Enhanced inhibitory control by neuropeptide Y Y5 receptor blockade in rats.

RATIONALE: The neuropeptide Y (NPY) system acts in synergy with the classic neurotransmitters to regulate a large variety of functions including autonomic, affective, and cognitive processes. Research on the effects of NPY in the central nervous system has focused on food intake control and affective processes, but growing evidence of NPY involvement in attention-deficit/hyperactivity disorder (ADHD) and other psychiatric conditions motivated the present study. OBJECTIVES: We tested the effects of the novel and highly selective NPY Y5 receptor antagonist Lu AE00654 on impulsivity and the underlying cortico-striatal circuitry in rats to further explore the possible involvement of the NPY system in pathologies characterized by inattention and impulsive behavior. RESULTS: A low dose of Lu AE00654 (0.03 mg/kg) selectively facilitated response inhibition as measured by the stop-signal task, whereas no effects were found at higher doses (0.3 and 3 mg/kg). Systemic administration of Lu AE00654 also enhanced the inhibitory influence of the dorsal frontal cortex on neurons in the caudate-putamen, this fronto-striatal circuitry being implicated in the executive control of behavior. Finally, by locally injecting a Y5 agonist, we observed reciprocal activation between dorsal frontal cortex and caudate-putamen neurons. Importantly, the effects of the Y5 agonist were attenuated by pretreatment with Lu AE00654, confirming the presence of Y5 binding sites modulating functional interactions within frontal-subcortical circuits. CONCLUSIONS: These results suggest that the NPY system modulates inhibitory neurotransmission in brain areas important for impulse control, and may be relevant for the treatment of pathologies such as ADHD and drug abuse.

[Health promotion within health care - analysis of employees' smoking habits, consequences for patient care and resources for future smoking cessation initiatives]. / Gesundheitsförderung im Gesundheitswesen - Analyse der Rauchgewohnheiten der Mitarbeiter, Konsequenzen für die Patientenbehandlung und Ressourcen für zukünftige Tabakentwöhnungsinitiativen.

Smoking is still one of the most dangerous and avoidable health risks. This study "Healthy air at work" analysed smoking habits, state of change, the influence of the diagnosis F.17.0 in patient treatment and estimation of subjective workloads and personal resources in health-care workers. Almost 2 000 questionnaires were analysed. 19.9% of this study population were smokers, while 26.4% were considered to be heavy or very heavy smokers. Half of the current smokers were willing to change, while the majority had already tried to quit multiple times. The most important motive to stop smoking was fear of consequences (44.4%), followed by other reasons (42.3%) (e. g., pregnancy) and expenses (33.9%). Protection against second-hand smoke was estimated mostly as very relevant, especially for patients. Being a role model in terms of tobacco consumption seems to be important for health-care workers. 61.3% of all health-care workers stated that patients' nicotine dependency had been diagnosed and out of these 46.5% say it is a relevant factor in therapy. 60% of all interviewed employees evaluated themselves as working quantitatively under heavy and very heavy workloads, while 20% had to deal with high qualitative challenges. In terms of future work ability and personal resources 75% were considerably optimistic. We did not find any relation in terms of workloads and smoking habits. Rather few health-care workers used nicotine replacement therapy during former cessation trials. Health-care workers could play an important role in the treatment and prevention of smoking dependency. This potential is not used to its full extent up to now.

Rainforest aerosols as biogenic nuclei of clouds and precipitation in the Amazon.

The Amazon is one of the few continental regions where atmospheric aerosol particles and their effects on climate are not dominated by anthropogenic sources. During the wet season, the ambient conditions approach those of the pristine pre-industrial era. We show that the fine submicrometer particles accounting for most cloud condensation nuclei are predominantly composed of secondary organic material formed by oxidation of gaseous biogenic precursors. Supermicrometer particles, which are relevant as ice nuclei, consist mostly of primary biological material directly released from rainforest biota. The Amazon Basin appears to be a biogeochemical reactor, in which the biosphere and atmospheric photochemistry produce nuclei for clouds and precipitation sustaining the hydrological cycle. The prevailing regime of aerosol-cloud interactions in this natural environment is distinctly different from polluted regions.

