S-16924 [(R)-2-[1-[2-(2,3-dihydro-benzo[1,4]dioxin-5-yloxy)-ethyl]- pyrrolidin-3yl]-1-(4-fluorophenyl)-ethanone], a novel, potential antipsychotic with marked serotonin1A agonist properties: III. Anxiolytic actions in comparison with clozapine and haloperidol.
S-16924 is a potential antipsychotic that displays agonist and antagonist properties at serotonin (5-HT)1A and 5-HT2A/2C receptors, respectively. In a pigeon conflict procedure, the benzodiazepine clorazepate (CLZ) increased punished responses, an action mimicked by S-16924, whereas the atypical antipsychotic clozapine and the neuroleptic haloperidol were inactive. Similarly, in a Vogel conflict paradigm in rats, CLZ increased punished responses, an action shared by S-16924 but not by clozapine or haloperidol. This action of S-16924 was abolished by the 5-HT1A antagonist WAY-100,635. Ultrasonic vocalizations in rats were inhibited by CLZ, S-16924, clozapine, and haloperidol. However, although WAY-100,635 abolished the action of S-16924, it did not affect clozapine and haloperidol. In a rat elevated plus-maze, CLZ, but not S-16924, clozapine, and haloperidol, increased open-arm entries. Like CLZ, S-16924 increased social interaction in rats, whereas clozapine and haloperidol were inactive. WAY-100,635 abolished this action of S-16924. CLZ, S-16924, clozapine, and haloperidol decreased aggressive interactions in isolated mice, but this effect of S-16924 was not blocked by WAY-100, 635. All drugs inhibited motor behavior, but the separation to anxiolytic doses was more pronounced for S-16924 than for CLZ. Finally, in freely moving rats, CLZ and S-16924, but not clozapine and haloperidol, decreased dialysis levels of 5-HT in the nucleus accumbens: this action of S-16924 was blocked by WAY-100,165. In conclusion, in contrast to haloperidol and clozapine, S-16924 possessed a broad-based profile of anxiolytic activity at doses lower than those provoking motor disruption. Its principal mechanism of action was activation of 5-HT1A (auto)receptors. (+info)
Selective antiaggressive effects of alnespirone in resident-intruder test are mediated via 5-hydroxytryptamine1A receptors: A comparative pharmacological study with 8-hydroxy-2-dipropylaminotetralin, ipsapirone, buspirone, eltoprazine, and WAY-100635.
The present study characterized the effects of the novel, selective, and potent 5-hydroxytryptamine1A (serotonin) (5-HT1A) receptor agonist, alnespirone [S-20499, (S)-N-4-[5-methoxychroman-3-yl)propylamino)butyl- 8-azaspiro-(4,5)-diacetamide, hydrochloride] on offensive and defensive resident-intruder aggression in wild-type rats and compared its actions with those of the prototypical full 5-HT1A agonist 8-hydroxy-2- dipropylaminotetralin (8-OH-DPAT), the partial 5-HT1A agonists ipsapirone and buspirone, and the mixed 5-HT1A/1B agonist eltoprazine. All five agonists exerted effective dose-dependent decreases of offensive aggressive behavior in resident rats; 8-OH-DPAT was the most potent (ID50 = 0.074 mg/kg), followed by eltoprazine (0.24), buspirone (0.72), ipsapirone (1.08), and alnespirone (1.24). However, in terms of selectivity of the antiaggressive effects as determined by the absence of decrements in social interest and general motor activity, alnespirone appeared to be superior. In the defensive aggression test, neither alnespirone nor any of the other four agonists changed defensive behaviors in the intruder rats. The involvement of 5-HT1A receptors in the antiaggressive actions of these drugs was confirmed by showing that the selective 5-HT1A receptor antagonist WAY-100635 (N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2- pyridinyl)cyclohexanecarboxamide trihydrochloride), which was inactive alone, fully prevented the antiaggressive effects of alnespirone, 8-OH-DPAT, and buspirone and partly reversed those of ipsapirone and eltoprazine. The data clearly indicate that alnespirone effectively suppresses offensive aggression with an advantageous profile of action compared with other full or partial 5-HT1A agonists. These selective antiaggressive actions of alnespirone are mediated by stimulating 5-HT1A receptors, presumably the somatodendritic autoreceptors at the raphe nuclei. Furthermore, the data provide evidence for a major involvement of these 5-HT1A receptors in the modulation of aggressive behavior by 8-OH-DPAT, ipsapirone, buspirone, and eltoprazine. (+info)
Measuring intermediate outcomes of violence prevention programs targeting African-American male youth: an exploratory assessment of the psychometric properties of six psychosocial measures.
This study examined the psychometric properties of six psychosocial measures that may be useful indicators of intermediate outcomes of violence prevention programs targeting African-American male youth. Baseline and 6 month follow-up survey data are used from 223 African-American male 12-16 year olds participating in a violence prevention program evaluation study. The constructs of interest are beliefs supporting aggression, aggressive conflict-resolution style, hostility, ethnic identity, self-esteem and hopelessness. Each construct is measured as a multi-item scale. Exploratory factor analysis results provided limited support for the unidimensionality of these scales, thus suggesting that further scale development is warranted. Reliability coefficients for the scales ranged from 0.55 to 0.80. Bivariate analyses with baseline data indicate that all six measures have construct and criterion-related validity, as they are associated with each other and with four behavioral criteria in the expected directions. Predictive validity was also demonstrated for beliefs supporting aggression, aggressive conflict-resolution style, hostility and hopelessness which were associated with weapon-carrying behaviors measured in the 6 month follow-up survey both before and after controlling for corresponding behaviors measured in the baseline survey. (+info)
d,l-fenfluramine response in impulsive personality disorder assessed with [18F]fluorodeoxyglucose positron emission tomography.
