Involvement of Central Amygdalar and Bed Nucleus of the Stria Terminalis Corticotropin-Releasing Factor in Behavioral Responses to Social Defeat.

The authors investigated whether corticotropin-releasing factor (CRF) within the central nucleus of the amygdala (CeA) and bed nucleus of the stria terminalis (BNST) is a critical component of the neural circuitry mediating conditioned defeat. In this model, hamsters that have experienced social defeat subsequently display only submissive-defensive agonistic behavior instead of territorial aggression. Conditioned defeat was significantly reduced following infusion of the CRF receptor antagonist D-Phe CRF(12-41) into the BNST but not into the CeA. In another experiment, hamsters given unilateral lesions of the CeA and infusions of D-Phe CRF(12-41) into the contralateral BNST displayed significantly less submissive behavior than did controls. These data suggest that CRF acts within a neural circuit that includes the amygdala and the BNST to modulate agonistic behavior following social defeat. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Role of central interleukin-1 beta in gastrointestinal motor disturbances induced by lipopolysaccharide in sheep

Cytokines are involved in the symptoms of the acute phase response induced by infectious diseases in humans as well as in animals, and interleukin-1 beta (IL-1 beta) has a pivotal role in these changes. The role of central IL-1 beta in the gastrointestinal hypomotility and fever evoked by intravenous administration of lipopolysaccharide (LPS) and the mechanisms involved, were investigated in sheep as an experimental model. LPS (0.1 microgram/kg, intravenously) induced gastrointestinal hypomotility and fever that were significantly reduced by prior intracerebroventricular administration of IL-1 receptor antagonist protein (IL-1ra, 2 micrograms/kg). The effects of LPS were mimicked by intracerebroventricular IL-1 beta (50 ng/kg), whereas IL-1 beta injected intravenously at the same dose only caused a slight and transient fever without modifying the gastrointestinal motility. Prior intracerebroventricular administration of the cyclooxygenase inhibitor indomethacin (100 micrograms/kg) but not the corticotropin-releasing factor (CRF) receptor antagonist alpha-helical CRF9-41 (5 micrograms/kg) blocked all effects by both LPS and IL-1 beta. These results suggest that in sheep, LPS induces digestive motor disturbances through a central release of IL-1 beta and prostaglandins.     

The human neuroblastoma cell line, IMR-32, expresses functional corticotropin-releasing factor receptors

Corticotropin-releasing factor (CRF) receptors in IMR-32 human neuroblastoma cells were characterized after differentiation with 2.5 microM 5'-bromo-2'-deoxyuridine for 10 days. Scatchard analysis of [125I-Tyr0]ovine CRF binding revealed a high affinity binding site with a dissociation constant of 0.59 nM and a maximum binding capacity of 142 fmol/mg, the affinity of which was decreased by guanosine 5'-o-(3-thiotriphosphate). This binding was displaced in the following order of potency: human/rat CRF > ovine CRF > urotensin I > sauvagine > bovine CRF > [D-Phe12, Nle21,38, C alpha-MeLeu37]human/rat CRF-(12-41) > alpha-helical CRF-(9-41), indicative of the CRF1 receptor subtype. Functional coupling of this receptor was confirmed by CRF-induced increases in cyclic AMP, which were antagonised by alpha-helical CRF-(9-41) and [D-Phe12,Nle21,38,C alpha-MeLeu37] human/rat CRF-(12-41).     

Acute immobilization stress and intraventricular injection of CRF suppress naloxone-induced LH release in ovariectomized estrogen-primed rats

