Mirogabalin prevents repeated restraint stress-induced dysfunction in mice.

Gabapentinoids, which are the common analgesics, are also thought to be an effective treatment for anxiety disorder, which is one of several psychiatric disorders triggered and exacerbated by stress. The aim of the present study was to investigate whether mirogabalin, a recently launched gabapentinoid, protects multiple brain functions against repeated restraint stress. Adult male ddY mice were restrained for 7 days (repeated restraint stress: 2 h/day) or for 30 min (single restraint stress). Mirogabalin (intraperitoneal, intracerebroventricular or intrahippocampal injection) was administered prior to the restraint stress. Y-maze, elevated-plus maze and c-Fos immunohistochemistry were performed to evaluate learning function, anxiety levels and hippocampal neuronal activities, respectively, after the 7th day of the repeated restraint stress. Intestinal function was evaluated in terms of defecation, which was scored after the 5th day of repeated restraint stress and by the number of fecal pellets excreted after a single session of restraint stress. Repeated restraint stress induced memory dysfunction, anxiety-like behavior, an abnormal defecation score and increased hippocampal c-Fos expression. These changes were prevented by systemic administration of mirogabalin. Abnormal defecation was also induced by single restraint stress, and was inhibited by both systemic and central administration of mirogabalin, suggesting that the effect on the intestinal function was also mediated via the central nervous system. Enhancement of c-Fos expression by repeated stress was decreased by intrahippocampal injection of mirogabalin. Together, these observations suggest that mirogabalin protects multiple brain functions from repeated stress, which may be mediated by inhibition of hippocampal neuron hyperactivation.

Maternal-Neonatal Pheromone/Interomone Added to Cat Litter Improves Litter Box Use and Reduces Aggression in Pair-Housed Cats.

Introducing a new cat into a household with one or more resident cats can be a significant source of stress for the cats involved. These studies sought to determine if rabbit maternal-neonatal pheromone (2-methyl-2-butenal [2M2B]) in litter impacted cat social behaviors and litter box use. Study 1 determined that cats preferred to eliminate in litter containing 2M2B; other semiochemicals tested did not change litter box use. Cats prone to aggression were identified in an intermediate pilot study, and eight pairs of these cats were selected for Study 2. In Study 2, cat pairs were provided litter containing either vehicle or 2M2B for 24 hours. Cats experiencing control litter displayed more aggression during the first 6 hours (p < .01) and spent more time using the litter box 12 hours and 18 hours after pairing compared with cats experiencing litter with 2M2B (p = .02). These results suggest 2M2B-infused cat litter may act as an interomone in cats housed domestically to prevent initial occurrences of aggression and may improve cat welfare in multicat households.

Mixture of cis-3-hexenol and trans-2-hexenal attenuates behavioral and stress responses induced by 2,5-dihydro-2,4,5-trimethylthiazoline and electric footshock stress in rats.

Green odor (GO), a mixture of cis-3-hexenol and trans-2-hexenal, attenuates stress responses and anxiety to psychological stressors in rodents; however, it remains unknown whether GO affects behavioral and stress responses to risk-related olfactory stimuli and actual noxious stimuli. The present study investigated the effects of green odor on behavioral and plasma adrenocorticotropic hormone (ACTH) responses to 2,5-dihydro-2,4,5-trimethylthiazoline (TMT), a component of fox feces, and electric footshock (FS) stress. When rats were simultaneously exposed to TMT and GO, they showed decreases in immobility and plasma ACTH levels compared with TMT alone. GO exposure after TMT increased immobility, but blocked the elevation of plasma ACTH levels compared with rats exposed to distilled water after TMT. This means that GO presentation during TMT attenuated the TMT-induced behavioral response and GO presentation during and after TMT inhibited TMT-induced elevation of plasma ACTH levels. Furthermore, electric FS-induced plasma ACTH elevations were attenuated by simultaneous GO and FS exposure. GO presentation after FS attenuated plasma ACTH elevations and fecal responses. These findings reveal that GO has alleviating effects on olfactory stimulus- and noxious stimulus-induced behavioral and endocrinal responses.

Anxiolytic effect of a herbal medicine, yokukansan, in aged rats: involvement of serotonergic and dopaminergic transmissions in the prefrontal cortex.

