Behavioural effects in mice of subchronic chlordiazepoxide, maprotiline, and fluvoxamine. I. Social interactions.

The present study compares the effects of subchronic administration (daily. 21 days) of chlordiazepoxide (CD), maprotiline and fluvoxamine on the behavior of male mice during dyadic social interactions. Maprotiline like chlordiazepoxide, stimulated aggression at 4 mg/kg and 2 mg/kg respectively (intermediate dose levels), whereas effects of fluvoxamine (3-8 mg/kg) were mainly sedative. Non-social activity was reduced by CD at 4 and 8 mg/kg and by maprotiline at 0.5 mg/kg. At the highest dose tested (10 mg/kg), maprotiline increased immobility, resembling the effects of fluvoxamine, while at 2 mg/kg, it reduced social investigation. Thus, despite some commonalities, there were several differences in behavioral profile of the compounds tested. Data are discussed in relation to the efficacy of each of these compounds in treating anxiety and depressive disorders.

Behavioural effects in mice of subchronic chlordiazepoxide, maprotiline and fluvoxamine. II. The elevated plus-maze.

In view of apparent commonalities in the aetiology, symptomatology, and pharmacotherapy of anxiety and depressive disorders, the present study compares the effects of the benzodiazepine, chlordiazepoxide (1.0-8.0 mg/kg), the selective noradrenaline (NA) reuptake inhibitor, maprotiline (0.5-10.0 mg/kg), and the serotonin (5-HT)-selective reuptake inhibitor, fluvoxamine (2.0-8.0 mg/kg), on the behaviour of mice in the elevated plus-maze test of anxiety. To more accurately reflect the clinical situation, subjects were treated daily for 21 days prior to testing, and comprehensive behavioural profiles were obtained through the application of an ethological scoring technique. Results show that subchronic treatment with chlordiazepoxide produced clear anxiolytic-like effects at the highest dose tested, coupled with an inhibition of risk assessment over the entire dose range. With the exception of risk assessment measures, anxiolytic-like effects were also seen with a low dose (0.5 mg/kg) of maprotiline: these effects were lost at higher doses. In contrast to these data, fluvoxamine produced minimal behavioural change under present test conditions. Findings are discussed in relation to the relative efficacy of selective monoamine. reuptake inhibitors in the treatment of anxiety disorders, and the nature of anxiety evoked in mice by exposure to the elevated plus-maze.

Behavioural effects in mice of subchronic buspirone, ondansetron and tianeptine. I. Social interactions.

In a continuation of recent work on effects of a benzodiazepine (chlordiazepoxide) and selective monoamine reuptake inhibitors (maprotiline and fluvoxamine), the current study compares effects of the 5-HT1A receptor partial agonist, buspirone (0.75-3.0 mg/kg), the 5-HT3 receptor antagonist, ondansetron (0.1-100 micrograms/kg) and the novel antidepressant, tianeptine (2.5-10.0 mg/kg). Compounds were given daily to mice for 21 days prior to testing and the subsequent behaviour of the animals during social interactions was assessed by ethopharmacological procedures. Buspirone, at 0.75 mg/kg, increased immobility and reduced occurrence of the aggressive act, "attack." At 1.5 and 3.0 mg/kg, it enhanced olfactory exploration of the sawdust substrate, but had no effect on social investigation. Ondansetron increased the duration of environmental exploration at 0.1 microgram/kg, while at 100 micrograms/kg it increased the duration of digging in the substrate. Ondansetron had no effect on the categories of behaviour and failed to induce an anxiolytic-like enhancement of social investigation. Tianeptine produced an anxiogenic-like effect at 10 mg/kg, while at 5 mg/kg it enhanced flight and immobility. The relevance of these findings is discussed in relation of the reported behavioural actions of these compounds and to current pharmacotherapy of anxiety and depression. The apparent anxiogenic effect of tianeptine is a novel finding which requires further study.

Behavioural effects in mice of subchronic buspirone, ondansetron and tianeptine. II. The elevated plus-maze.