The present study was undertaken to evaluate the role and possible interaction of the endogenous opioid peptide (EOP) and corticotropin-releasing factor (CRF) in the acute stress-induced suppression of gonadotropin secretion in ovariectomized estrogen-primed rats. An intravenous (i.v.) injection of naloxone (10 or 20 mg/kg), an EOP antagonist, significantly elevated serum luteinizing hormone (LH) levels within 10 min in non-stressed animals. The naloxone-induced LH release was completely eliminated when tested 30 min after the onset of acute immobilization. In a subsequent study, it was found that suppression of the naloxone-induced LH release occurred as early as 5 min after the stress onset, and was still evident 60 min after the end of a 30-min period of immobilization. The effect of naloxone was restored 3 h after liberation of the animal from the 30-min immobilization. An intraventricular (i.c.v.) injection of CRF (1 or 5 micrograms) also significantly suppressed, in a dose-related manner, the effect of a subsequent i.v. injection of naloxone. However, an i.c.v. injection of alpha-helical CRF(9-41) (25 or 50 micrograms), a CRF antagonist, prior to immobilization, could not interfere with the suppressive effect of stress on naloxone-induced LH release. These results suggest that both acute immobilization stress and CRF can inhibit the LH secretory activity without mediation by EOP neurons. However, the stress-related suppression may involve non-CRF mechanism(s).     

The role of corticotropin-releasing factor and corticosterone in stress- and cocaine-induced relapse to cocaine seeking in rats

We have shown previously that footshock stress and priming injections of cocaine reinstate cocaine seeking in rats after prolonged drug-free periods (Erb et al., 1996). Here we examined the role of brain corticotropin-releasing factor (CRF) and the adrenal hormone corticosterone in stress- and cocaine-induced reinstatement of cocaine seeking in rats. The ability of footshock stress and priming injections of cocaine to induce relapse to cocaine seeking was studied after intracerebroventricular infusions of the CRF receptor antagonist D-Phe CRF12-41, after adrenalectomy, and after adrenalectomy with corticosterone replacement. Rats were allowed to self-administer cocaine (1.0 mg/kg/infusion, i.v) for 3 hr daily for 10-14 d and were then placed on an extinction schedule during which saline was substituted for cocaine. Tests for reinstatement were given after intermittent footshock (10 min; 0.5 mA) and after priming injections of saline and cocaine (20 mg/kg, i.p.). Footshock reinstated cocaine seeking in both intact animals and animals with corticosterone replacement but not in adrenalectomized animals. The CRF receptor antagonist D-Phe CRF12-41 blocked footshock-induced reinstatement at all doses tested in both intact animals and animals with corticosterone replacement. Reinstatement by priming injections of cocaine was only minimally attenuated by adrenalectomy and by pretreatment with D-Phe CRF12-41. These data suggest that brain CRF plays a critical role in stress-induced, but only a modulatory role in cocaine-induced, reinstatement of cocaine seeking. Furthermore, the data show that although reinstatement of cocaine seeking by footshock stress requires minimal, basal, levels of corticosterone, stress-induced increases in corticosterone do not play a role in this effect.     

Stimulation of neuropeptide Y overflow in the rat paraventricular nucleus by corticotropin-releasing factor

Neuropeptide Y (NPY) and corticotropin-releasing factor (CRF) are present at high concentrations in the hypothalamus where they mediate important endocrine and autonomic functions. Morphological and physiological studies have suggested an interaction between these peptides, and opposing actions of CRF and NPY have been reported on feeding and other behaviors. This study investigated the effect of CRF on NPY release in vivo, measured by push-pull techniques, in the anesthetized rat. Push-pull probes implanted into the paraventricular nucleus of the hypothalamus (PVN) were perfused with modified Ringer solution containing bovine serum albumin at 15 microl/min, and the perfusate was lyophilized prior to NPY radioimmunoassay. NPY overflow from the rat PVN was increased threefold by perfusion of a depolarizing concentration of potassium (50 mmol/L KCl). When CRF was administered into the PVN via the push-pull cannula at 1 or 5 microg/ml, dose-dependent increases in NPY overflow of two- and fivefold were observed (p < 0.05). These increases were abolished by prior intracerebroventricular (i.c.v.) administration of the CRF antagonist [D-Phe12,Nle(21,38),C(alpha)MeLeu32]CRF (12-41) at 1 or 5 microg/microl, respectively. NPY overflow returned promptly to resting levels following CRF administration. In contrast, when CRF was administered by i.c.v. bolus at a similar total dose (2 microg), no significant effect on NPY overflow was observed. These data provide in vivo evidence for an interaction between CRF and NPY at the level of the PVN.     

