[Botulinum Toxin in Functional Hypersalivation--All about Dosage?]. / Botulinumtoxin bei funktioneller Hypersalivation--alles eine Frage der Dosis?

BACKGROUND: The use of botulinum toxin injection in the salivary gland, is taking an increasing significance in the treatment of functional hypersalivation today. With due regard to the off -label use and the prospect of success, dosage levels are not yet standardized. MATERIAL AND METHODS: In a retrospective study, 54 patients resp. 117 treatments were analysed over a period of 5 years according to their dosage levels of botulinum toxin, outcome and side effects. RESULTS: In 90% of the cases, a reduction of saliva after botulinum toxin injections was reported, although a significant number of patients wished for an even greater effect. Compared to the first botulinum toxin injection, we therefore used a higher dosage plan in the following treatment in order to achieve better clinical results. Besides not enough saliva reduction, the main side effects were swallowing problems and thick or sticky saliva in patients with a tracheal cannula. With the exception of insufficient saliva reduction, the other described side effects were irrespective to the dosage level. CONCLUSIONS: Botulinum toxin injection as a treatment of hypersalivation is an effective method with only minor side effects, even in increased dosage levels. Nevertheless, certain modifications according to each individual treatment are required. Possible side effects such as swallowing problems or non-responding situations should always be part of informed consent, especially as the latter is even possible for higher dosage levels.

Plant functional trait response to environmental drivers across European temperate forest understorey communities.

Functional traits respond to environmental drivers, hence evaluating trait-environment relationships across spatial environmental gradients can help to understand how multiple drivers influence plant communities. Global-change drivers such as changes in atmospheric nitrogen deposition occur worldwide, but affect community trait distributions at the local scale, where resources (e.g. light availability) and conditions (e.g. soil pH) also influence plant communities. We investigate how multiple environmental drivers affect community trait responses related to resource acquisition (plant height, specific leaf area (SLA), woodiness, and mycorrhizal status) and regeneration (seed mass, lateral spread) of European temperate deciduous forest understoreys. We sampled understorey communities and derived trait responses across spatial gradients of global-change drivers (temperature, precipitation, nitrogen deposition, and past land use), while integrating in-situ plot measurements on resources and conditions (soil type, Olsen phosphorus (P), Ellenberg soil moisture, light, litter mass, and litter quality). Among the global-change drivers, mean annual temperature strongly influenced traits related to resource acquisition. Higher temperatures were associated with taller understoreys producing leaves with lower SLA, and a higher proportional cover of woody and obligate mycorrhizal (OM) species. Communities in plots with higher Ellenberg soil moisture content had smaller seeds and lower proportional cover of woody and OM species. Finally, plots with thicker litter layers hosted taller understoreys with larger seeds and a higher proportional cover of OM species. Our findings suggest potential community shifts in temperate forest understoreys with global warming, and highlight the importance of local resources and conditions as well as global-change drivers for community trait variation.

Temporal ontogeny of circuit activation prior to the onset of seizure susceptibility in EL/Suz mice.

The EL/Suz (EL) mouse is a model of multifactorial temporal lobe epilepsy in which seizures begin around 90 days of age, but can be hastened through increased exposure to human handling. In order to better understand seizure etiology in this mouse strain relative to seizure-resistant control mice, the present study examined region-specific neuronal activation in response to non-seizure-inducing handling implemented before the onset of seizure susceptibility. Immediate-early gene (cFos) expression emerged in EL mice by postnatal day (PND) 21 in the primary motor cortex, progressed to the locus ceruleus and prefrontal cortex by PND 35, and appeared in the hippocampus and amygdala by PND 70, as mice neared the age of onset for seizure susceptibility. Thus, mirroring the pattern observed during the course of a seizure, specific brain regions were differentially recruited to a neural network for seizure predisposition before the onset of seizure susceptibility. This developmental pattern of early and transient neural activation represents an important window for the study of causal mechanisms of seizure susceptibility following exposure to environmental triggers.

