Influence of flumazenil on the learning-enhancing effect of ambocarb in rats.

The effects of flumazenil (Ro 15-1788) and a new beta-carboline, ambocarb (AMB), on learning were investigated using the multichoice maze. The drugs, administered either alone or simultaneously, were injected once a day before training for eight days. AMB, administered alone, improved the performance and decreased the working errors, whilst flumazenil had no effect on performance during its sole administration but weakly prevented the learning-improving effect of AMB. More significantly, flumazenil antagonized the motor activity depressed by AMB. In the study ex vivo, flumazenil decreased and AMB increased the apparent affinity of [3H]flunitrazepam to the central benzodiazepine receptors. Flumazenil reversed the action of AMB on the central benzodiazepine receptors, but failed to reduce significantly the modulative effects of AMB on [3H]muscimol and [35S]t-butylbicyclophosphorothionate ([35S]TBPS) binding. These data indicate that flumazenil, due to its action on the central benzodiazepine receptors, more effectively reverses the inhibition of motor activity than the performance-improving effect of AMB.

Acute neurobehavioural effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in Han/Wistar rats.

The neurobehavioural effects of a single non-lethal dose (1000 micrograms/kg intraperitoneally) of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) were assessed in young male Han/Wistar rats, highly resistant to acute lethality of TCDD. TCDD decreased body weight significantly compared with ad libitum fed controls. TCDD did not change the behaviour or the motility of rats in the open field test 8 days after the treatment nor did it affect the spontaneous motor activity up to 27 days after the exposure. In the elevated plus-maze test for anxiety, TCDD-treated rats did not differ from either ad libitum fed controls or pair-fed controls. In the 24-hr passive avoidance test, the learning of TCDD-treated rats did not differ significantly from that of ad libitum fed controls or pair-fed controls from 8 hr to 16 days after the treatment. TCDD did not affect the motor coordination or the maintenance of balance on the rotating rod but it impaired them slightly in the elevated horizontal bridge test 16 hr after exposure. It did not affect nociception in the hot plate test 16 hr or 8 days after the injection. The results suggest that a single sublethal dose of TCDD does not alter markedly the general behaviour of Han/Wistar rats, in contrast to its striking effect on feeding behaviour which results in a marked decrease in body weight gain.

Amygdala kindling increased fear-response, but did not impair spatial memory in rats.

The behavioral effects of amygdala kindling, a model of experimental epilepsy in rats, are reported. The animals were stimulated twice a day until stage 5 (generalized clonic) seizures were obtained three times. Two weeks later the performance of the amygdala-kindled and sham-operated rats was tested in the open-field test, on the elevated plus maze, elevated bridges, and in the Morris water maze. The results show that amygdala kindling decreased exploratory and other motor activity in the open-field test, had anxiogenic effects on the elevated plus-maze, decreased boldness on the elevated bridges, but had a negligible affect in the spatial memory task. These results suggest that amygdala kindling affects the normal fear reaction of rats, a response that is known to be mediated through the amygdaloid pathways.

Acute neurobehavioural toxicity of trichothecene T-2 toxin in the rat.

The acute effects of single oral doses, 0.4 and 2.0 mg/kg, of trichothecene T-2 mycotoxin on behaviour, motor performance and nociception were studied in male Wistar rats. Both doses are sublethal and did not cause overt acute signs of intoxication. In the open field test, 2.0 mg/kg of T-2 toxin increased motionlessness and decreased sniffing (P less than 0.05) 4 hr after the administration. The higher dose shortened step-through latencies in the test trial of the 24-hr passive avoidance test (two-way shuttle box). The exponential data analysis showed that, in those rats that did not learn to avoid the dark (unsafe) compartment of the box, the retention after 2.0 mg/kg of T-2 toxin was only 25% of that in controls (P less than 0.001). T-2 toxin had no effect on motor coordination in the rotarod test and in the bridge walking test 7-8 hr after administration. T-2 toxin had no effect on nociception in the hot place test 8.5 hr after administration. The results suggest that T-2 toxin has some inactivating effects on behaviour of rats, and it seems to cause an impairment in the passive avoidance test at dose 2.0 mg/kg.

3H-atipamezole binding sites in mouse cerebral cortex: possible involvement of alpha 2-adrenoceptors in sexual behavior.