AIM OF THE STUDY: Aging is thought to affect emotions including anxiety, and a herbal medicine, yokukansan (YKS), is used to treat emotional disturbances associated with age-related neurodegenerative disorders such as Alzheimer's disease, but its pharmacological properties have not been fully understood. The present study was designed to examine whether YKS improves age-related anxiety using F344/N aged rats. Moreover, the effects of YKS on liver function were examined. MATERIALS AND METHODS: YKS was administered to 21-month-old aged rats for 3 months. Locomotor activity of young control (4 months old), aged control (24 months old), and YKS-treated aged rats was examined, and the anxiety-related responses of these animals were evaluated by counting the number of excrements during locomotor activity measurement and in the elevated plus-maze test. The extracellular concentrations of serotonin and dopamine in the prefrontal cortex (PFC) were also measured using a microdialysis technique. Moreover, concentrations of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and ammonia (NH(3)) in plasma were measured. RESULTS: Although locomotor activity did not change among any experimental groups, the number of excrements was significantly increased in aged rats compared to young rats, and this increase was significantly improved by YKS treatment. Aged rats also showed significant decreases in time and frequency in the open arm of the elevated plus-maze, and these decreases were significantly improved by YKS treatment. Extracellular concentrations of serotonin and dopamine in the aged PFC were significantly decreased; serotonin was increased over the level of young rats and dopamine was partially improved by YKS treatment, respectively. In addition, YKS improved age-related increase in NH(3) concentration, but did not affect AST and ALT. CONCLUSIONS: YKS has improving activity for age-related increased anxiety and enhances serotonergic and dopaminergic transmissions in the aged PFC. These mechanisms provide information important for the treatment of anxiety in the elderly. Furthermore, the present data confirm partially the Kampo concept "liver disease".

PRX-00023, a selective serotonin 1A receptor agonist, reduces ultrasonic vocalizations in infant rats bred for high infantile anxiety.

To address the development of early anxiety disorders across the lifespan, the High USV line of rats was bred based on rates of infant ultrasonic vocalization in the 40-50 kHz range of predominant frequencies (USV) to maternal separation at postnatal day (P) 10. In this study, rates of USV in High line infants (pups: Postnatal Day 11+/-1) were compared to those of randomly-bred controls in response to EPIX compound PRX-00023, a unique serotonin (5-HT) agonist, acting exclusively at the 5-HT1A receptor, or buspirone, a nonspecific 5HT1A agonist. After testing, pups were examined for sedation and other drug-related effects. The results indicated that all doses of buspirone reduced USV rates in isolation, consistent with other reports. PRX-00023 significantly reduced USV rates at the lowest doses (0.01-0.05 mg/kg). None of the PRX-00023 doses produced sedation, whereas all but the lowest dose of buspirone (0.1 mg/kg) produced sedation effects. The results suggest that this compound alleviates infantile anxiety-like behavior with great specificity in rats bred for high anxiety/depressive phenotypes by selectively targeting 5-HT1A receptors, possibly by both pre- and post-synaptic mechanisms.

Identified motoneurons involved in sexual and eliminative functions in the rat are powerfully excited by vasopressin and tachykinins.

The pudendal motor system is constituted by striated muscles of the pelvic floor and the spinal motoneurons that innervate them. It plays a role in eliminative functions of the bladder and intestine and in sexual function. Pudendal motoneurons are located in the ventral horn of the caudal lumbar spinal cord and send their axon into the pudendal nerve. In the rat, binding sites for vasopressin and tachykinin are present in the dorsomedial and dorsolateral pudendal nuclei, suggesting that these neuropeptides may affect pudendal motoneurons. The aim of the present study was to investigate possible effects of vasopressin and tachykinins on these motoneurons. Recordings were performed in spinal cord slices of young male rats using the whole-cell patch-clamp technique. Before recording, motoneurons were identified by 1,1'-dilinoleyl-3,3,3',3'-tetramethylindocarbocyanine, 4-chlorobenzenesulfonate retrograde labeling. The identification was confirmed, a posteriori, by choline acetyltransferase immunocytochemistry. Vasopressin and tachykinins caused a powerful excitation of pudendal motoneurons. The peptide-evoked depolarization, or the peptide-evoked inward current, persisted in the presence of tetrodotoxin, indicating that these effects were mainly postsynaptic. By using selective receptor agonists and antagonist, we determined that vasopressin acted via vasopressin 1a (V1a), but not V1b, V2, or oxytocin receptors, whereas tachykinins acted via neurokinin 1 (NK1), but not NK2 or NK3, receptors. Vasopressin acted by enhancing a nonselective cationic conductance; in some motoneurons, it also probably suppressed a resting K+ conductance. Our data show that vasopressin and tachykinins can excite pudendal motoneurons and thus influence the force of striated perineal muscles involved in eliminative and sexual functions.