Cannabinoid modulation of rat pup ultrasonic vocalizations

The present study investigated the effects of the cannabinoid receptor agonist CP 55,940 (1-)-cis-3-[2-hydroxy-4-(1,1-dimethylheptyl) phenyl]-trans-4-(3-hydroxypropyl)cyclohexanol) and the cannabinoid receptor antagonist SR 141716A (N-(piperidin-l-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-me thyl-1 H-pyrazole-3-carboxamide hydrochloride) on ultrasonic vocalizations, body temperature and activity in 11-13-day-old rat pups. Testing occurred in a 5-min session 30 min following drug administration. CP 55,940 produced a dose-dependent decrease in ultrasonic vocalizations, with a 1000-micrograms/kg dose causing an almost complete inhibition of calls. Doses of 100 and 1000 micrograms/kg of CP 55,940, but not 10 micrograms/kg, caused significant hypothermia in the pups and the 1000 micrograms/kg dose also inhibited activity. The cannabinoid receptor antagonist SR 141716A (20 mg/kg) reversed the effects of 1000 micrograms/kg CP 55,940 on ultrasonic vocalizations and body temperature, but the benzodiazepine receptor antagonist flumazenil (20 mg/kg), the dopamine D1 receptor antagonist SCH 23390 (0.5 mg/kg) and the opioid receptor antagonist naloxone (1 mg/kg) did not. When administered alone, SR 141716A (20 mg/kg) increased pup ultrasonic vocalizations without affecting body temperature or activity. These results indicate that cannabinoids modulate ultrasonic vocalization production in rat pups in a manner that is independent of hypothermia. The increase in ultrasonic vocalizations produced by SR 141716A is one of the first reported behavioural effects of this drug and suggests that the endogenous cannabinoid ligand anandamide may be involved in the regulation of ultrasonic vocalizations.     

CB1 cannabinoid receptor antagonist-induced opiate withdrawal in morphine-dependent rats

Recent reports have provided evidence of a link between the endogenous brain cannabinoid system and the endogenous central opioid systems. Here we report that the selective CB1 receptor antagonist SR 141716A induced behavioral and endocrine alterations associated with opiate withdrawal in morphine-dependent animals in a dose-dependent manner and that naloxone induced an opiate withdrawal syndrome in animals made cannabinoid-dependent by repeated administration of the potent cannabinoid agonist HU-210. Additionally CB1 and mu-opioid receptor mRNAs were co-localized in brain areas relevant for opiate withdrawal such as the nucleus accumbens, septum, dorsal striatum, the central amygdaloid nucleus and the habenular complex. These results suggest that CB1 cannabinoid receptors may play a role in the neuroadaptive processes associated with opiate dependence, and they lend further support for the hypothesis of a potential role of cannabinoid receptors in the neurobiological changes that culminate in drug addiction.     

Relaxing actions of corticotropin-releasing factor on rat resistance arteries

1. Although it well established that corticotropin-releasing factor (CRF) injected i.v. can cause hypotension and vasodilatation, there is no in vitro evidence that CRF acts as a vasodilator. We have therefore tested the hypothesis that the hypotensive effect of i.v. CRF is due to a direct vasodilator action by carrying out experiments in vitro on rat resistance arteries (i.d. 150-300 microns). 2. Initial in vivo experiments confirmed that CRF (1.5 nmol.kg-1) injected i.v. caused hypotension in rats, this being partially antagonized by the CRF analogue CRF9-41. 3. For the in vitro experiments, vessels were taken from the mesenteric, cerebral and femoral vascular beds, and mounted as ring preparations in an isometric myograph. The vessels were pre-contracted with one of 3 agonists (prostaglandin F2 alpha, arginine vasopressin or noradrenaline) or with a high-potassium solution (K+). 4. With maximal concentrations of the agonists, CRF caused relaxation of mesenteric and cerebral vessels with 10 nM, and near complete relaxation with 100 nM. Femoral vessels pre-constricted with agonists and all vessels pre-constricted with K+ were less affected by CRF. In the mesenteric vessels, with sub-maximal levels of pre-constriction, CRF caused substantial relaxation at 1 nM and could cause complete relaxation at 10 nM. 5. The relaxant effect of CRF on contractions of mesenteric vessels was antagonized by 100 nM CRF9-41. Neither tetraethyl ammonium (30 mM) nor glibenclamide (3 microM) antagonized the relaxant effect of CRF. 6. The relaxant effect of CRF on mesenteric small arteries was found to be unaffected by removal of the endothelium. 7. The results indicate that CRF causes an endothelial-independent vasodilatation of rat resistance arteries under in vitro conditions at concentrations which are consistent with this being an important cause of the hypotension observed with i.v. injection of CRF.     