Influence of promoter DNA topology on sequence-specific DNA binding and transactivation by tumor suppressor p53.

Transcriptional activation by the tumor suppressor p53 is regulated at multiple levels, including posttranslational modifications of the p53 protein, interaction of p53 with various regulatory proteins, or at the level of sequence-specific DNA binding to the response elements in p53's target genes. We here propose as an additional regulatory mechanism that the DNA topology of p53-responsive promoters may determine the interaction of p53 with its target genes. We demonstrate that sequence-specific DNA binding (SSDB) and transcriptional activation by p53 of the mdm2 promoter is inhibited when this promoter is present in supercoiled DNA, where it forms a non-B-DNA structure which spans the p53-responsive elements. Relaxation of the supercoiled DNA in vitro resulted in conversion of the non-B-DNA to a B-DNA conformation within the mdm2 promoter, and correlated with an enhanced SSDB of p53 and an elevated expression of a reporter gene. In contrast, sequence specific DNA binding and transcriptional activation of the p21 promoter were not inhibited by DNA supercoiling. We propose that conformational alterations within p53-responsive sites, which either promote or prohibit sequence specific DNA binding of p53, are an important feature in orchestrating the activation of different p53 responsive promoters.

Variability of the metabolic effect of soluble insulin and the rapid-acting insulin analog insulin aspart.

OBJECTIVE: To study the intra- and interindividual variability of the metabolic activity of soluble insulin and of the rapid-acting insulin analog insulin aspart after subcutaneous injection. RESEARCH DESIGN AND METHODS: A total of nine healthy male volunteers received subcutaneous injections of soluble insulin (0.2 U/kg) in the abdominal region on each of the four study days. Another 10 volunteers received an injection of insulin aspart four times. Glucose infusion rates necessary to neutralize the blood glucose-lowering effect of the administered insulin were registered during euglycemic glucose clamps (blood glucose 5.0 mmol/l; basal intravenous insulin infusion 0.15 mU x kg(-1) x min(-1) over the subsequent 600 min. We investigated the variation in metabolic activity by calculating coefficients of variation (CVs). RESULTS: In comparison to soluble insulin, subcutaneous injections of insulin aspart led to a more rapid onset of action and a shorter duration of action. Subcutaneous injection of the insulin preparations resulted in intraindividual CVs of the summary measures between 10 and 30% (soluble insulin vs. insulin aspart: maximal metabolic activity 15+/-7 vs. 16+/-10%, time to maximal metabolic activity 14+/-10 vs. 11+/-6%; NS between the preparations [means +/- SD]). The decline to half-maximal activity after maximal activity showed a lower intraindividual CV with insulin aspart (19+/-9 vs. 11+/-5%; P = 0.018). The interindividual CVs were higher than the intraindividual CVs (26 vs. 28, 23 vs. 19, and 26 vs. 17%). Generally, the pharmacodynamic variability was higher than the pharmacokinetic variability. For the pharmacokinetic measures, the intra- and interindividual variability in t(max) was lower for insulin aspart than for soluble insulin. CONCLUSIONS: The metabolic effect of soluble insulin shows an intraindividual variability of 10-20% in healthy volunteers, even under strictly controlled experimental conditions. The overall variability of action of insulin aspart was comparable to that of soluble insulin.

Time-action profiles of novel premixed preparations of insulin lispro and NPL insulin.