In follow-up to recent work on benzodiazepines (chlordiazepoxide) and selective monoamine reuptake inhibitors (maprotiline and fluvoxamine), the present study compares the effects of the 5-HT1A receptor partial agonist, buspirone (0.75-3.0 mg/kg), the 5-HT3 receptor antagonist, ondansetron (0.1-100 micrograms/kg), and the novel antidepressant, tianeptine (2.5-10.0 mg/kg), on the behaviour of mice in the elevated plus-maze test of anxiety. Compounds were administered daily for 21 days prior to testing, and an ethological scoring technique was used to generate comprehensive behavioural profiles. Results show that subchronic treatment with ondansetron failed to influence the behaviour of mice in the plus-maze, while the limited changes induced by buspirone could not be attributed to anxiety-related processes. In contrast, tianeptine produced unambiguous anxiogenic-like effects at the top dose tested (10.0 mg/kg), a profile that was not secondary to changes in general levels of locomotor activity or exploration. Data are discussed in relation to current pharmacotherapy of anxiety and depressive disorders, and the nature of anxiety induced by animal models.

Effects of acute and chronic administration of the antidepressants, imipramine, phenelzine and mianserin, on the social behaviour of mice.

Effects of imipramine, phenelzine and mianserin on the behaviour of male CDl mice were examined after a single intraperitoneal injection (imipramine, 15.8 and 63.2 mumol/kg; phenelzine, 1 and 8 mumol/kg); mianserin, 0.12 and 0.48 mumol/kg) and after administration for 12-16 days in the drinking fluid (mean daily intake; imipramine, 15.8 and 63.2 mumol/kg; phenelzine, 1 and 8 mumol/kg; mianserin, 0.12, 0.48 and 1.92 mumol/kg). Behaviour was examined by ethological procedures during 5 min encounters with an untreated partner in a familiar situation, the animal's home cage, and in the more aversive environment of an unfamiliar cage. At 30 min after injection, the higher doses of acutely administered imipramine and mianserin decreased aggressive behaviour in the unfamiliar cage. In the home cage, effects of mianserin were only slight, whereas imipramine reduced social investigation at the larger dose and in both test environments decreased digging. Phenelzine increased social investigation in both environments. After chronic administration, each of the drugs increased social investigation in the neutral cage and home cage at some of the dose levels, indicating potential anxiolytic efficacy. Mianserin showed the additional effect of enhancing digging during tests in the neutral cage, which may correlate with its anxiolytic actions. Phenelzine was the only antidepressant to increase aggression during encounters in the neutral cage after chronic administration. The significance of these findings is discussed.

Effects of chlordiazepoxide, buspirone and the 5-HT3 receptor antagonist, BRL 46470, on the behaviour of oestrous and dioestrous female mice when encountering male partners.

Ethological procedures were employed to examine the differences in behaviour between oestrous and dioestrous control mice, and to investigate the changes to behavioural responsiveness in oestrous and dioestrous mice induced by treatment with the anxiolytic compounds, chlordiazepoxide (CDP, 21.5 mg/l), buspirone (12.8 mg/l) and the 5-HT3 receptor antagonist, BRL 46470 (40 micrograms/l). Compounds were given in drinking fluid for 6-8 days prior to behavioural observations (average daily intake: CDP--5 mg/kg; buspirone--2.5 mg/kg; BRL 46470--10 micrograms/kg). Behaviour of the females was examined in the "approach-avoidance" situation of 5 min encounters with an unfamiliar male in a neutral cage. Oestrous controls spent more time in social investigation, sniffing of the substrate and scanning than dioestrous controls and spent less time in digging and exploration. Each of the anxiolytic compounds, CDP, buspirone and BRL 46470, significantly raised the duration of social investigation both in oestrous and dioestrous females. Each of these compounds also increased the duration of "digging" by oestrous females, and duration of the social element "investigate" in dioestrous females. Effects on the occurrence of other individual elements within each behavioural category depended on the anxiolytic compound administered and the stage of the ovarian cycle at the time of testing. There were few significant differences between the behaviour of the male partners in each group. It is concluded that in this paradigm both oestrous and dioestrous females are sensitive to the enhancement of social investigation by anxiolytic compounds and that the use of female mice in this test situation may provide a potentially useful method in drug screening.