Role of endogenous and exogenous cholecystokinin in experimental acute pancreatitis induced in rats by the duodenal loop technique

The role of endogenous cholecystokinin (CCK) release and exogenous CCK-8 administration in the development and progression of acute pancreatitis and in the early recovery phase of acute pancreatitis were investigated in rats with closed duodenal loop (CDL)-induced pancreatitis. The subcutaneous injection of CCK-8 (2 micrograms/kg) stimulated a physiological level of pancreatic enzyme secretion in normal control rats, but did not lead to any biochemical or histological evidence of acute pancreatitis. A higher dose of CCK-8 (8 micrograms/kg), however, did produce both biochemical and histological evidence of acute pancreatitis in the normal control rats. When 2 micrograms/kg of CCK-8 was injected subcutaneously in rats 6 and 12 h after the creation of the CDL, neither the biochemical nor the histological findings of acute pancreatitis showed any progression compared with the changes in controls given no CCK-8. Serum CCK levels, measured by radio-immunoassay, increased significantly from mean levels of 5.39 pg/ml (+/- 0.95 SD) before creation of the CDL to 42.06 pg/ml (+/- 2.27 SD) 6 h after, and 41.95 pg/ml (+/- 1.88 SD) 12 h after its creation (P < 0.01). The difference between serum CCK levels at 6 and 12 h was not statistically significant. Following the release of the loop, serum CCK levels decreased gradually, especially in rats in which the loop was released 6 h after being created. Although no marked biochemical and histological changes of acute pancreatitis were observed following the administration of 2 micrograms/kg of CCK-8 to rats upon release of the loop 6 h and 12 h after its creation, a higher dose of CCK-8 (8 micrograms/kg) in these rats adversely affected both the biochemical and histological findings of acute pancreatitis. Based on these findings, it was concluded that neither endogenous CCK release, as a result of the CDL, nor physiological stimulation of the pancreas by exogenous CCK-8 administration, caused progression from edematous to hemorrhagic acute pancreatitis, and neither CCK treatment had any adverse effect on the early recovery phase of CDL-induced acute pancreatitis. A pharmacological dose of CCK, however, exacerbated the acute pancreatitis, even in the early recovery stage.     

Differences in the sensitivity to purinergic stimulation of myelinating and non-myelinating Schwann cells in peripheral human and rat nerve

The administration of the 5-hydroxytryptamine (5-HT) precursor 5-hydroxytryptophan (5-HTP) (25 mg/kg i.p.), in combination with an inhibitor of peripheral 5-HTP decarboxylase, produced a dose-dependent increase in the ejaculation latency of male rats, and this effect was enhanced by additional treatment with the 5-HT1 receptor antagonist (-)-pindolol (2 mg/kg s.c.). The 5-HT2A/C receptor agonist (+/-) 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) (0.125-0.5 mg/kg s.c.) did not by itself affect male ejaculatory behavior, but additional treatment with (-)-pindolol (2 mg/kg s.c.) produced a dose-dependent decrease in number of ejaculating animals. The increased ejaculation latency produced by 5-HTP was fully antagonized by treatment with the 5-HT1B receptor antagonist isamoltane (4 mg/kg s.c.), but not by ritanserin (2 mg/kg s.c.) treatment. The selective 5-HT1A receptor antagonist WAY-100635 (0.15 mg/kg s.c.) enhanced the inhibitory actions of 5-HTP on the male rat ejaculatory behavior, and this dose of WAY-100635 fully antagonized 8-OH-DPAT-induced facilitation (0.25 mg/kg s.c.) of the ejaculatory behavior. WAY-100635 (0.04-0.60 mg/kg s.c.) did not, by itself, significantly affect male rat sexual behavior. Taken together, the results suggest an inhibitory role for postsynaptic 5-HT1B receptors in the effects produced by 5-HTP on male rat ejaculatory behavior. Furthermore, 5-HTP-induced inhibition of male rat ejaculatory behavior is partially controlled by stimulation of inhibitory 5-HT1A autoreceptors, since the effects of 5-HTP were accentuated by treatment with (-)-pindolol, as well as by the more selective 5-HT1A receptor antagonist WAY-100635.     