OBJECTIVE: To study the pharmacodynamic properties of three premixed formulations of the rapid-acting insulin analog insulin lispro and its protamine-retarded preparation, neutral protamine lispro (NPL) insulin. RESEARCH DESIGN AND METHODS: In this open, single-center, euglycemic glucose clamp study, 30 healthy volunteers (12 women, 18 men) aged 27 +/- 2 years (mean +/- SD), whose BMI was 23.0 +/- 2.3 kg/m2, received subcutaneous injections of 0.3 U/kg body wt of insulin mixture (high-mixture 75/25, mid-mixture 50/50, or low-mixture 25/75 insulin lispro/NPL insulin), insulin lispro, or NPL insulin on one of the five study days in randomized order. Glucose infusion rates were determined over a period of 24 h after administration. RESULTS: Maximal metabolic activity decreased after subcutaneous injection of the mixtures with lower insulin lispro content; however, the time point of maximal and of early half-maximal metabolic activity was comparable among the three mixtures. Higher proportions of insulin lispro resulted in higher values for area under the curve within the first 360 min after injection and a more rapid decline to late half-maximal activity. Serum insulin concentrations showed a similar pattern. CONCLUSIONS: This study shows that the pharmacodynamic and pharmacokinetic properties of insulin lispro are preserved in stable mixtures with NPL insulin.

Selective impairment of corticotropin-releasing factor1 (CRF1) receptor-mediated function using CRF coupled to saporin.

CRF is the main component in the brain neuropeptide effector system responsible for the behavioral, endocrine, and physiological activation that accompanies stress activation. Reduced CRF system activation plays a role in the etiology of a variety of psychiatric and metabolic disease states. We have developed a novel protein conjugate that joins native rat/human CRF to a ribosome-inactivating protein, saporin (CRF-SAP), for the purpose of targeted inactivation of CRF receptor-expressing cells. Cytotoxicity measurements revealed that CRF-SAP (1-100 nM) produced concentration-dependent and progressive cell death over time in CRF1 receptor-transfected L cells, but at similar concentrations had no effect on CRF2alpha receptor-transfected cells. The CRF-SAP-induced toxicity in CRF1-transfected cells was prevented by coincubation with the competitive CRF1/CRF2 receptor peptide antagonist, [D-Phe12]CRF-(12-41), or the selective nonpeptide CRF1 receptor antagonist, NBI 27914. Finally, in cultured rat pituitary cells that express native CRF1 receptors, CRF-SAP suppressed CRF-induced (1 nM) ACTH release. GnRH (1-10 nM) stimulated LH release was also assessed in the same pituitary cultures. Although there was a slight decrease in LH release from these cultures, this decrease was observed with CRF-SAP or SAP alone, suggesting that the response was nonspecific. Taken together, these results suggest the utility of CRF-SAP as a specific and subtype-selective tool for long term impairment of CRF1 receptor-expressing cells.

Recent advances with the CRF1 receptor: design of small molecule inhibitors, receptor subtypes and clinical indications.

Corticotropin-releasing factor (CRF) has been widely implicated as playing a major role in modulating the endocrine, autonomic, behavioral and immune responses to stress. The recent cloning of multiple receptors for CRF as well as the discovery of non-peptide receptor antagonists for CRF receptors have begun a new era of CRF study. Presently, there are five distinct targets for CRF with unique cDNA sequences, pharmacology and localization. These fall into three distinct classes, encoded by three different genes and have been termed the CRF1 and CRF2 receptors (belonging to the superfamily of G-protein coupled receptors) and the CRF-binding protein. The CRF2 receptor exists as three splice variants of the same gene and have been designated CRF2a CRF2b and CRF2g. The pharmacology and localization of all of these proteins in brain has been well established. The CRF1 receptor subtype is localized primarily to cortical and cerebellar regions while the CRF2a receptor is localized to subcortical regions including the lateral septum, and paraventricular and ventromedial nuclei of the hypothalamus. The CRF2b receptor is primarily localized to heart, skeletal muscle and in the brain, to cerebral arterioles and choroid plexus. The CRF2g receptor has most recently been identified in human amygdala. Expression of these receptors in mammalian cell lines has made possible the identification of non-peptide, high affinity, selective receptor antagonists. While the natural mammalian ligands oCRF and r/hCRF have high affinity for the CRF1 receptor subtype, they have lower affinity for the CRF2 receptor family making them ineffective labels for CRF2 receptors. [125I]Sauvagine has been characterized as a high affinity ligand for both the CRF1 and the CRF2 receptor subtypes and has been used in both radioligand binding and receptor autoradiographic studies as a tool to aid in the discovery of selective small molecule receptor antagonists. A number of non-peptide CRF1 receptor antagonists that can specifically and selectively block the CRF1 receptor subtype have recently been identified. Compounds such as CP 154,526 (12), NBI 27914 (129) and Antalarmin (154) inhibit CRF-stimulation of cAMP or CRF-stimulated ACTH release from cultured rat anterior pituitary cells. Furthermore, when administered peripherally, these compounds compete for ex vivo [125I]sauvagine binding to CRF1 receptors in brain sections demonstrating their ability to cross the blood-brain-barrier. In in vivo studies, peripheral administration of these compounds attenuate stress-induced elevations in plasma ACTH levels in rats demonstrating that CRF1 receptors can be blocked in the periphery. Furthermore, peripherally administered CRF1 receptor antagonists have also been demonstrated to inhibit CRF-induced seizure activity. These data clearly demonstrate that non-peptide CRF1 receptor antagonists, when administered systemically, can specifically block central CRF1 receptors and provide tools that can be used to determine the role of CRF1 receptors in various neuropsychiatric and neurodegenerative disorders. In addition, these molecules will prove useful in the discovery and development of potential orally active therapeutics for these disorders.

