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The present study investigated the effects of perinatal flumazenil (Ro 15-1788, a benzodiazepine receptor antagonist), given from gestational day 15 to the 14th day after giving birth, at two doses (3.5 and 6.3 mg/kg/ day) on the behavior of female RLA/Verh rats. This rat line has been selectively bred for non-acquisition of two-way active avoidance. Offspring of treated/non-treated dams were tested when adults for two-way active (shuttle box) avoidance acquisition. For comparison reasons additional offspring coming from the same treatments were used in an hyponeophagia test and in both an open field and a plus maze tests. The results show that perinatal flumazenil, specially the lower dose (and also the highest dose, although only in the final phases of the shuttle box training) was able to improve two-way active avoidance acquisition, as it has been previously found with males, whereas it failed to show any effect in the hyponeophagia task, the open field and the plus-maze tests. As two-way active avoidance acquisition can be enhanced both by reducing emotionality/anxiety or by improving memory, it is suggested that flumazenil treatment could have affected either one or both processes.

The present series of studies investigated the effects of intensive training, postnatal handling-stimulation and/or perinatal flumazenil (Ro 15-1788, benzodiazepine receptor antagonist) on the acquisition of two-way active avoidance by Roman low-avoidance (RLA/Verh) rats. This rat line has been selectively bred for poor avoidance in the shuttle box, while their Roman high-avoidance counterparts (RHA/Verh) have been selectively bred for their extremely good performance in that task. In the first experiment, RLA/Verh rats submitted to a long and intensive training procedure (unlike those submitted to short training) were able to achieve a performance of 56% of avoidances per session. In the second experiment both postnatal handling and perinatal flumazenil treatments increased avoidance responding in another group of RLA/Verh rats tested at the age of 18 months. Finally, in the last experiment, the performance of a third stock of RLA/Verh rats of the same age which had received perinatal flumazenil did not differ, on the later phases of training, from that shown by RHA/Verh animals. The results are discussed in terms of the "warm up" phenomena which seems to be highly involved in the selection of RLA/Verh rats, as well as on the possibility that central benzodiazepine receptors could play a role in the genetic deficit shown by RLA/Verh rats, which apparently confers a greater emotivity.

The possible involvement of anxiety and learning/memory processes in escape-directed (struggling) behavior in a two-trial swimming test was investigated in mice, as well as the differential effects that low doses of flumazenil (a benzodiazepine receptor antagonist) could display depending on the animals' anxiety levels. Mice showing less anxiety in the plus-maze test exhibited less struggling behavior in the first swimming trial than the more anxious animals, suggesting a relationship between anxiety and struggling behavior in the swimming test. Flumazenil (5 mg/kg) given before the first swimming trial displayed differential effects depending upon the animals' anxiety levels. Thus, it increased struggling behavior in the first swimming trial in 'low-anxiety' mice whereas the opposite tendency was observed in 'high-anxiety' animals. Struggling decreased in the second swimming trial in all the animals, giving support to the involvement of learning/memory processes in the two-trial swimming test. That reduction in escape-directed behavior was greater in animals treated with flumazenil before the first swimming session, thus indicating a slight enhancement of retention.

The effects of diazepam (DZ, 4 mg/kg), alprazolam (ALP, 1.25 mg/kg) and adinazolam (ADIN, 6 mg/kg), as well as their interaction with the benzodiazepine receptor antagonist flumazenil (Ro15-1788), were studied on the early acquisition of two-way active (shuttlebox) avoidance in male Sprague-Dawley rats. The three benzodiazepines increased shuttlebox avoidance acquisition, and their effects were prevented (antagonized) by flumazenil (10 mg/kg). The present results indicate that central benzodiazepine (BZ) receptors are involved in the anxiolytic effects of diazepam and triazolobenzodiazepines on the early acquisition of two-way active avoidance.

The effect of infantile handling stimulation and/or perinatal flumazenil (Ro 15-1788; a benzodiazepine receptor antagonist; 3.7 mg/kg/day) administration on exploratory and emotional-related behavior was investigated using adult females from the Roman high- and low-avoidance (RHA/Verh and RLA/Verh) lines. When rats (6 months old) were exposed to a hexagonal tunnel maze including an illuminated central arena, it was found that RHA/Verh rats were more active, explored more maze area, showed more outward preference, and more frequently entered the illuminated center than RLA/Verh rats. In addition, postnatal stimulation decreased emotional-related behavior in both lines of rats, as expressed by increased entry into, and time spent in, the central arena. Perinatal flumazenil treatment decreased entry into the maze central arena in both rat lines but this effect was counteracted by postnatal (handling) stimulation. Thus, the present study extends to adult RHA/Verh and RLA/Verh rats the positive long-lasting effects of postnatal handling and shows postnatal handling x flumazenil interactions in some behavioral parameters related to the pattern of exploration and exploratory efficiency.

The effect of infantile handling-stimulation and/or perinatal flumazenil (3.7 mg/kg/day) administration on exploratory and emotional-related behavior was investigated using Roman high- and low-avoidance (RHA/Verh and RLA/Verh) rats. Postnatal handling increased exploration in 30-day-old rats of both psychogenetically selected lines when they were exposed to a hexagonal tunnel maze including an illuminated central arena. Likewise, postnatal stimulation decreased emotional reactivity in both lines of rats, as expressed by increased entry into the central arena, decreased defecation and vocalization frequency, but these effects were more pronounced in the RLA/Verh line. There were interactions between perinatal flumazenil treatment and rat line, indicating that flumazenil enhanced entry into the maze central arena in handled-RLA/Verh rats, whereas a tendency toward the opposite effect was observed in drug-treated and handled-RHA/Verh animals. Thus, the present study emphasizes that the effects of environmental manipulations are partly dependent upon genetic factors, and that pharmacological effects also depend on both genetic and environmentally-induced predisposition.

The present study shows that postnatal 'consistent' handling (CH; which consisted of removing the pups from the nest and placing them individually in plastic cages lined with paper towel for a period of 15 min daily between 1 and 22 postnatal days) of rats had long-lasting improving effects on coping with a stressful task (i.e. enhancement on the early acquisition of two-way active avoidance), but such effects were completely prevented when CH treatment was combined with chronic perinatal Ro 15-1788 (7 mg/kg/day, between prenatal day 19 and postnatal day 22) administration (i.e. blockade of benzodiazepine receptor (BZR)). A long-lasting decremental effect was also observed in the same task in rats which received postnatal 'inconsistent' handling (INCH; in which stimulation of pups was changed every day between 1 and 22 postnatal days), without being affected by the concomitant perinatal Ro 15-1788 treatment. These results suggest that intact ontogeny of BZRs is necessary to obtain the enduring positive effects of CH on emotional behavior (i.e. early acquisition of two-way active avoidance).

Both postnatal handling of rat pups and perinatal treatment with Ro 15-1788 have been reported to reduce the emotional reactivity of the rats in adulthood, as measured by open field behavior, by the corticosterone response to stress, and by labyrinth and novelty-induced behaviors. We now report results obtained with a well-validated animal model of anxiety (i.e. the elevated plus-maze) that support and extend these previous findings. The results show the clearest reduction of anxiety-related behavior when postnatal handling and perinatal Ro 15-1788 administration were simultaneous.