We will describe how we have made use of the LD50-values in the safety evaluation process. We will compare LD50-values with the dose levels used in longterm toxicity both after single or repeated administration and with therapeutical dose levels in man for different classes of drugs. These data will enable us to demonstrate the value of the LD50-determinations. As we are of the opinion that the LD50-value itself has a limited value for the total safety evaluation of drugs we will look into the possibility of replacing the LD50-determination with something else as an indication of lethal toxicity. In order to minimize the number of animals used and the number of animals dying because of dosing in studies on lethal toxicity we will try to support a proposal to use the maximal nonlethal dose (MNLD) as an indication of lethal toxicity in small animals.

Degradation of ochratoxin A by a ruminant.

The fate of ochratoxin A during incubation with contents from the four stomachs of the cow was studied. It was concluded that ochratoxin A was cleaved into the nontoxic ochratoxin alpha and phenylalanine by the contents from all but the abomasum.