Asenapine: a novel psychopharmacologic agent with a unique human receptor signature.

Asenapine is a novel psychopharmacologic agent under development for the treatment of schizophrenia and bipolar disorder. We determined and compared the human receptor binding affinities and functional characteristics of asenapine and several antipsychotic drugs. Compounds were tested under comparable assay conditions using cloned human receptors. In comparison with the antipsychotics, asenapine showed high affinity and a different rank order of binding affinities (pKi) for serotonin receptors (5-HT1A [8.6], 5-HT1B [8.4], 5-HT2A [10.2], 5-HT2B [9.8], 5-HT2C [10.5], 5-HT5 [8.8], 5-HT6 [9.6] and 5-HT7 [9.9]), adrenoceptors (alpha1 [8.9], alpha2A [8.9], alpha2B [9.5] and alpha2C [8.9]), dopamine receptors (D1 [8.9], D2 [8.9], D3 [9.4] and D4 [9.0]) and histamine receptors (H1 [9.0] and H2 [8.2]). It had much lower affinity (pKi

Reentrant condensation of proteins in solution induced by multivalent counterions.

Negatively charged globular proteins in solution undergo a condensation upon adding trivalent counterions between two critical concentrations C and C, C

Ziprasidone: a novel antipsychotic agent with a unique human receptor binding profile.

Ziprasidone is a novel antipsychotic agent with a unique combination of pharmacological activities at human receptors. Ziprasidone has high affinity for human 5-HT receptors and for human dopamine D(2) receptors. Ziprasidone is a 5-HT(1A) receptor agonist and an antagonist at 5-HT(2A), 5-HT(2C) and 5-HT(1B/1D) receptors. Additionally, ziprasidone inhibits neuronal uptake of 5-HT and norepinephrine comparable to the antidepressant imipramine. This unique pharmacological profile of ziprasidone may be related to its clinical effectiveness as a treatment for the positive, negative and affective symptoms of schizophrenia with a low propensity for extrapyramidal side effects, cognitive deficits and weight gain.

Blockade of drug-induced deficits in prepulse inhibition of acoustic startle by ziprasidone.

Ziprasidone, an antipsychotic with efficacy against core symptoms of schizophrenia and schizoaffective disorder, has a low incidence of extrapyramidal syndrome (EPS). Because of its high 5-HT(2A)/D(2) binding-affinity ratio and low EPS liability, ziprasidone is considered to belong to the newer class of "novel" antipsychotics typified by clozapine. Its unique pharmacological profile, however, distinguishes it from other novel agents. We evaluated ziprasidone in the prepulse inhibition (PPI) model, which is sensitive to clinically active antipsychotics. Male Wistar rats were tested in acoustic startle sessions in which some startle-eliciting stimuli were presented alone, and others were preceded by a weak prepulse. Administration of the dopamine agonist apomorphine (1 mg/kg) or the N-methyl-D-aspartate (NMDA) antagonist ketamine (10 mg/kg) significantly disrupted PPI. When coadministered with either of these compounds, clozapine (1-5.6 mg/kg sc) and ziprasidone (5.6-17.8 mg/kg po) significantly attenuated the declines in PPI. Haloperidol (0.03-0.56 mg/kg) also attenuated drug-induced deficits in PPI but to a lesser extent (and at higher doses) with ketamine than with apomorphine. Together, these data confirm that ziprasidone shares common effects in PPI models with other novel antipsychotics. Ziprasidone's affinity for non-D(2) receptors in the central nervous system may partly account for its attenuation of ketamine's effect.

The pharmacology of weight gain with antipsychotics.

In general, antipsychotic agents have diverse actions on a wide range of neurotransmitter systems. Data strongly suggest that a number of these systems may play a role in the regulation of body weight. In addition to having very distinct pharmacologic profiles, individual agents possess discrete weight gain liabilities. This article briefly reviews the evidence for the involvement of specific neurotransmitter systems in the control of body weight and describes the relevant pharmacologic characteristics of individual antipsychotic agents. By comparing the pharmacologic profiles of specific antipsychotic agents with their respective weight gain liabilities, this article attempts to gain an insight into the specific receptors underlying a drug's propensity to induce weight gain. However, there is still much to be learned concerning weight control mechanisms, and the role of many of the receptors at which antipsychotic agents are active remains unclear. In spite of this, an overview of current knowledge in the field may facilitate prediction of a potential novel antipsychotic agent's weight gain liability.