Anti-stress action of a corticotropin-releasing factor antagonist on behavioral reactivity to stressors of varying type and intensity.

Central administration of a Corticotropin-Releasing Factor (CRF) antagonist is well documented to attenuate a variety of behavioral responses to several distinct stressors; however, it is not yet clear whether the activation of CRF neurons is dependent on the type or intensity of the experimental stressor, or rather on the particular behavioral response to stress under study. To test the generality of the stress-protective effect of the CRF antagonist, alpha-helical CRF9-41, (1, 5 or 25 micrograms intracerebroventricularly), the present experiments employed a sensitive index of anxiogenic-like behavior by measuring suppression in exploration on the elevated plus-maze following exposure to social, swim, or restraint stressors. A 1 but not 5 or 25 micrograms dose of the CRF antagonist administered just prior to social, swim, or restraint stress reversed the stress-induced inhibition of exploratory behavior. Chlordiazepoxide and the steroid anesthetic, alphaxalone, also attenuated the anxiogenic-like effect of restraint stress and elevated the baseline exploratory behavior of nonstressed control groups. Although the stressors produced a graded secretion of adrenocorticotropin (ACTH) with the ranking restraint > swim > social, the relative amplitude of behavioral reactivity to social, swim, and restraint stress was comparable. The relative efficacy of the CRF antagonist to reverse the stressor effects was also comparable. These results suggest that antagonism of activated brain CRF systems attenuates the behavioral response to stress regardless of the type or intensity of the stressor as measured by ACTH secretion.

Anxiolytic-like action of neuropeptide Y: mediation by Y1 receptors in amygdala, and dissociation from food intake effects.

Evidence from animal and human studies suggests that neuropeptide Y (NPY) may be a potent endogenous anxiolytic. The anatomic structures mediating this action of the peptide remain unknown. Furthermore, in addition to its anxiolytic-like effects, intracerebroventricular administration of NPY induces food intake through hypothalamic mechanisms, making the anxiolytic-like action of the peptide more difficult to interpret. The purpose of this study was to examine the anatomic substrate for the effects of NPY on anxiety, and to characterize the NPY receptors mediating these effects. Intracerebroventricular injection of NPY produced increased food intake in free-feeding animals, and dose-dependent anticonflict/anxiolytic-like effects in an established animal model of anxiety, the Geller-Seifter punished responding test. In contrast, microinjection of NPY into the central nucleus of the amygdala did not increase food intake in free-feeding animals, did not affect unpunished lever pressing for food, but did reproduce the anticonflict/anxiolytic-like effect with high potency. The selective NPY-Y1 agonist, p[Leu31,Pro34]NPY was approximately equipotent with native NPY in the conflict paradigm, and markedly more potent than the Y2 agonist, NPY13-36. Intrastriatal injections had no effect on conflict behavior. Thus, activation of Y1 receptors in the central nucleus of the amygdala produces effects similar to established anxiolytics without affecting food intake, suggesting that Y1-receptors in the amygdala may be a substrate for anxiolytic actions of NPY.

