Urinary polyamine excretion during growth and regression of 1,12-dimethylbenz[a]anthracene-induced rat mammary carcinoma.

The correlation of urinary excretion of polyamines and tumor mass was examined with the use of a controlled experimental model. Mammary carcinoma growth was induced in Sprague-Dawley virgin rats by intragastric administration of 7,12-dimethylbenz[a]anthracene. Tumors were palpable after about 45 days. After a period of growth, regression of the estrogen-dependent tumors was induced by bilateral ovariectomy. Tumor volume and 24-hour urinary excretion of polyamines were measured during the course of tumor growth and regression. Urinary polyamines were analyzed after acid hydrolysis to determine the total amount of bound and free polyamines. Putrescine excretion followed closely the changes in tumor volume during the course of tumor growth and regression. Urinary spermidine excretion, however, remained essentially unchanged in ovariectomized rats; spermine was barely detectable in any of the urines. There was a high positive correlation between the 24-hour urinary putrescine excretion and urine volume. In nonovariectomized rats, the mammary tumor(s) continued to grow. An unexpected result of the advanced tumor progression was that urinary excretion of both putrescine and spermidine decreased steadily with time as did urine volume. This phenomenon may be due to the fact that complex disturbances of the host metabolism, manifested in decreasing body weight.

The effects of lesions in the mesencephalic raphe systems on male rat sexual behavior and locomotor activity.

Lesions were produced in the median and the dorsal raphe nuclei of the rat, and the effects of these injuries on various behaviors were studied. The median raphe lesions had facilitatory effects on the male rat sexual behavior, as evidenced by a decrease in the number of intromissions prior to ejaculation, as well as shortening of the ejaculation latency and the postejaculatory interval. No effects were seen on the masculine sexual behavior after lesions in the dorsal raphe nucleus. The median raphe lesions drastically increased the locomotory activity whereas the dorsal raphe lesions did not. Treatment with FG5893, a 5-HT1A agonist/5-HT2A receptor antagonist, increased the locomotor activity of the dorsal-raphe-lesioned rats but did not affect the median-raphe-lesioned animals. These results suggest that the dorsal and the median raphe nuclei play different roles in the neural regulation of the sexual behavior and locomotor activity of the male rat. The median raphe nucleus appears to exert a modulatory influence upon these behaviors, which probably is mediated by serotonergic neural pathways.

Involvement of the 5-HT2 receptor in the 5-HT receptor-mediated stimulation of prolactin release.

The present study examined the involvement of 5-HT1C and 5-HT2 receptors in the regulation of prolactin release in the rat. Both the mixed 5-HT2/5-HT1C receptor agonist, 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI), and the preferential 5-HT1C agonist, 2-chloro-6-(1-piperazinyl)pyrazine monohydrochloride (MK-212), elicited a significant increase in plasma prolactin concentration with DOI about 20 times more potent than MK-212. Treatment with DOI, but not with MK-212, induced head twitching in the rat, and this behavior was inhibited by both the mixed 5-HT2/5-HT1C receptor antagonist, ritanserin, and the selective 5-HT2 receptor antagonist, amperozide. DOI-induced prolactin release was also antagonized by ritanserin and amperozide, whereas only ritanserin affected MK-212-induced prolactin release. Furthermore, amperozide did not attenuate d-fenfluramine-elicited prolactin release, which is known to be antagonized by ritanserin. These data suggest that the pharmacological stimulation of prolactin release by DOI is mediated via the 5-HT2 receptor and that the 5-HT1C receptor may be of importance for the physiological regulation of prolactin release.

Preclinical pharmacology of FG5893: a potential anxiolytic drug with high affinity for both 5-HT1A and 5-HT2A receptors.

The effects of FG5893 were evaluated by several different methods; rats were used as experimental animals. Receptor binding studies revealed that FG5893 (2-(4-(4,4-bis(4-fluorophenyl)butyl)-1-piperazinyl)-3-pyridinecarboxy lic acid methyl ester) binds with high affinity to both 5-HT1A (Ki = 0.7 nM) and 5-HT2A receptors (Ki = 4.0 nM) but has only low affinity for the 5-HT2C receptor (Ki = 170 nM). FG5893 dose dependently reduced body temperature, and this effect was inhibited by pretreatment with (+/-)-pindolol. FG5893 (0.1 mg/kg) significantly inhibited head twitch behaviour induced by DOI (1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane) and FG5893 was also a potent inhibitor of ultrasound vocalization in rat pups (0.3 mg/kg) and of a passive avoidance response (0.1 mg/kg) in mature animals. FG5893 inhibited the cage-leaving response and induced part of the 5-HT behavioural syndrome, but only at very high doses (5 and 10 mg/kg, respectively). At increased doses (1 mg/kg), FG5893 also elicited corticosterone release and reduced the immobility time in the forced-swim test (1 mg/kg). Together, these data indicate that the mixed 5-HT1A receptor agonist/5-HT2A receptor antagonist FG5983 is a potent stimulator of presynaptic 5-HT1A receptors but is less active at the postsynaptic site. FG5893 had potent anxiolytic-like effects both on separation-induced ultrasound vocalization in rat pups and on a passive avoidance response. At increased doses, FG5893 possessed an antidepressant-like property.

The effect of amperozide, a new antipsychotic drug, on plasma corticosterone concentration in the rat.