Effects of corticotropin-releasing factor on brain serotonergic activity

The serotonergic dorsal raphe nucleus is innervated by corticotropin-releasing factor (CRF) and expresses CRF receptors, suggesting that endogenous CRF impacts on this system. The present study characterized interactions between CRF and the dorsal raphe serotonin (5-HT) system. The effects of intracerebroventricularly (i.c.v.) administered CRF on microdialysate concentrations of 5-HT in the lateral striatum of freely moving rats were determined. CRF had biphasic effects, with 0.1 and 0.3 microgram decreasing, and 3.0 micrograms increasing 5-HT dialysate concentrations. i.c.v. administration of CRF inhibited neuronal activity of the majority of dorsal raphe neurons at both low (0.3 microgram) and high (3 micrograms) doses. Likewise, intraraphe administration of CRF (0.3 and 1.0 ng) had predominantly inhibitory effects on discharge rate. Together, these results suggest that CRF is positioned to regulate the function of the dorsal raphe serotonergic system via actions within the cell body region. This regulation may play a role in stress-related psychiatric disorders in which 5-HT has been implicated.     

Effects of alpha helical CRF 9-41 on neurophysiological and autonomic patterns induced by CRF in the rabbit

The EEGraphic, behavioural and autonomic effects related to the separated and simultaneous central administration of CRF and CRF antagonist (alpha-helical CRF 9-41) were evaluated in the rabbit. CRF produced a decrease of cortical EEG power spectrum, a biphasic effect on the heart rate, a hyperthermia and tachypnoea. 9-41 CRF significantly increased the EEG power spectrum, but it did not affect the autonomic parameters. The simultaneous administration of these peptides resulted in a significative and rapid inhibition of all the CRF effects. The intrinsic properties of 9-41 CRF on EEG and the interaction with CRF were discussed.     

Role of 5-HT1A receptors in the antinociceptive action of 8-hydroxy-2-(di-n- propylamino)tetralin in the rat

The role of 5-HT1A receptors in the antinociceptive action of 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) was investigated by using the shock titration test in rats. A subcutaneous injection of 300 micrograms/kg 8-OH-DPAT significantly raised the threshold for flinching, jumping and vocalization whereas 100 micrograms/kg only inhibited the flinch response. l-Propranolol and (+)-[N-tert-butyl-3-4-(2-methoxyphenyl)piperazin-1-yl-2-phenyl propanamide dihydrochloride], (+)-WAY100135, two antagonists at 5-HT1A receptors at 10 mg/kg s.c. antagonized the effect of 300 micrograms/kg 8-OH-DPAT on all measures. The effect of 300 micrograms/kg 8-OH-DPAT on the three measures was unmodified in rats which had received 150 micrograms 5,7-dihydroxytryptamine intracerebroventricularly 10 days before testing. The results suggest that 8-OH-DPAT inhibits nociceptive responses by stimulating postsynaptic 5-HT1A receptors.     

Corticotropin-releasing factor antagonist attenuates defensive-withdrawal behavior elicited by odors of stressed conspecifics.

This study examined the hypothesis that defensive responsiveness induced by threatening stimuli of biological origin is mediated by the action of endogenous corticotropin-releasing factor (CRF). Rats were exposed for 15 min to a large open field containing a small chamber. Twenty-four hours later, rats received intracerebroventricular injections of either vehicle or 20 μg of α-helical CRF(9–41), a CRF receptor antagonist. After 20 min, rats were reexposed to the open field, which now contained odors of urine and feces from a stressed conspecific. In the reexposure test, vehicle- and antagonist-treated rats withdrew rapidly into the chamber. Antagonist-treated rats, however, emerged subsequently from the chamber to explore the open field as indicated by a significant increase in the number of passages made between the chamber and the open field. Results suggest that central injection of α-helical CRF(9–41) reduces the level of fear induced by odors associated with threat. In addition, CRF receptors are implicated in mediating the species-typical display of defensive withdrawal behavior. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Incidence and outcome of schizophrenia in whites, African-Caribbeans and Asians in London