The role of corticotropin-releasing factor and its receptors in the central nervous system.

Corticotropin-releasing factor (CRF) is a pluripotent neurohormone system, which implements endocrine, physiological and behavioral responses to stressor exposure. Built-in biological diversity and selectivity of CRF system function is provided by multiple endogenous ligands and receptors, which are heterologously distributed in both brain and peripheral tissues across species. Significant gains in knowledge about the physiological role of CRF receptors in the brain have emerged over the past year due to the proliferation of novel, high affinity, receptor selective pharmacological tools as well as multiple knockout and knockin mutant mouse models. These results support a role for CRF binding sites in coordinating stress reactivity, emotionality and energy balance over the life span of the organism.

Learning impairment in transgenic mice with central overexpression of corticotropin-releasing factor.

The present studies were designed to test the learning and memory capacities of transgenic mice with central overexpression of corticotropin-releasing factor in a forced alternation water T-maze task and in the Morris water maze. In T-maze testing, littermate control mice reached a criterion of 70% correct responses after five days of trials, while the performance of transgenic subjects was still random after the same training. In Morris maze testing, control subjects reached the submerged platform significantly faster (F(1.48) = 4.51, P < 0.05) after three days of trials, while the performance of transgenic mice was unimproved over the same period. The deficit in Morris maze performance in transgenic mice was reversed when the platform was visible above the surface of the water. Pre-test administration of the benzodiazepine anxiolytic, chlordiazepoxide (10 mg/kg), before acquisition training also produced a significant (F(4.40) = 16.61, P < 0.001) and persistent improvement in Morris maze performance in transgenic mice when compared to vehicle-treated transgenic litter mates. Finally, there was no evidence of hippocampal cell loss in transgenic brains. The results suggest that corticotropin-releasing factor-overexpressing mice exhibit a profound learning deficit without sensory or motor-related impairments, and that memory plasticity can be restored by anxiolytic pre-treatment. Thus, constitutive overabundance of brain corticotropin-releasing factor may produce hyperemotionality that interferes with learned behaviors. Stress-related disorders characterized by co-morbid deficits in learning/memory may benefit from pharmacological normalization of brain corticotropin-releasing factor systems.

Alcohol, the reward system and dependence.

Evidence is presented to show that multiple neurotransmitter systems of the brain reward systems including GABA, glutamate, dopamine, serotonin and opioid peptides are involved in alcohol reinforcement. Dependence is associated with changes in many of these same systems, but also with changes in other neurotransmitters, such as brain corticotropin releasing factor. A midbrain forebrain circuitry that involves parts of the nucleus accumbens and amygdala is hypothesized to be the focus for the neuropharmacology of alcohol reinforcement.

Therapeutic potential of CRF receptor antagonists: a gut-brain perspective.

Activation of the corticotropin-releasing factor (CRF) family of neuropeptide receptors in the brain and periphery appears to mediate stress-related changes in a variety of physiological and functional domains. Comparative pharmacology of CRF receptor agonists suggests that CRF, urocortin, sauvagine and urotensin consistently mimic, and conversely peptide CRF receptor antagonists lessen, the functional consequences of stressor exposure. Together with the development of novel non-peptide CRF receptor antagonists, a growing number of CRF receptor selective ligands are available to elucidate the neurobiology and physiological role of CRF systems. The present review considers available preclinical evidence as well as results from one Phase II clinical trial which address the hypothesis that CRF receptor antagonists may represent a new option for pharmacotherapy of stress-related disorders.

Anti-sexual and anxiogenic behavioral consequences of corticotropin-releasing factor overexpression are centrally mediated.