Comparison of the effects of yohimbine and clonidine on the behaviour of female mice during social encounters in an "approach-avoidance" situation.

Effects of yohimbine (2 and 5 mg/kg, i.p.) and clonidine (10 and 50 micrograms/kg, i.p.) on the behaviour of adult female CD1 mice during 5 min encounters in a neutral cage with unfamiliar male partners have been examined by ethological procedures at 30 min after injection. Yohimbine induced dose-related increases in the frequency, bout length and duration of the immobile postures, "sit" and "social crouch", while decreasing the frequency of "explore", "scan", "attend" and "investigate", and increasing their bout lengths in a dose-related manner. These results suggest that yohimbine decreased the rate of switching from one behavioural act to another. Pausing between acts was increased by yohimbine to a similar extent at both of the tested dose levels. The act "wash" was increased in duration by yohimbine, whereas the strenuous activity of "digging" showed a dose-related decrease in frequency, duration and bout length. It is proposed that these effects are induced by the known interactions of yohimbine with receptors for dopamine as well as with alpha 2-adrenoceptors. Clonidine reduced motor activity, evident as a dose-related increase in the frequency and duration of "sitting" coupled with decreased frequency and increased bout length of the act, "explore" (significant at 50 micrograms/kg). Clonidine also dose-dependently reduced the frequency and duration of substrate "sniffing". Clonidine decreased occurrence of the specific social acts, "attend" and "investigate", as well as reducing frequency although not duration of overall social investigation. These findings have parallels with reported clinical effects of clonidine, such as sedation and impairments of attention, which must limit its clinical usefulness.

Buspirone increases social investigation in pair-housed male mice; comparison with the effects of chlordiazepoxide.

Effects of buspirone (1, 5 and 10 mg/kg, i.p.) on the behaviour of adult male CD1 mice have been compared with those of chlordiazepoxide (1, 4 and 8 mg/kg, i.p.). Commencing at 30 min after injection, the behaviour of each mouse was examined by ethological procedures during 5 min social encounters with an untreated partner in the animal's home cage and in the more aversive situation of an unfamiliar neutral cage. In both test environments, buspirone at 1 and 5 mg/kg and chlordiazepoxide (CDP) at 1 and 4 mg/kg increased social investigation and some of its constituent elements, while decreasing non-social activity and the element, "explore" (and for CDP, of "scanning" also). In both test environments, the increase of social investigation by buspirone and CDP was less marked at 10 and 8 mg/kg, respectively. For CDP, although not for buspirone, this effect was related to dose-dependent increases of immobility coupled with reductions of exploratory non-social activity and scanning below those occurring at the intermediate dose level. Buspirone at 5 mg/kg increased social investigation to a greater extent in the home cage (P < 0.01) than in the unfamiliar neutral cage (P < 0.05), whereas CDP was approximately equipotent in the two test situations. In the neutral cage, buspirone at all dose levels showed an additional effect of increasing the time spent by the mice in digging, whereas chlordiazepoxide dose-dependently increased aggression. These results indicate anxiolytic activity by both compounds after acute administration, and identify certain differences in the profile of their other effects on social behaviour.

Effects of acute and subchronic administration of ritanserin on the social behaviour of mice.