5-HT(1A) receptor activation contributes to ziprasidone-induced dopamine release in the rat prefrontal cortex.

BACKGROUND: Ziprasidone (Zeldox) is a novel antipsychotic with a unique combination of antagonist activities at monoaminergic receptors and transporters and potent agonist activity at serotonin 5-HT(1A) receptors. 5-HT(1A) receptor agonism may be an important feature in ziprasidone's clinical actions because 5-HT(1A) agonists increase cortical dopamine release, which may underlie efficacy against negative symptoms and reduce dopamine D(2) antagonist-induced extrapyramidal side effects. This study investigated the in vivo 5-HT(1A) agonist activity of ziprasidone by measuring the contribution of 5-HT(1A) receptor activation to the ziprasidone-induced cortical dopamine release in rats. METHODS: Effects on dopamine release were measured by microdialysis in prefrontal cortex and striatum. The role of 5-HT(1A) receptor activation was estimated by assessing the sensitivity of the response to pretreatment with the 5-HT(1A) antagonist, WAY-100635. For comparison, the D(2)/5-HT(2A) antagonists clozapine and olanzapine, the D(2) antagonist haloperidol, the 5-HT(2A) antagonist MDL 100,907 and the 5-HT(1A) agonist 8-OHDPAT were included. RESULTS: Low doses (<3.2 mg/kg) of ziprasidone, clozapine, and olanzapine increased dopamine release to approximately the same extent in prefrontal cortex as in striatum, but higher doses (> or =3.2 mg/kg) resulted in an increasingly preferential effect on cortical dopamine release. The 5-HT(1A) agonist 8-OHDPAT produced a robust increase in cortical dopamine (DA) release without affecting striatal DA release. In contrast, the D(2) antagonist haloperidol selectively increased striatal DA release, whereas the 5-HT(2A) antagonist MDL 100,907 had no effect on cortical or striatal DA release. Prior administration of WAY-100635 completely blocked the cortical DA increase produced by 8-OHDPAT and significantly attenuated the ziprasidone- and clozapine-induced cortical DA increase. WAY-100635 pretreatment had no effect on the olanzapine-induced DA increase. CONCLUSIONS: The preferential increase in DA release in rat prefrontal cortex produced by ziprasidone is mediated by 5-HT(1A) receptor activation. This result extends and confirms other in vitro and in vivo data suggesting that ziprasidone, like clozapine, acts as a 5-HT(1A) receptor agonist in vivo, which may contribute to its activity as an antipsychotic with efficacy against negative symptoms and a low extrapyramidal side effect liability.

Abdominal ultrasonography in pet guinea pigs.

Ultrasonographic examination of 40 pet guinea pigs was performed in the framework of this study. Preparation of the patient for ultrasonography and the examination procedure are described. Normal ultrasonographic findings of the abdominal organs including the liver, spleen, kidney and urinary bladder are presented and illustrated for the first time in this species. Ultrasonography was found to be a useful investigative tool in the diagnosis of abdominal diseases in guinea pigs. In comparison to other diagnostic methods like physical examination including palpation, haematological examination, radiography and diagnostic laparotomy, ultrasonography offers a rapid, non-invasive and reliable means of diagnosing abdominal diseases in this species.

Ultrasonographic detection of abdominal abscess in two guinea pigs.

Two guinea pigs (Cavia porcellus) with clinical signs of anorexia, weight loss, depression and abdominal enlargement were examined. During ultrasound examination, a fluid-filled anechogenic structure 3-4 cm in diameter, with echogenic spots and a highly echogenic thick wall, was found in the pelvic region in one case and connected to the liver in the other case. An abscess or a cyst was suspected and surgical treatment including laparotomy was performed. By histopathological examination performed after surgery, a liver abscess was diagnosed in one guinea pig and an abscess in the pelvic region in the other animal.

