Biomedical subjects

K C Rice

Publications and source records attributed to K C Rice.

At least 37 records · Page 2Linked to original sources

PubMed2001

The development of a potential single photon emission computed tomography (SPECT) imaging agent for the corticotropin-releasing hormone receptor type.

A high-affinity radioligand for CRHR1 has been prepared that can serve as a template for the development of SPECT imaging agents. The 5-chloro-N-cyclopropylmethyl-N-(2,6-dichloro-4-iodophenyl)-2-methyl-N-propylpyrimidine-4,6-diamine (6b, Ki = 14 nM), and the corresponding 4-bromophenyl analogue (6a, Ki = 21 nM), were synthesized in four steps from compound 3.

Animals↗

PubMed2001

Amphetamine-type central nervous system stimulants release norepinephrine more potently than they release dopamine and serotonin.

A large body of evidence supports the hypothesis that mesolimbic dopamine (DA) mediates, in animal models, the reinforcing effects of central nervous system stimulants such as cocaine and amphetamine. The role DA plays in mediating amphetamine-type subjective effects of stimulants in humans remains to be established. Both amphetamine and cocaine increase norepinephrine (NE) via stimulation of release and inhibition of reuptake, respectively. If increases in NE mediate amphetamine-type subjective effects of stimulants in humans, then one would predict that stimulant medications that produce amphetamine-type subjective effects in humans should share the ability to increase NE. To test this hypothesis, we determined, using in vitro methods, the neurochemical mechanism of action of amphetamine, 3,4-methylenedioxymethamphetamine (MDMA), (+)-methamphetamine, ephedrine, phentermine, and aminorex. As expected, their rank order of potency for DA release was similar to their rank order of potency in published self-administration studies. Interestingly, the results demonstrated that the most potent effect of these stimulants is to release NE. Importantly, the oral dose of these stimulants, which produce amphetamine-type subjective effects in humans, correlated with the their potency in releasing NE, not DA, and did not decrease plasma prolactin, an effect mediated by DA release. These results suggest that NE may contribute to the amphetamine-type subjective effects of stimulants in humans.

Amphetamine↗

PubMed2001

Opioid peptide receptor studies. 14. Stereochemistry determines agonist efficacy and intrinsic efficacy in the [(35)S]GTP-gamma-S functional binding assay.

Previous data obtained with the cloned rat mu opioid receptor demonstrated that stereochemistry affects the four parameters of the ligand-receptor interaction: potency (ED(50)), efficacy (maximal stimulation), intrinsic efficacy (effect as a function of receptor occupation), and binding affinity. This study evaluated the activities of structurally diverse opioid receptor ligands in the [(35)S]GTP-gamma-S binding assay, comparing the relationship between receptor binding, activation, efficacy, and intrinsic efficacy. The data, obtained with cloned rat mu receptors, demonstrated that an analgetic, (-)-5-m-hydroxyphenyl-2-methylmorphan (NIH8508), and its (+)-isomer (NIH8509), behave as partial agonists, but had different intrinsic efficacy in the [(35)S]GTP-gamma-S binding assay. Replacement of the methyl group with the phenethyl group on the piperidine nitrogen of NIH8508 and NIH8509 [(1R,5S)-AH019 and (1S, 5R)-AH019] increased affinity for the mu receptor and eliminated any agonist effect, supporting the hypothesis that certain structural features make these compounds antagonists. These study also show that all of the fully efficacious mu agonists studied here had high levels of intrinsic efficacy, producing a 50% response at about 10% receptor occupancy. Comparison of the binding K(i) in competitively inhibiting [(125)I]IOXY binding to the functional K(i) for opioid antagonists [K(i)(IOXY)/K(i)(GTP-gamma-S)] provides more detailed evidence that the [(35)S]GTP-gamma-S binding assay can be used to reliably determine apparent functional antagonist K(i) values in addition to agonist ED(50), efficacy and intrinsic efficacy.

Analgesics, Opioid↗

PubMed2001

Corticotropin-releasing hormone promotes blastocyst implantation and early maternal tolerance.

The semi-allograft embryo in the blastocyst stage implants itself in the endometrium, yet no immune rejection processes are activated. Embryonic trophoblast and maternal decidua produce corticotropin-releasing hormone (CRH) and express Fas ligand (FasL), a proapoptotic cytokine. We found that antalarmin, a CRH receptor type 1 antagonist, decreased FasL expression and promoted apoptosis of activated T lymphocytes, an effect which was potentiated by CRH and inhibited by antalarmin. Female rats treated with antalarmin showed a marked decrease in implantation sites and live embryos and diminished endometrial FasL expression. Embryos from mothers that lacked T cells or from syngeneic matings were not rejected when the mothers were given antalarmin. These findings suggested that locally produced CRH promotes implantation and maintenance of early pregnancy primarily by killing activated T cells.