Amperozide is an atypical antipsychotic drug with high affinity for the serotonin 5-HT2 receptor but with low affinity for the dopamine D1 and D2 receptors. Amperozide dose-dependently increased the level of plasma corticocorticosterone in the rat. The effect of amperozide on plasma corticosterone was not inhibited by pretreatment with the 5-HT1A receptor antagonist pindolol or the 5-HT2 receptor antagonist ritanserin. Nor was it inhibited by the dopamine D2 receptor antagonist haloperidol. In contrast to ritanserin, amperozide did not antagonize plasma corticosterone elevation elicited by the serotonin receptor agonist MK-212. Similar to the serotonin uptake inhibitor fluoxetine, amperozide (0.5 mg/kg) significantly (p < 0.05) blocked p-chloroamphetamine (PCA) induced corticosterone release 4 and 16 hrs after amperozide administration. However, amperozide significantly increased the plasma corticosterone concentration also in rats pretreated with parachlorophenylalanine (PCPA). These data suggest that other mechanisms than a 5-HT uptake inhibitory effect are involved in the acute stimulation of corticosterone by amperozide.

Subclinical characteristics of the wasting pig syndrome.

The plasma concentrations of cortisol and corticosteroid-binding globulin and the adrenal synthesis capacity of cortisol were analysed in 10-week-old healthy and age-matched wasting or unthrifty pigs. Crypt cell multiplication, villus height and intestinal mucosal alkaline phosphatase (ALP) activity were also investigated. Furthermore, the effect of amperozide, a psychotropic drug with specific effects on emotional behaviour, was analysed for its effect on plasma ALP activity and villus height. Although the wasting pigs exhibited an increased cortisol synthesis capacity, there was a decreased plasma concentration of cortisol in these pigs. Furthermore, the plasma cortisol binding capacity was found to be significantly lowered in wasting pigs. There was also a reduced crypt cell proliferation, a reduced villus height and a decreased ALP activity in the ileal mucosa. Treatment with amperozide resulted in a normalisation of plasma ALP activity in unthrifty pigs, indicating a stimulation of body growth. The results indicate that the growth depression of wasting pigs is most probably a chronic stress syndrome caused by the inability of these animals to cope with the events following weaning and mixing.

Effect of amperozide on the dopamine synthesis activity in the tuberoinfundibular neurons.

The ability of amperozide (N-ethyl-4-[4,4-bis(p-fluorophenyl)butyl]-1-piperazinecarboxamide) , a potentially antipsychotic agent, to activate the tuberoinfundibular dopamine (TIDA) neurons was studied by measuring the accumulation of dihydroxyphenylalanine (DOPA) in the median eminence after inhibition of DOPA decarboxylase. The activity of the TIDA neurons was markedly elevated in a dose-related manner after treatment with amperozide (1 and 10 mg/kg). A significant stimulation was also found following treatment with the atypical antipsychotic agent clozapine (20 mg/kg) while the typical antipsychotic drug haloperiodol had no effect on TIDA neuron activity. The stimulatory effect of amperiozide on the TIDA neurons is suggested to be mediated by a non-dopaminergic mechanism.

Amperozide--effect on prolactin release in the rat.

Amperozide, a new putatively antipsychotic drug was investigated for its effect on prolactin release in the rat. A significant decrease in the plasma concentration of prolactin was found at 30 minutes after treatment with amperozide. However, there was no effect of amperozide on prolactin release from isolated pituitary cells. These results suggest that there is no direct effect of amperozide on the pituitary lactotrophs and that the attenuation of prolactin secretion in vivo is mediated at a higher level.

Proportion of Swedish school nurses' time devoted to different health care activities.

School nurses play an important role in the preventive health care of children and adolescents. This study aimed to describe and investigate the school nurses' different activities and time spent on these activities. By completion of a time study record form all 26 school nurses, in a medium-sized town in Sweden, documented their activities during 10 working-days. Altogether 635 record forms were received. It was found that almost half of the school nurses' time was used for individual pupil activities, 17% for groups of pupils and 34% for administrative activities. School nurses spent 17% of all their working time at the school clinic, which in some way may reflect the pupils need of the nurse in the school. These results highlighted the importance of school nurses and resulted in internal structural changes of school nurses' working time.

In the search for a novel class of antipsychotic drugs: preclinical pharmacology of FG5803, a 1-piperazinecarboxamide derivative.

Comparative studies of the 1-piperazinecarboxamide derivative 4-[3-(4-fluorobenzoyl)propyl]-N-cyclohexyl-1-piperazinecarboxamide hydrochloride (FG5803) were made with clozapine and haloperidol. Receptor studies revealed that FG5803 potently and selectively bound to the serotonin type 2A receptors (Ki = 13 nM). FG5803 inhibited 5-hydroxytrophan- and 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane-induced head twitches, which indicated potent in vivo serotonin type 2A receptor antagonism. FG5803 caused an acute activation of the tuberoinfundibular dopamine neurons and produced only a transient rise in plasma prolactin. In behavioral studies in rats, FG5803 showed strong antagonistic action on presynaptic dopaminergic autoreceptors but only weak postsynaptic dopamine D2 blockade. FG5803 was not cataleptogenic and did not antagonize amphetamine-induced stereotypies. FG5803 was active in the reduction of aggressive behavior and spontaneous exploratory behavior in mice and rats. Therefore, FG5803 is expected to constitute a promising approach in the search for a novel class of antipsychotic drugs that have a broader spectrum of activity and fewer adverse effects than the conventional, antidopaminergic antipsychotics.