Atipamezole is a new specific alpha 2-adrenoceptor antagonist. In this study, first, the presence of specific 3H-atipamezole binding sites in the sagittal and coronal sections of mouse brain was established using autoradiography. In vitro experiments with mouse cerebral cortex membranes indicated that d-medetomidine, a new alpha 2-adrenoceptor agonist structurally related to atipamezole, displaces labelled atipamezole more potently than noradrenaline. The saturation isotherm with d-medetomidine demonstrated high affinity binding with the apparent number of binding sites KD 1.36 nM and 760 fmol/mg, respectively. In the next series of experiments male mice were sacrificed immediately after copulation and cerebral cortex 3H-atipamezole and 3H-flumazenil binding was studied. Oxymetazoline and prazosin are known to label preferably alpha 2A and alpha 2B subtypes of alpha 2-adrenoceptors. Therefore, parallelly with noradrenaline both these compounds were used to determine non-specific binding of 3H-atipamezole. When noradrenaline or oxymetazoline were used as displacing agents copulation caused a significant increase of 3H-atipamezole binding sites. No significant changes were observed when prazosin was used. 3H-Flumazenil binding remained unchanged by copulation. The up-regulation of 3H-atipamezole binding sites indicates that not only alpha 2-adrenoceptors in the periphery but also in the CNS may participate in the regulation of sexual behavior. Moreover, in regulation of sexual behavior central alpha 2-adrenoceptors may be more important than benzodiazepine receptors.

Assessment of acute behavioral toxicity of low doses of diisopropylfluorophosphate (DFP) in rats.

The effect on behavior of single subtoxic doses (100 and 600 micrograms/kg i.p., i.e. 1/77 and 1/13 of LD50, respectively) of an organophosphorous compound, diisopropylfluorophosphate (DFP), was studied in male Wistar rats. In the open-field test, the lower dose of DFP tended to increase ambulation, while the higher dose showed a trend towards a decrease in ambulation, rearing and frequency of defecation. In the elevated plus-maze, rotarod, elevated bridges and hot plate tests, DFP-treated rats did not differ significantly from the olive oil-treated controls. DFP significantly impaired the performance of rats in the one-trial passive avoidance task and dose-dependently decreased spontaneous locomotor activity for 4 hours after administration. At the doses used DFP only slightly inhibited acetylcholinesterase activity in the blood and different brain areas. The results show that the higher dose of DFP had an inactivating effect on the behavior of rats, while the lower dose did not markedly change their behavioral pattern. Our findings indicate that anticholinesterase compounds, such as DFP, can alter behavior even after single small subtoxic doses.

Acute behavioural effects of the organophosphates sarin and soman in rats.

The effects on behaviour of single subtoxic doses of two potent organophosphorous compounds, sarin (isopropyl methylphosphonofluoridate, 12.5 and 50 micrograms/kg, intraperitoneally) and soman (pinacolyl methylphosphonofluoridate, 4 and 20 micrograms/kg, intraperitoneally) were studied in male Wistar rats. In the open field test, soman dose-dependently decreased rearing and ambulation and increased non-mobile exploration. The higher dose of sarin changed only the rearing and grooming behaviour. Sarin and soman decreased locomotor activity on the Animex for at least one hour at the beginning of the monitoring period. In the doses used, both organophosphates inhibited acetylcholinesterase (AChE) activity significantly in the blood. The results suggest that small doses of sarin and soman have inactivating effects on the behaviour of rats. Although the findings cannot be extrapolated directly to behavioural changes in man, they indicate that subtle behavioural dysfunctions could also occur in humans at exposures which do not cause acute toxicity.

Neurobehavioral toxicity with low doses of sarin and soman.

The acute effects of single subtoxic doses (1/48-1/9 of LD50) of two potent organophosphates (OPs), sarin (12.5 and 50 micrograms/kg i.p.) and soman (4 and 20 micrograms/kg i.p.), were studied on behavior, motor performance and nociception in male Wistar rats. On the elevated plus-maze with two open + two closed arms, higher doses of soman and sarin decreased the proportion of entries made onto open arms (p less than 0.05), while the total number of entries onto open + closed arms was unchanged. On the narrow elevated horizontal bridge, the latencies to reach the safe platform were prolonged with the higher dose of sarin (p less than 0.05) but not with that of soman. On the broad and rod bridges, the latencies of OP-treated rats did not differ significantly from those of controls. OPs did not significantly impair either learning frequency in one-trial passive avoidance test, rotarod performance or nociception in hot plate test. The results suggest that in acutely nontoxic doses sarin and soman affect the behavior of rats, and that the action profiles of the OPs differ from each other. Both soman and sarin change the behavior of rats in the plus-maze test but only sarin seems likely to impair motor coordination/balance.