The endogenous, meal-contingent release of bombesin (BN)-like peptides is thought to contribute to the termination of a meal. In the following experiments the potency of BN receptor antagonists to attenuate the ability of nutrients to suppress food intake was tested. First, the effectiveness of BN receptor subtype antagonists was verified by testing their ability to block the effects of exogenous BN on food intake. Rats were administered intraperitoneal (i.p.) injections of either saline or 0.1 mg/kg [D-Phe12,Leu14]BN (binds both GRP and NMB receptors), [D-Phe6]BN(6-13) ethyl amide (binds GRP > NMB), and cyclo-SS-octa (BIM-23042; binds NMB > GRP). Five minutes later rats were administered 8 micrograms/kg BN (i.p.) and milk intake was measured. Injections of [D-Phe12,Leu14]BN and [D-Phe6]BN(6-13) ethyl amide reliably attenuated the ability of BN to suppress milk intake whereas BIM-23042 was ineffective. The results show that the antagonists were behaviorally effective and that exogenous BN may exert its effects on food intake primarily through the GRP receptor subtype. Next, the antagonists were administered either 5 min prior to or 5 min after an intragastric nutrient load or no load in both overnight-deprived and nondeprived rats, and milk intake was then measured. Stomach loads reduced intake and this effect was not attenuated by BN receptor antagonists. Finally, rats were allowed to prefeed and the milk was then removed. Rats were then administered a BN receptor antagonist (0.1 and 1.0 mg/kg) or saline either immediately after the prefeed, 10 min later, or 20 min later. Milk diet was then returned and intake was measured. Peripheral injections of the BN receptor antagonist had no effect compared to saline on milk intake. Collectively, the results indicate that the blockade of peripheral Bn peptide receptors is not sufficient to attenuate the safety signals generated by stomach loads or prefeeding.     

Effect of endothelin-1 in man--impact on basal and stimulated concentrations of luteinizing hormone, follicle-stimulating hormone, thyrotropin, growth hormone, corticotropin, and prolactin

The effect of endothelin-1 on basal and stimulated serum (plasma) concentrations of luteinizing hormone (LH), follicle-stimulating hormone (FSH), thyrotropin (TSH), prolactin (PRL), growth hormone (GH), and corticotropin was investigated in healthy male volunteers (n = 5). Intravenous (IV) administration of endothelin-1 (5 ng/kg/min for 15 minutes, followed by 2.5 ng/kg/min for 105 minutes) induced an increase in basal plasma concentrations of corticotropin. Serum concentrations of PRL, TSH, LH, FSH, and GH remained unchanged. The increase in serum concentrations of these pituitary hormones induced by IV administration of LH-releasing hormone ([LH-RH] 100 micrograms), thyrotropin RH ([TRH] 400 micrograms), GH-RH (100 micrograms), and corticotropin-releasing factor ([CRF] 100 micrograms) was suppressed in regard to PRL (P < .01) and GH (P < .01) and enhanced in regard to corticotropin (P < .01). Stimulated serum concentrations of LH and FSH also tended to be higher following administration of endothelin-1 (P < .05), whereas the increase in serum concentrations of TSH remained unchanged. Thus, when administered in pharmacological doses, endothelin-1 influences pituitary hormone secretion in man.     

Phase I/II study of combined granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor administration for the mobilization of hematopoietic progenitor cells