The effects of ritanserin on the behaviour of adult male CD1 mice were examined after acute intraperitoneal injection (0.1, 0.3 and 0.6 mg/kg) and after administration for 12-15 days in the drinking fluid at 1.6 mg/l (0.32 mg/kg daily) and 3.1 mg/l (0.7 mg/kg daily). The behaviour of each mouse was examined by ethological procedures during 5 min social encounters with an untreated partner in an aversive situation, an unfamiliar neutral cage, and in a familiar situation, the animal's home cage. Behaviour also was monitored for 5 min in the light-dark box. In the acute studies, behavioural observations commenced at 30 min after injection. In the home cage, ritanserin significantly increased social investigation during social encounters and reduced exploratory activity at all doses tested, after both acute and subchronic administration. In the neutral cage, acutely administered ritanserin increased social investigation and reduced non-social activity at all dose levels. Effects were maximal at 0.3 mg/kg, and at this dose it also increased aggression. In the neutral cage after subchronic administration, ritanserin at both dose levels increased aggression, digging and investigation of the substrate and occurrence of the social act, "attend", while reducing the time spent in non-social exploration. Ritanserin did not affect behaviour in the light-dark box. The significance of these findings relative to the anxiolytic and antidepressant effects of ritanserin is discussed.

Effects of quinpirole on the behaviour shown by mice in the light-dark box and during social interactions.

Quinpirole (0.25, 0.5 and 1.0 mg/kg) was administered by intraperitoneal injection to pair-housed adult DBA/2 mice. Controls received injections of physiological saline. Effects on behaviour during 5 min social encounters with untreated partners were examined by ethological procedures, commencing at 30 min after injection. Behaviour was examined in an aversive and less aversive situation, an unfamiliar neutral cage and the home cage. Behavioural effects were then assessed in a two-compartment black and white test box. Quinpirole dose-dependently increased the frequency and duration of flight, including the specific element "retreat". At 0.5 mg/kg, the element, "freeze", was also increased during encounters in the neutral cage. Immobility (a flaccid sitting posture) and sniffing of the substrate were increased by quinpirole to a similar extent at all dose levels, while non-social activity and social investigation were reduced. The significance of the effects of quinpirole in the home cage and neutral cage were qualitatively similar; the only quantitative differences were a greater enhancement of the duration of immobility and the frequency of substrate sniffing in the home cage. In the light-dark box, quinpirole reduced the number of transitions between light and dark compartments and decreased line crossings and scans/unit time in the light compartment, although it increased the amount of time in the light compartment into which mice had been originally placed. The induction of immobility and decrease of several active behavioural responses may arise from a D2 autoreceptor inhibition of locomotor activity.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of acute and subchronic administration of propranolol on the social behaviour of mice; an ethopharmacological study.

The effects of dl-propranolol on the behaviour of adult male CD1 mice were examined after acute intraperitoneal injection (1.5 and 6 mg/kg) and after administration for 10-13 days in the drinking fluid at 12.4 mg/l (1.9 mg/kg daily) and 24.9 mg/l (4.6 mg/kg daily). The behaviour of each mouse was examined by ethological procedures during 5 min social encounters with an untreated partner in an aversive and a less aversive situation, an unfamiliar neutral cage and the animals' home cage. The behaviour of each mouse also was monitored for 5 min in the light-dark box. In the acute studies, behavioural observations commenced at 30 min after the injection. In the light-dark box, propranolol, after acute administration, increased the number of transitions between the light and dark compartments and increased scanning in the light area but propranolol had no significant effect after subchronic administration. In the home cage, propranolol significantly increased social investigation during social encounters and reduced exploratory activity at all doses tested, after both acute and subchronic administration. In the neutral cage, propranolol, after acute administration, increased digging of the sawdust and decreased exploratory activity at both dose levels, while at the largest dose it also increased social investigation. In the neutral cage, propranolol, given by subchronic administration, increased aggressive behaviour as well as social investigation and digging of the sawdust at both dose levels, while reducing non-social exploratory activity. The largest dose of propranolol also increased investigation of the substrate. These results indicate that propranolol increased reactivity to normal environmental and social stimuli, in addition to its anxiolytic profile of behavioural effects.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of acute administration of the 5-HT3 receptor antagonist, BRL 46470A, on the behaviour of mice in a two compartment light-dark box and during social interactions in their home cage and an unfamiliar neutral cage.