Control of musth in an Asian elephant bull (Elephas maximus) using leuprolide acetate.

The results of long-term administration of leuprolide acetate (LA) depot in a 52-yr-old Asian elephant bull (Elephas maximus) for control of musth are presented. Twelve injections were administered for 6 yr during our interpretation of early musth or "premusth." Intervals between musth periods during the study varied from 2 to 34 mo. Blood samples, drawn weekly, were assayed for serum testosterone concentrations; mean levels were 11.78 +/- 1.97 nmol/L throughout the first 26 mo of the study, 7.28 +/- 1.28 nmol/L during the following 21 mo, and 0.45 +/- 0.035 nmol/L in the last 34 mo of this study. Early musth signs ceased within 3 days of drug administration after 10 of 12 injections. The mean serum testosterone concentrations were significantly decreased by the last 34 mo of the study. The results suggest leuprolide is a suitable alternative for controlling or preventing (or both) musth in captive Asian elephants, although permanent reproductive effects may occur. Zoos and wildlife conservation institutions could benefit from the use of LA in Asian elephants to increase the male availability in captivity, consequently ensuring genetic diversity and the perpetuation of the species.

A pilot study using synthetic feline facial pheromone for the management of feline idiopathic cystitis.

Synthetic feline facial pheromone (FFP) (Feliway; Ceva Animal Health) was assessed for the management of cats with recurrent feline idiopathic cystitis (FIC). Nine of 12 cats completed the randomised, double-blinded, placebo-controlled, crossover pilot study. They had their environment treated daily with either FFP or placebo for 2 months, after which time the treatment groups were reversed. Owners used visual analogue scales to define the severity of their cat's clinical signs and behavioural changes. Five (56%) of the owners stated that their cat's overall health was better when they were using FFP. Four (44%) of the owners noticed no difference between when using the FFP and when using the placebo. While there were no statistical differences between the two treatment groups there was a trend for the cats exposed to FFP to show fewer days with clinical signs of cystitis (FFP total, mean per cat+/-standard deviation, 30, 4.3+/-6.7; placebo 69, 9.9+/-19.1), a lower overall clinical score (1667, 238+/-476; 2009, 287+/-425), a reduced number of episodes of cystitis (9, 1.3+/-2.0; 10, 1.4+/-2.1) and reduced negative behavioural traits (e.g., less aggression and fear) (-128, -18.3+/-65.8; -73, -10.4+/-35.1).

Current research in canine and feline pheromones.

Pheromonotherapy seems to be a new therapeutic approach allowing practitioners to tackle the treatment of behavioral disorders in a natural, specific, and safe way. Although the efficacy of pheromones has been assessed in some specific behavioral problems, it seems that their range of action could cover the wide field of reduction of stress. Therefore, the use of pheromones should not be reduced to treatment of behavioral disorders (potentially associated with psychotropes or a behavioral modification program) but should be included in a strategy of improving the welfare of pets in veterinary structures (during examination and hospitalization) and in breeding networks (separation from the mother and transport). Moreover, further studies may allow the veterinary practitioner to use pheromone analogues in the field of diagnostics to determine the behavioral status of a pet (e.g., anxious or not, dominant or not). Pheromonotherapy is at its beginning, and the use of pheromones in various fields of medicine is heartening.

Clinical trial of a feline pheromone analogue for feline urine marking.