Reduced serotonergic activity has been associated with impulsive aggression in personality disordered patients in metabolite and pharmacologic challenge studies. This study used positron emission tomography to explore whether reduced serotonergic function occurs in critical brain regions such as orbital frontal and cingulate cortex that, may play a role in modulating aggression. Six impulsive-aggressive patients and five healthy volunteers were evaluated for changes in regional glucose metabolism after administration of the serotonergic releasing agent d,l-fenfluramine (60 mg, p.o.) or placebo. Volunteers demonstrated increases in orbital frontal and adjacent ventral medial frontal cortex, cingulate, and inferior parietal cortex, whereas impulsive-aggressive patients showed no significant increases in glucose metabolism after fenfluramine in any region. Compared with volunteers, patients showed significantly blunted metabolic responses in orbital frontal, adjacent ventral medial and cingulate cortex, but not in inferior parietal lobe. These results are consistent with reduced serotonergic modulation of orbital frontal, ventral medial frontal, and cingulate cortex in patients with impulsive-aggressive personality disorders. (+info)
Side effects of extinction: prevalence of bursting and aggression during the treatment of self-injurious behavior.
Findings from basic and applied research suggest that treatment with operant extinction may produce adverse side effects; two of these commonly noted are an increase in the frequency of the target response (extinction burst) and an increase in aggression (extinction-induced aggression). Although extinction is often used to treat problem behavior in clinical settings, few applied studies have examined the prevalence of these side effects or their possible attenuation with other operant procedures. An analysis of 41 data sets for individuals who received treatment for self-injurious behavior indicated that extinction bursts or increases in aggression occurred in nearly one half of the cases. The prevalence of bursting and aggression was substantially lower when extinction was implemented as part of a treatment package rather than as the sole intervention. (+info)
An evaluation of "informed consent" with volunteer prisoner subjects.
"Informed consent" sets a goal for investigators experimenting with human subjects, but little is known about how to achieve or evaluate it in an experiment. In a 3-year, double-blind study with incarcerated men, we attempted to provide a "free and informed consent" and evaluated our efforts with an unannounced questionnaire administered to subjects after they completed the experiment. At that time, approximately two-thirds had sufficient information for an informed consent, but only one-third was well informed about all key aspects of the experiment and one-third was insufficiently informed to give an informed consent. We found that institution- or study-based coercion was minimal in our experiment. From our evaluation of the questionnaire and experience at the study institution, we conclude that an experiment with human subjects should be designed to include an ongoing evaluation of informed consent, and active attempts should be made to avoid or minimize coercive inducements. Experiments with significant risk, which require a long duration and/or large sample size relative to the institution's population, should probably not be performed on prisoner subjects. The experimenter should be independent of the penal institution's power structure. Presenting and explaining a consent form to volunteers on one occasion is probably an in adequate procedure for obtaining and maintaining an informed consent. (+info)
Practical approaches to reduce the impact of bullying.
Bullying has serious long term consequences for all concerned. The cost of ignoring bullying is great, and it is no longer acceptable to view bullying as a normal part of everyday life that children have to learn to tolerate. Effective strategies exist to reduce the frequency of bullying and to make this type of aggressive behaviour less likely to occur. (+info)
Emotional stress and characteristics of brain noradrenaline release in the rat.
We have investigated several characteristics of the rat brain noradrenaline (NA) release caused by various stressful situations. Stresses such as immobilization or electric foot shock, wherein the physical factors rather than emotional ones were greatly involved, caused more marked increases in NA release in the more extended brain regions, as compared to psychological stress and conditioned fear, which caused increases in NA release preferentially in the hypothalamus, amygdala and locus coeruleus (LC) region. When the electric shock stress and psychological stress for 1 hr daily were repeated for 5 consecutive days, increases in brain NA release induced by electric shock were rapidly reduced, but those caused by psychological stress were enhanced rather than reduced. Rats with no stressor controllability (uncontrollable) had more severe gastric lesions and more marked increases in NA release in such brain regions as the hypothalamus and amygdala after 21 hrs of training than controllable rats. Rats with no opportunity to predict electric shock exhibited more severe gastric lesions and more marked increases in hypothalamic NA release than the predictable rats. The rats not allowed to express their aggression had more severe gastric mucosal lesions and a more noticeable and persistent increases in extracellular NA content in the amygdala determined by intracerebral microdialysis than the rats allowed to express aggression by biting a wooden stick in front of them during stress exposure. In aged rats (12 months old), recovery from increases in NA release in the hypothalamus and amygdala and increases in plasma corticosterone were much later than in young (2-month-old) rats. When rats were exposed to a series of six 15-min stress interrupted by 18-min non-stress periods for 180 min, they had much greater increases in brain NA release than rats stressed continuously for 180 min. Based upon these findings, we suggest that such stresses might be harmful to our health as psychological, uncontrollable and unpredictable stresses, stress unable to express aggression, stress in elderly people, and stress with lack of suitable rest. (+info)