Adult male CD1 mice received the 5-HT3 receptor antagonist, BRL 46470A, by intraperitoneal injection at three dose levels (2.5 mg/kg, 25 and 2.5 micrograms/kg). Controls were injected with physiological saline. At 30 min after injection, the behaviour of each mouse was examined by ethological procedures, when encountering an untreated partner for 5 min in its home cage and for 5 min in the more aversive situation of an unfamiliar neutral cage. The behaviour of each mouse also was monitored for 5 min in a two compartment light-dark box. At all doses tested, BRL 46470A increased the time spent in the light compartment of the light-dark box. At the smallest dose (2.5 micrograms/kg), the number of transitions between light and dark compartments was increased and there also was an increase (per unit time) in the numbers of squares crossed and number of scans in the light compartment. At all doses tested, BRL 46470A increased social investigation and reduced non-social exploratory activity in both the home cage and the unfamiliar neutral cage. In both test situations, increase of social investigation was maximum at 25 micrograms/kg, and at this dose, aggressive behaviour was also enhanced. In the neutral cage, digging in the sawdust by drug-treated mice showed a progressive dose-related increase. These results indicate potent anxiolytic-like activity by BRL 46470A and also demonstrate increased reactivity to unfamiliar environmental stimuli, such as novel sawdust. The significance of these findings is discussed.

Effects of sub-chronic treatment with chlordiazepoxide, buspirone and the 5-HT3 receptor antagonist, BRL 46470, on the social behaviour of mice.

Chlordiazepoxide (21.5 mg/l; 5 mg/kg daily), buspirone (12.8 g/l; 3.4 mg/kg daily) and the 5-HT3 receptor antagonist, BRL 46470, (40 micrograms/l; 10 micrograms/kg daily) were each given in the drinking fluid for 12-14 days to adult male CD1 mice. Controls received tap water. Effects of the treatments on behaviour during 5 min social encounters with untreated partners were examined by ethological procedures in an aversive and less aversive situation, an unfamiliar neutral cage and the home cage. In the neutral cage all compounds increased the occurrence of the social act, "nose" and enhanced digging of the unfamiliar sawdust, at the expense of exploration. In the home cage, all compounds increased social investigation and reduced non-social activity. The drug BRL 46470 evoked more marked effects on behaviour than did buspirone or chlordiazepoxide and in the neutral cage it enhanced some acts of aggression. These results show that all compounds increased reactivity to normal social and environmental stimuli, in addition to their anxiolytic profile of behavioural effects.

Effects of the benzodiazepine receptor inverse agonist, DMCM, on the behaviour of mice: an ethopharmacological study.

Ethopharmacological procedures and a two-compartment black and white test box were used to examine behavioural effects produced by the benzodiazepine receptor inverse agonist, methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM), when given by intraperitoneal injection (0.4 and 1.0 mg/kg) to pair-housed adult CD1 male mice. Control mice received injections of the solvent. Behaviour in the light-dark box was examined at 30 min after the injection and behaviour during encounters with an untreated group-housed male, in a neutral cage, was then assessed by ethological procedures. In dominant mice, aggressive behaviour was significantly reduced and the ratio of flight, relative to aggression received, was significantly increased by DMCM at 0.4 mg/kg. At 1 mg/kg but not 0.4 mg/kg, DMCM decreased time spent by dominant mice in the light compartment of the test box. In both dominant and subordinate mice, flight was increased by DMCM at 1 mg/kg to a level close to statistical significance. Treatment with DMCM had no other detectable effect on the behaviour of subordinate animals. It is suggested that anxiogenic activity of this compound might induce a shift of agonistic behaviour from aggression to "fear-induced flight".

A comparative study of the effects of delta-aminolaevulinic acid and the GABAA agonist, muscimol, in rat jejunal preparations.