PURPOSE: To study the toxicity and efficacy of combined granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) administration for mobilization of hematopoietic progenitor cells (HPCs). MATERIALS AND METHODS: Cohorts of a minimum of five patients each were treated subcutaneously as follows: G-CSF 5 micrograms/kg on days 1 to 12 and GM-CSF at .5, 1, or 5 micrograms/kg on days 7 to 12 (cohorts 1, 2, and 3); GM-CSF 5 micrograms/kg on days 1 to 12 and G-CSF 5 micrograms/kg on days 7 to 12 (cohort 4); and G-CSF and GM-CSF 5 micrograms/kg each on days 1 to 12 (cohort 5). Ten-liter aphereses were performed on days 1 (baseline, pre-CSF), 5, 7, 11, and 13. Colony assays for granulocyte-macrophage colony-forming units (CFU-GM) and erythroid burst-forming units (BFU-E) were performed on each harvest. RESULTS: The principal toxicities were myalgias, bone pain, fever, nausea, and mild thrombocytopenia, but none was dose-limiting. Four days of treatment with either G-CSF or GM-CSF resulted in dramatic and sustained increases in the numbers of CFU-GM per kilogram collected per harvest that represented 35.6 +/- 8.9- and 33.7 +/- 13.0-fold increases over baseline, respectively. This increment was attributable both to increased numbers of mononuclear cells collected per 10-L apheresis and to increased concentrations of progenitors within each collection. The administration of G-CSF to patients already receiving GM-CSF (cohort 4) caused the HPC content to surge to nearly 80-fold the baseline (P = .024); the reverse sequence, ie, the addition of GM-CSF to G-CSF, was less effective. The CFU-GM content of the baseline aphereses correlated with the maximal mobilization achieved (r = .74, P = .001). CONCLUSION: Combined G-CSF and GM-CSF administration effectively and predictably mobilizes HPCs and facilitates apheresis.     

Central CRF receptor antagonist α-helical CRF9-41 blocks reinstatement of extinguished fear: The role of the bed nucleus of the stria terminalis.

The present experiments assessed the necessity of central CRF in reinstatement of extinguished fear. Using the fear-potentiated startle procedure, rats were given light-shock pairings (fear conditioning) followed by light-alone extinction training. Rats were then given unsignaled shocks to reinstate fear to the light conditioned stimulus (CS). Intracerebroventricular administration of the CRF antagonist α-Helical CRF9-41 prior to reinstatement training dose-dependently prevented reinstatement. Further, α-Helical CRF9-41 administration prior to reinstatement training or the test for reinstatement of fear to the extinguished CS prevented reinstatement at both treatment times, suggesting that CRF activity is critical for this type of return of fear to an extinguished CS. The abolition of reinstatement by drug administration was not due to state-dependent learning, as rats treated with the drug prior to both reinstatement training or testing also failed α-Helical CRF9-41 in the bed nucleus of the stria terminalis suggested that this area is a site at which central CRF is involved in this form of relapse. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Antinociceptive effect of dihydroetorphine in diabetic mice

The antinociceptive potency of dihydroetorphine in diabetic mice was examined. Subcutaneous administration of dihydroetorphine produced a dose-dependent antinociception in both non-diabetic and diabetic mice. The antinociceptive potency of s.c. dihydroetorphine was less in diabetic mice than in non-diabetic mice. The antinociception induced by i.c.v. dihydroetorphine (0.02 microgram) was also significantly less in diabetic mice than in non-diabetic mice. The antinociceptive effects of dihydroetorphine (10 micrograms/kg i.p.) in both diabetic and non-diabetic mice were significantly antagonized by s.c. administration of beta-funaltrexamine, a selective mu-opioid receptor antagonist. Furthermore, the antinociceptive effect of dihydroetorphine (10 micrograms/kg i.p.) in non-diabetic mice, but not in diabetic mice, was also significantly antagonized by naloxonazine, a selective mu 1-opioid receptor antagonist. The time course and the potency of the antinociceptive effect of dihydroetorphine (10 micrograms/kg i.p.) in diabetic mice were similar to those in naloxonazine-treated non-diabetic mice. Naltrindole, a selective delta-opioid receptor antagonist, or nor-binaltorphimine, a selective kappa-opioid receptor antagonist, had no significant effect on the antinociceptive effect of dihydroetorphine (10 micrograms/kg i.p.) in both diabetic and non-diabetic mice. These results suggest that dihydroetorphine produces an antinociceptive effect through the activation of both mu 1- and mu 2-opioid receptors in mice. Furthermore, the reduction in dihydroetorphine-induced antinociception in diabetic mice, as compared with non-diabetic mice, may be due to the hyporesponsive to supraspinal mu 1-opioid receptor-mediated antinociception in diabetic mice.