Thirty-six cases of feline urine marking problem were collected through the cooperation of veterinary practitioners in the Kanto, Chubu, and Kansai areas in Japan, for an assessment of the clinical effect of treatment with a synthetic analogue of a feline cheek gland pheromone-like product. The mean frequency of urine marking was 14.2 times/week (median, 10; range, 1-77) at pre-treatment week (preW), and decreased significantly from the first week of treatment, dropping to 4.2 times/week (median, 2; range, 0-44) at the fourth week of treatment. This effect continued until the fourth week after cessation of treatment. These 36 cases were divided into 3 groups based on the effectiveness of treatment as demonstrated in the fourth week of treatment; 37% was categorized as the totally eliminated group (urine marking was not seen), 40% as the reduced group (the frequency of urine marking was equal to or less than 50% that of the preW), and 23% as the unchanged group (the frequency of urine marking was more than 50% that of the preW). Effectiveness of treatment in these groups was 38%, 24%, and 38% at the fourth week after the cessation of treatment, respectively. The decreasing rate of urine marking was compared between cats with and without intercat aggression, and it was revealed that the frequency of marking was sustained at high level in cats with intercat aggression. These results suggest that this pheromone treatment is as effective in Japan as has been reported in other countries for solving feline urine marking problems.

Feline inappropriate elimination.

Cases involving inappropriate elimination can be treated successfully through careful diagnosis, identification of causative factors, and development of an appropriate treatment plan. Veterinarians can provide a valuable service to their clients through case workups, educational information, and timely referrals. Normal elimination and marking behavior and causative factors involved in inappropriate elimination cases are reviewed. Treatments, including behavior modification techniques and drug therapy suggestions, also are included in this article.

Single-dose and 13-week repeated-dose neurotoxicity screening studies of chlorpyrifos insecticide.

Chlorpyrifos (CPF), a widely used organophosphate insecticide, was screened for neurotoxic effects in Fischer 344 rats using United States Environmental Protection Agency 1991 guidelines for single-dose and 13-wk repeated dose studies. The studies emphasized a functional observational battery (which included grip performance and hindlimb splay tests), automated motor activity testing and comprehensive neurohistopathology of perfused tissues. Doses of up to 100 mg/kg body weight in corn oil by gavage in the single-dose study and up to 15 mg/kg body weight/day in diet for 13 wk in the repeated dose study were administered. It is known that CPF and other phosphorothionates can be activated to the oxon in local (extrahepatic) tissues. Local activation could possibly cause different effects in different tissues with cholinergic innervation, and thereby create syndromes unique to each phosphorothionate according to their structure. Consequently, the conduct of CPF neurotoxicity screening studies by contemporary guidelines offered opportunity to characterize the CPF over-exposure syndrome in rats. Single-dose high levels of oral exposure to CPF caused a range of clinical signs characteristic of cholinergic overstimulation. Although there was no clinical evidence of wide differences in sensitivity of one cholinergic response versus another, motor dysfunction (incoordination etc.) was more prominent than other signs, for example soiling. Effects were much more apparent in females and regressed over several days. Effects were minimal in the 13-wk study, and there was no evidence of accumulation of toxicity during the 13 wk of daily dietary exposure. Motor activity was decreased at the high dose in males and females at wk 4, but was not significantly different from controls in subsequent weeks. The 'normalization' of motor activity later in the study was interpreted as tolerance to repeated administration of CPF. Comprehensive neuropathological examination revealed no treatment-related lesions in either study.

Effects of diazepam and cyclohexyladenosine on open-field behavior in rats perinatally exposed to caffeine.

Adult rat offspring earlier exposed to maternally ingested caffeine during both gestation and lactation were observed in an open field following acute administration of diazepam or cyclohexyladenosine. While both drugs reduced measures of locomotion and emotional reactivity, caffeine-exposed rats showed evidence of greater sensitivity to cyclohexyladenosine (but not diazepam) as determined by its effects on grooming behavior and tendencies to occupy the center squares of the apparatus. This suggested that adenosine (A1) rather than benzodiazepine receptor activity had been affected by the perinatal caffeine experience which also reduced locomotor activity while increasing center occupancy. The acute effects of diazepam and cyclohexyladenosine also depended largely on the sex of the subjects. Diazepam affected locomotor activity more and both drugs affected defecation less in females than in males. No other interaction involving sex was significant.

Memory storage and effect of repeated treatment with a new antidepressant drug: rubidium chloride.

Following 15 days' treatment with saline, 48 mg/kg rubidium chloride, 5 mg/kg imipramine hydrochloride, 10 mg/kg sodium phenobarbitone, 1000 mg/kg piracetam, or 0.20 mg/kg strychnine nitrate all administered intraperitoneally, mice were evaluated by habituation of exploratory activity using an open-field apparatus. In control animals a significant (P less than 0.05) decrease in open-field responses (ambulation, rearing and defaecation) was seen following a 1-day intersession interval and there was no retention of exploratory activity after a 5-day intersession interval. Administration of imipramine or phenobarbitone for 15 days was found to impair retention of memory after 1 day, whereas treatment with rubidium chloride, piracetam, or strychnine for 15 days improve retention after a 5-day intersession interval.