Corticotropin-releasing factor (CRF) acts as a neurotransmitter in brain to promote behavioral responses such as flight and immobility, which have adaptive value in the context of exposure to environmental stressors. CRF also suppresses behavioral repertoires such as mating, which are incompatible with such threat-related coping responses. In this study, we employed transgenic (Tg) mice which overexpress CRF in brain and exhibit a constitutive and persistent phenotype of emotionality in order to determine the consequences of long-term CRF excess on indices of reproductive success, male sexual performance and female sexual receptivity. Sexual performance of CRF Tg males was relatively intact, whereas female receptivity was masked in CRF Tg mice by active rejection of sexually experienced male counterparts. This impairment in social interaction was only partially normalized by the serotonin antagonist, methysergide, which enhanced olfactory exploration of the still non-receptive CRF Tg females. Moreover, the anxiogenic-like character of CRF Tg mice is likely to be centrally mediated, since attenuation of hypercorticosteronemia by adrenalectomy did not alter either impaired sexual receptivity or fear-like behavior in an animal model of anxiety. Thus, overexpression of CRF in the brain results in a variety of adverse consequences including diminished social interactions.

Blockade of pituitary-adrenal axis activation induced by peripheral immunoneutralization of corticotropin-releasing factor does not affect the behavioral response to social defeat stress in rats.

Specific in vivo immunoneutralization of hypophysiotrophic corticotropin-releasing factor (CRF) and vasopressin (AVP) was used to investigate the respective roles of these circulating peptides in the hormonal response to a social stressor in Wistar rats. The effect of peripheral immunoneutralization on the behavioral response to the same social stressor was also studied. Stress was produced using social defeat in a resident-intruder paradigm, in which an intruder male rat, equipped with an indwelling IV catheter, was confronted with a dominant resident male rat. To minimize the physical component of the agonistic interaction, the intruder was protected immediately after the resident's first attack in a Plexiglas/wire-mesh enclosure. In the following time interval, the resident continued to threaten the protected intruder, which showed a significant increase in plasma immunoreactive adrenocorticotropic hormone (ACTH) and corticosterone levels compared to those measured in rats exposed to a control procedure. The hypothalamo-pituitary-adrenal (HPA) axis response to social defeat stress was totally abolished by pretreatment with an anti-CRF serum (0.3 ml IV) but not an anti-AVP serum (0.75 ml IV). An animal model for anxiety in rodents, the elevated plus-maze, was used to study the emotional response to social defeat stress in rats given anti-CRF serum or normal serum. A significant reduction of open-arm exploration was observed in defeated rats tested 10 min after the end of the agonistic interaction when compared with control animals for all antisera treatment group, indicating an "anxiogenic-like" emotional response to the social defeat stress. Pretreatment with anti-CRF serum did not affect the behavioral performance of defeated and control rats. These results suggest that: 1) social defeat stress produced an activation of the HPA axis in the rat which is mediated by hypophysiotrophic CRF but not AVP; and 2) the peripheral activation of the HPA axis induced by social defeat stress is not involved in the behavioral response to stress as measured in the elevated plus-maze.

Corticotropin-releasing factor modulates dietary preference in nutritionally and physically stressed rats.

In order to evaluate the action of central nervous system Corticotropin-Releasing Factor (CRF) in the control of feeding behavior the present studies employed a dietary self-selection task sensitive both to overall appetite as well as preferential intake of familiar versus unfamiliar foods. Prior to the diet selection test, one group of nutritionally stressed animals was fed a protein deficient diet in order to increase the preference for unfamiliar foods relative to nutritionally replete subjects. Both CRF (0.05 and 0.5 micrograms ICV) and physical restraint (30 min) attenuated selectively the consumption of a novel food choice by deficient animals without affecting concurrent intake of familiar food. Further, CRF administration did not alter water intake or consumption of either diet by the replete control group suggesting that the peptide produced a stress dependent, enhanced response to novelty without a general effect on appetite. The CRF antagonist, alpha-helical CRF9-41 (1, 5 and 25 micrograms ICV), increased familiar diet consumption in nutritionally deficient subjects without affecting the self-selection pattern or replete controls. Chlordiazepoxide (5 mg/kg) also increased selectively the intake of familiar food suggesting that this action is the anxiolytic complement of the effect of stress in this paradigm. The CRF antagonist (5 and 25 micrograms) reversed the anorexia produced by CRF (0.5 micrograms) as well as that induced by restraint stress. These results favor a direct role for endogenous CRF systems in coordinating the behavioral responses to dietary stress.