Preparations of rat jejunum were tested for their responsiveness to the GABAA receptor agonist, muscimol, and to the haem precursor, delta-aminolaevulinic acid (ALA). Both muscimol (1.0-30 microM) and ALA (1.0 microM-3.0 mM) elicited a concentration-dependent increase in tone. Pretreatment with the GABAA antagonist, bicuculline (10(-5) M), blocked effects of muscimol at all concentrations tested and attenuated effects of 0.3 mM ALA. However, bicuculline enhanced responsiveness of the preparations to ALA at low concentrations (0.01-0.05 microM), as also did picrotoxin (10(-5) M), eliciting a significant increase of tone. The significance of these findings is discussed. This finding of pharmacological activity by ALA at concentrations comparable with its blood levels during acute attacks of intermittent porphyria provides support for the proposal that is may play a role in the aetiology of the gastrointestinal manifestations of this disease.

An ethological study of the effects of buspirone and the 5-HT3 receptor antagonist, BRL 43694 (granisetron) on behaviour during social interactions in female and male mice.

Buspirone (12.8 mg/l; 2.3-2.6 mg/kg daily) and the 5-HT3 receptor antagonist, BRL 43694 (granisetron) (40 micrograms/l; 10 micrograms/kg daily), were each given in drinking fluid to male and female DBA/2 mice for 5-10 days. Controls received tap water. Effects on behaviour were examined by ethological procedures during 5 min encounters with unfamiliar BKW partners. One group of DBA/2 males acted as intruders in a resident-intruder paradigm and another group encountered oestrous females in a neutral cage. The DBA/2 females each encountered a group-housed male in a neutral cage. Both buspirone and BRL 43694 decreased flight in females and increased the duration of their active social investigation. In females, BRL 43694 also reduced the occurrence of "scan" and prolonged the bout length of exploration. In male mice, buspirone increased social investigation, including the specific elements "sniff" and "follow" in encounters with female partners, but its only effect on behaviour during encounters with isolated resident males, was to decrease duration of the element, "attend". In males, BRL 43694 did not significantly affect behaviour in heterosexual encounters and had only a slight effect on behaviour during encounters with resident males, decreasing the occurrence of "eat". Overall, these results suggest that records of effects of drugs on flight responses of female mice, in encounters with male partners, may provide a sensitive index of the anxiolytic profile of novel compounds.

Behavioural effects in gerbils of the 5-HT3 receptor antagonists, BRL 43694 and ICS 205-930, under circumstances of high and low light intensity.

The 5-HT3 receptor antagonists, BRL 43694 and ICS 205-930, were each given for 21 days in the drinking fluid at 1.3 mg/l (120 micrograms/kg daily), to Mongolian gerbils, while the controls received tap water to drink. Effects of the treatments in reducing aversion to a brightly lit environment were assessed on behaviour during social encounters with an unfamiliar untreated resident, under bright white light and in a two-compartment black and white test box, after 12-16 days of treatment. Effects on behaviour under dim red illumination, when encountering unfamiliar untreated residents, were examined after 17-19 days. Behaviour during social encounters was recorded by ethological procedures. During encounters under bright white light, the frequency and duration of the social element "attend" were increased by BRL 43694 and ICS 205-930 and the frequency of "nose" was increased by BRL 43694. In the light-dark box, BRL 43694, though not ICS 205-930, reduced the time spent in the dark compartment. Under dim red light, BRL 43694 and ICS 205-930 increased the occurrence of the social elements, "sniff", "follow" and "sniff chin", suggesting increased sensitivity to olfactory stimuli. Increases of social investigation were associated with compensatory changes to non-social behaviour. It is suggested that 5-HT3 receptor antagonists may, on the one hand, increase sensitivity to social stimuli under dim red illumination and, on the other hand, show an apparent anxiolytic potential, associated with increase of other elements of social investigation under the more aversive test conditions of bright white light.

Pharmacological activities of delta-aminolaevulinic acid, protoporphyrin IX and haemin in isolated preparations of rabbit gastric fundus and jejunum.