[Effect of intracerebroventricular injection of histamine on the behavior of the white rat]. / Efectos de la inyección intracerebroventricular de histamina sobre el comportamiento de la rata blanca.

Previous references showed that the histamine injected peripherically produced a deterioration of the learning in experimental animals. The effects of 100 and 200 micrograms of histamine administered in the cerebral lateral ventricle, have been tested using an experimental paradigm which isolated attentional, motivational, and motor factor from the complex learned behavior. The obtained results showed to be similar to those produced by peripheric injection, and demonstrated a worsening in attentional, motivational, and motor parameters.

Regulatory changes following kainic acid-induced striatal lesions.

Kainic acid-induced lesions (KAL) of the striatum produce body weight and regulatory deficits in the rat. Unlike lateral hypothalamic rats. KAL rats drink more during food deprivation and eat more afterwards as compared to both baseline conditions and control rats. The present study investigated these effects further. As in previous studies, food deprivation was found to cause polydipsia and increased postdeprivational food intake in the KAL animal. Urination and defecation, often used as an index of emotionality, were also found to increase under these conditions. When the antidiuretic hormone vasopressin was injected, all of these differences remained with the exception of postdeprivational feeding--KAL rats no longer ate more than controls. These findings suggest that psychogenic factors--but not hormonal influences--may play a primary role in the regulatory peculiarities seen in the KAL rat.

Effect of perinatal antisteroid treatment on territorial marking behavior in the mongolian gerbil.

Sex differences have been observed in the perinatal sexual differentiation of the neural substrate which regulates territorial marking behavior in the Mongolian gerbil. The present study examines the relative contribution of prenatal and postnatal steroid environment to sexual differentiation in the male and androgenized female using territorial marking behavior as an endpoint. Selective suppression of steroid effects in the pre- and postnatal period was accomplished with the antiandrogen flutamide or the antiestrogen MER-25. Treatment was given prenatally (for 5 days before expected parturition), on the day of birth, and postnatally (to day 10) or prenatally and on the day of birth only. Animals without postnatal antisteroid treatment were intact or were gonadectomized on day 2 and given testosterone propionate (TP) treatment on day 7. (It has previously been shown that day 7 is beyond the period of maximum steroid responsiveness in the male but not in the androgenized female.) MER-25, flutamide, or day-2 ovariectomy had no effect on adult marking behavior responsiveness in females given TP on day 7. All groups marked at normal male frequencies. The presence of flutamide prenatally and on the day of birth in day-2 castrates given TP on day 7 yielded adults with marking responsiveness equivalent to day-7 TP-treated females. In contrast, males given day-7 TP without prenatal and birthday flutamide showed significantly lower marking frequencies, suggesting that the presence of androgen prenatally and on the day of birth rendered day-2 castrates less responsive to TP given on day 7.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of testosterone on ontogeny of urinary behavior in male and female dogs.

Development of urinary behavior from birth to adulthood was observed in six groups of beagles including normal males (NM), normal females (NF), males castrated soon after birth (CM), males castrated soon after birth and treated with testosterone (T) for the next 90 days (CMT), females exposed to T in utero (FTU), and females exposed to T in utero and during infancy, i.e., the first 30-40 days postpartum (FTUI). Prenatal treatment with T had masculinizing effects on juvenile urinary behavior in FTU and FTUI. On the other hand normal development of fully adult masculine urinary patterns in males and females necessitated both prenatal and postnatal androgenic stimulation. It was not necessary that T be present at the time the overt behavior developed. For example, adult male behavior appeared in FTUI at the same time as in NM, i.e., 6-10 months, although the supply of exogenous androgen in FTUI had been exhausted within 30-40 days after birth. CMT showed precocious development of all components of the adult male pattern. Development of adult responses was markedly retarded in most CM, and their performance did not equal that of NM at 23 months. They were then injected with TP which promptly evoked completely normal male urinary behavior. It is tentatively concluded that T acting before birth and during the juvenile period "prepares" critical CNS mechanisms so that when general maturation reaches the appropriate point adult male behavior develops. Although the preparatory role of T is essential, the behavior is not dependent on T after it has developed.