Corticotropin-releasing factor receptor blockade enhances conditioned aversive properties of cocaine in rats.

The behavioral profile of corticotropin-releasing factor (CRF) in mediating anxiogenic-like and aversive responses to stressors may be particularly relevant for dependence and withdrawal in drug-experienced organisms. Moreover, stressful aspects of drug exposure in the drug naive organism may also induce CRF system activation. In the present studies, the dependence of aversive properties of cocaine on activation of endogenous CRF systems has been evaluated in rats using taste conditioning and runway self-administration paradigms. Systemic cocaine administration (20 mg/kg i.p.) produced a conditioned saccharin aversion which was dose-dependently potentiated by central administration of the CRF receptor antagonist, D-phe CRF (12 41). In addition, i.v. cocaine administration (0.75 mg/kg per injection i.v.) produced runway goal-box avoidance and conditioned place avoidance responses which were significantly accelerated by CRF antagonist treatment. In contrast, CRF receptor stimulation using CRF itself abolished cocaine-induced increases in goal latency in the runway paradigm. This generalized involvement of CRF systems in cocaine-related motivational/associative states is consistent with the comprehensive role of CRF in mediating emotional responses to non-drug stressors.

The role of limbic and hypothalamic corticotropin-releasing factor in behavioral responses to stress.

CRF in the central nervous system appears to have activating properties on behavior and to coordinate behavioral responses to stress. These behavioral effects of CRF appear to be independent of the pituitary-adrenal axis and can be reversed by a CRF antagonist, alpha-helical CRF9-41. The CRF antagonist reverses not only decreases in behavior associated with stress, but also increases in behavior associated with stress, thus suggesting that the role of CRF is stress dependent and not intrinsic to a given behavioral response. Further, microinjection of alpha-helical CRF9-41 and immunotargeting of CRF neurons in separate brain compartments reveal a link between the anatomical sites that contain CRF and the nature of the behavioral response to stress that can be modified by suppression of endogenous CRF activity therein. Hence, consistent with the dual role of other hypothalamic-releasing factors in integrating hormonal and neural mechanisms by acting both as secretagogues for anterior pituitary hormones and as extrapituitary peptide neurotransmitters, CRF may coordinate coping responses to stress at several bodily levels (Fig. 6). Moreover, dysfunction in such a fundamental homeostatic system may be the key to a variety of pathophysiological conditions including mental disorders.

The role of CRF in behavioral aspects of stress.

CRF in the central nervous system appears to hve activating properties on behavior and to coordinate behavioral responses to stressors. These behavioral effects of CRF appear to be independent of the pituitary-adrenal axis and can be reversed by CRF antagonists. CRF antagonist administration reverses not only decreases in behavior associated with stress, but also increases in behavior associated with stress, thus suggesting that the role of CRF is stress dependent and not intrinsic to a given behavioral response. Further, microinjection of alpha-helical CRF 9-41 and immunotargeting of CRF neurons in separate brain compartments reveal a link between the anatomical sites that contain CRF and the nature of the behavioral response to stressors that can be modified by suppression of endogenous CRF activity therein. These actions of CRF in coordinating coping responses to stress at several bodily levels are consistent with a role for CRF similar to the dual role of other hypothalamic releasing factors in integrating hormonal and neural mechanisms by acting both as secretagogues for anterior pituitary hormones and as extrapituitary peptide neurotransmitters. Moreover, dysfunction in such a fundamental homeostatic system may be the key to a variety of pathophysiological conditions including mental disorders.