1. Pharmacological effects of delta-aminolaevulinic acid (ALA), protoporphyrin IX and haemin were examined in isolated preparations of rabbit jejunum and gastric fundus suspended in oxygenated Ringer-Locke solution at pH 7.0. 2. In jejunal preparations, delta-aminolaevulinic acid (3.0-4.5 mM), protoporphyrin IX (1.1-2.2 mM) and haemin (3.0-4.5 mM) dose-dependently reduced the amplitude of contractions and increased resting length. Pretreatment with prazosin (10(-7) M) inhibited effects produced by delta-aminolaevulinic acid (3 mM) and protoporphyrin IX (1.1 mM) but not those of haemin (3 mM). 3. In fundic preparations, dose-dependent contracture occurred in response to delta-aminolaevulinic acid (0.1-3.0 mM) protoporphyrin IX (0.1-2.2 mM) and haemin (0.6-6.3 mM). Effects qualitatively resembled those of noradrenaline (0.1-0.4 microM). Prazosin (10(-7) M) attenuated these effects, depressing the maximum response and causing a rightward shift of the concentration-response curves. 4. It is concluded that actions of delta-aminolaevulinic acid at alpha 1-adrenoceptor sites are unlikely to be related to the autonomic neuropathy of acute porphyria. Its in vitro effects occurred only at comparatively high concentrations and were mimicked by protoporphyrin IX and haemin. It is suggested that ALA is more likely to modify autonomic functions by an indirect action, since it is known at low dose levels to influence GABA-ergic functioning.

The mauve factor of porphyria, 3-ethyl-5-hydroxy-4,5-dimethyl-delta-3-pyrroline-2-one: effects on behaviour of rats and mice.

The monopyrrole, 3-ethyl-5-hydroxy-4,5-dimethyl-delta 3-pyrroline-2-one (HPL), was given by intraperitoneal injection to rats (0.65 mmol/kg) and to mice (0.98 and 1.95 mmol/kg). Behaviour of the rats was assessed for 1.5 hr after injection by monitoring their spontaneous activity, while behaviour of the mice was examined by ethological procedures during dyadic encounters over a 5 min. period at 50-60 min. following injection. Activity of the rats, once habituated to the cage, was reduced by HPL. No other abnormalities were discernible. In mice, HPL at 1.95 mmol/kg increased the frequency of "head twitch" and evoked a smaller increase of "backward locomotion". There were no changes in overall agonistic, social or non-social behaviour in the HPL treated mice. Plasma concentrations of HPL in mice treated with the highest dose level amounted to 0.3 +/- 0.1 mmol/l, many-fold above its plasma concentrations during acute porphyric attacks in man. It thus appears that in rodents HPL has slight behavioural activity, but that it is unlikely to play any significant role in the psychiatric disturbances of acute porphyria.

Chronic administration of the 5-HT3 receptor antagonist BRL 43694; effects on reflex epilepsy and social behaviour of the Mongolian gerbil.

The 5-HT3 receptor antagonist BRL 43694 was administered in drinking fluid to Mongolian gerbils, previously selected for their propensity to exhibit seizures on mild stimulation, for 11 days at doses of 1.5 micrograms/kg, 150 micrograms/kg and 1 mg/kg daily, while controls received tap water. Effects upon behaviour during encounters under white light with an untreated resident gerbil were assessed using ethological procedures. Effects upon seizure susceptibility and severity were also examined. All doses of BRL 43694 significantly increased the time spent by gerbils in the social activity "attend", and acts of social investigation involving physical contact between animals were significantly increased only by the highest dose of 1 mg/kg, as was occurrence of the specific element, "groom". The duration of flight was increased in gerbils receiving the drugs at 1.5 micrograms/kg. The treatment had no effect upon seizure susceptibility or severity. It is suggested that BRL 43694 increases the sensitivity of gerbils to their social environment. At the lower dose this was seen as an increase in flight, at all doses it was associated with increase of the social activity "attend" and at the high dose it was manifested as an increase in active social interaction. Further investigations are required to assess the relevance of these findings to the purported anxiolytic activity of 5-HT3 receptor antagonists.