Mechanisms of typical and atypical antipsychotic drug action in relation to dopamine and NMDA receptor hypofunction hypotheses of schizophrenia.

Available evidence indicates that clozapine is the most effective antipsychotic currently used for the pharmacotherapy of schizophrenia. Unfortunately, clozapine can cause serious side effects that limit the use of the drug. The therapeutic mechanism of action of clozapine is poorly understood, and accordingly, it has been difficult to design new drugs with the advantageous therapeutic properties of clozapine. Based on hypotheses that dopaminergic and serotonergic receptor-blocking properties of clozapine account for its clinical efficacy, several novel antipsychotic drugs have been introduced recently. There is currently insufficient data to reach definitive conclusions regarding the efficacy of the newer 'atypical' antipsychotics in comparison to clozapine. However, most published studies, and general clinical impressions, suggest that none of the newer drugs are as effective as clozapine in treating patients resistant to typical antipsychotic drug therapy. The present paper briefly reviews the clinical experience with the newer 'atypical' antipsychotic drugs and then discusses clinical and preclinical data potentially relevant to mechanisms of action of clozapine in relation to the NMDA receptor hypofunction hypothesis of schizophrenia.

Comparison of the novel antipsychotic ziprasidone with clozapine and olanzapine: inhibition of dorsal raphe cell firing and the role of 5-HT1A receptor activation.

Ziprasidone is a novel antipsychotic agent which binds with high affinity to 5-HT1A receptors (Ki = 3.4 nM), in addition to 5-HT1D, 5-HT2, and D2 sites. While it is an antagonist at these latter receptors, ziprasidone behaves as a 5-HT1A agonist in vitro in adenylate cyclase measurements. The goal of the present study was to examine the 5-HT1A properties of ziprasidone in vivo using as a marker of central 5-HT1A activity the inhibition of firing of serotonin-containing neurons in the dorsal raphe nucleus. In anesthetized rats, ziprasidone dose-dependently slowed raphe unit activity (ED50 = 300 micrograms/kg i.v.) as did the atypical antipsychotics clozapine (ED50 = 250 micrograms/kg i.v.) and olanzapine (ED50 = 1000 micrograms/kg i.v.). Pretreatment with the 5-HT1A antagonist WAY-100,635 (10 micrograms/kg i.v.) prevented the ziprasidone-induced inhibition; the same dose of WAY-100,635 had little effect on the inhibition produced by clozapine and olanzapine. Because all three agents also bind to alpha 1 receptors, antagonists of which inhibit serotonin neuronal firing, this aspect of their pharmacology was assessed with desipramine (DMI), a NE re-uptake blocker previously shown to reverse the effects of alpha 1 antagonists on raphe unit activity. DMI (5 mg/kg i.v.) failed to reverse the inhibitory effect of ziprasidone but produced nearly complete reversal of that of clozapine and olanzapine. These profiles suggest a mechanism of action for each agent, 5-HT1A agonism for ziprasidone and alpha 1 antagonism for clozapine and olanzapine. The 5-HT1A agonist activity reported here clearly distinguishes ziprasidone from currently available antipsychotic agents and suggests that this property may play a significant role in its pharmacologic actions.

A new class of selective and potent inhibitors of neuronal nitric oxide synthase.

The synthesis and SAR of a series of 6-(4-(substituted)phenyl)-2-aminopyridines as inhibitors of nitric oxide synthase are described. Compound 3a from this series shows potent and selective inhibition of the human nNOS isoform, with pharmacokinetics sufficient to provide in vivo inhibition of nNOS activity.

Ultrasonic diagnosis of ovarian cysts in ten guinea pigs.

Ten guinea pigs with an ovarian cyst had clinical signs of anorexia, alopecia, or depression. Ultrasonographic features of the 2- to 3-cm diameter fluid-filled cysts included compartmentalization and connection to the ovary. In two animals, a unilateral cyst was present, and in two others, the cysts were bilateral. Diagnosis of the disease by plain radiography is difficult because of the similar opacity of ovarian cysts, abdominal neoplasms, and trichobezoars.

The discovery of potent and selective dopamine D4 receptor antagonists.

The identification of a novel dopamine receptor subtype, referred to as the D4 receptor, which binds the atypical antipsychotic drug clozapine with high potency, has led to the initiation of a drug discovery program that aims to find novel inhibitors of this receptor subtype. A selective screening strategy was utilized, in which 4500 compounds chosen on the basis of structural similarities to known biogenic amine receptor antagonists were tested against both the D4 and D2 dopamine receptor subtypes. A potent D4-selective compound was discovered.

Selective dopamine D4 receptor antagonists reverse apomorphine-induced blockade of prepulse inhibition.

Recent evidence suggests that the dopamine D4 receptor may play a role in schizophrenia, and that the atypical properties of the antipsychotic clozapine may be attributable in part to its antagonistic actions at this receptor. In the present study, clozapine and three other compounds having D4 dopamine receptor antagonist properties were examined for their effectiveness in reducing losses in prepulse inhibition (PPI) induced in rats by the dopamine receptor agonist apomorphine. Previously, activity in the PPI model has been shown to correlate highly with the antipsychotic potency of a number of neuroleptics. As previously reported, clozapine (1-5.6 mg/kg) significantly reduced apomorphine-induced PPI deficits. The three D4-selective compounds, CP-293,019 (5.6-17.8 mg/kg), U-101,387 (3-30 mg/kg) and L-745,870 (1-10 mg/kg), also significantly blocked the losses in PPI produced by apomorphine. Taken together, these results suggest that dopamine receptor antagonists with selectivity for the D4 dopamine receptor subtype may be effective in the treatment of schizophrenia, while being less likely to produce dyskinesias associated with D2 receptor antagonists.

Synthesis, SAR and pharmacology of CP-293,019: a potent, selective dopamine D4 receptor antagonist.

A series of novel, potent and selective pyrido[1,2-a]pyrazine dopamine D4 receptor antagonists are reported including CP-293,019 (D4 Ki = 3.4 nM, D2 Ki > 3,310 nM), which also inhibits apomorphine-induced hyperlocomotion in rats after oral dosing.

Cardiovascular effects of cholecystokinin-4 are mediated by the cholecystokinin-B receptor subtype in the conscious guinea pig and dog.

Panicogenic effects in humans of the selective cholecystokinin (CCK(B)) receptor agonist, cholecystokinin tetrapeptide (CCK4), have been reported to correlate with increases in heart rate (HR) and mean arterial pressure (MAP). Previous investigators have demonstrated that the nonselective CCK(A) and CCK(B) receptor agonist, sulfated cholecystokinin octapeptide, also produces increases in HR and mean arterial pressure. The purpose of our study is to determine if the cardiovascular changes induced by CCK4 are mediated by the CCK(A) or CCK(B) receptor subtype using selective CCK antagonists for both receptor subtypes. The rank order of potency of the CCK receptor antagonists affecting CCK4-induced HR and mean arterial pressure changes in the guinea pig corresponded to the rank order of potency for blockade of the CCK(B) receptor binding in rat cortex, phosphatidyl inositol turnover in AR 4-2J rat pancreatoma cells and inhibition of pentagastrin-induced acid secretion in the rat. The changes induced by CCK4 on HR, but not mean arterial pressure, appear to be species dependent as reflected by a decrease in the HR in the guinea pig and an increase in the dog. Nonetheless, the results from the antagonist studies indicate that the cardiovascular responses to CCK4 in both the guinea pig and dog are mediated by the CCK(B) receptor subtype.

Clozapine increases dopamine release in prefrontal cortex by 5-HT1A receptor activation.

Clozapine (1-10 mg/kg s.c.) produces a selective increase in dopamine release in rat prefrontal cortex which is, in large part (approximately 50%), mediated via activation of 5-HT1A receptors. Clozapine is a moderately potent, partial 5-HT1A receptor agonist and activation of 5-HT1A receptors may contribute to its efficacy against negative symptoms and reduced extrapyramidal side effect liability. Agonist affinity for 5-HT1A receptors could thus be a desirable feature in the design of new antipsychotics.