Animals↗

PubMed2001

Receptor-selective antagonism of opioid antinociception in female versus male rats.

This study was conducted to determine whether sex differences in opioid antinociception may be explained by sex differences in opioid receptor activation. The time course, dose-effect and selectivity of antagonists that have been previously shown to be relatively mu (beta-funaltrexamine, beta-FNA), kappa (norbinaltorphimine, norBNI), or delta (naltrindole, NTI) receptor selective in male animals were compared in female and male Sprague-Dawley rats using a 52 degrees C hotplate test. In both sexes, beta-FNA (10 or 20 microg intracerebroventricularly [i.c.v.]) dose-dependently blocked the antinociceptive effects of fentanyl (0.056 mg/kg subcutaneously); antagonism was observed 24 h after beta-FNA, and diminished within 7-14 days. In both sexes, norBNI (1 or 10 microg i.c.v.) dose-dependently blocked the antinociceptive effects of U69,593 (1.0 mg/kg subcutaneously); antagonism was maximal by 1-3 days post-norBNI and lasted longer than 56 days. NTI (1 or 10 microg i.c.v.) dose-dependently blocked the antinociceptive effects of [D-Pen2, D-Pen5]enkephalin (DPDPE, 100 nmol i.c.v.) in both sexes; however, the duration of action of NTI was shorter in females than in males. The antinociceptive effects of the mu receptor-preferring agonists fentanyl, morphine and buprenorphine were significantly and dose-dependently antagonized by beta-FNA, but not by norBNI or NTI, in both sexes. Beta-FNA antagonism was significantly greater in females compared with males given morphine, but not fentanyl or buprenorphine. The antinociceptive effects of the kappa receptor-preferring agonists U69,593 and U50,488 were significantly and dose-dependently antagonized by norBNI; U50,488 but not U69,593 was also antagonized to a lesser extent by NTI and beta-FNA, in both sexes. The antinociceptive effect of the delta receptor-preferring agonist SNC 80 was significantly antagonized by NTI, but not by norBNI or beta-FNA, in both sexes. The sex difference in beta-FNA antagonism of morphine suggests that there may be sex differences in functional mu opioid receptor reserve or signal transduction; however, the lack of consistency across all mu agonists weakens this hypothesis. Overall, the opioids tested had very similar receptor selectivity in male and female subjects.

Analgesics, Opioid↗

PubMed2001

Antinociceptive effects of delta-opioid agonists in Rhesus monkeys: effects on chemically induced thermal hypersensitivity.

The effects of SNC80 and other structurally related delta-opioid receptor agonists were assessed under conditions of chemically induced hypersensitivity to thermal stimuli in four rhesus monkeys. The shaved tail of each monkey was exposed to warm water (38, 42, 46, and 50 degrees C), and the tail-withdrawal latency from each temperature was recorded. The effects of drugs on the temperature that produced a 10-s tail-withdrawal latency (the T(10) value) were examined. Capsaicin (0.01-0.32 mg) injected into the tail of monkeys dose dependently decreased the T(10), indicating that capsaicin increased sensitivity to thermal stimuli. A dose of 0.1 mg of capsaicin decreased the T(10) from 48.0 to 42.1 degrees C (a -5.9 degrees C change) 15 min after injection. SNC80 (1.0-10.0 mg/kg s.c.) dose dependently blocked the capsaicin-induced decrease in the T(10), and 10.0 mg/kg SNC80 fully blocked the effects of capsaicin. The delta-selective antagonist naltrindole (0.1-1.0 mg/kg) dose dependently antagonized the effects of SNC80, whereas a mu-selective dose of the opioid antagonist quadazocine (0.1 mg/kg) did not. Two other delta-selective agonists, SNC162 (1.0-10.0 mg/kg) and SNC243A (1.0-10.0 mg/kg), also dose dependently blocked capsaicin-induced thermal hypersensitivity. In contrast, neither SNC67 (10.0 mg/kg), which is the (-)-enantiomer of SNC80, nor the nonsteroidal anti-inflammatory drug (NSAID) ketorolac (1.0-10.0 mg/kg) modified the effects of capsaicin. SNC80 was also effective in reversing thermal hypersensitivity induced by prostaglandin E(2) (0.0158 mg) and Freund's complete adjuvant (10% concentration). These findings suggest that delta-agonists have antinociceptive effects in primates under conditions of chemically induced thermal hypersensitivity and might be effective under a broader range of conditions than clinically available NSAIDs.

Analgesics↗

PubMed2001

Behavioral evidence for the interaction of oleamide with multiple neurotransmitter systems.

While the endogenous fatty acid amide oleamide has hypnotic properties, neither the breadth of its behavioral actions nor the mechanism(s) by which these behaviors may be mediated has been elucidated. Therefore, the effects of oleamide on the performance of rats in tests of motor function, analgesia, and anxiety were investigated. Oleamide reduced the distance traveled in the open field (ED50 = 14, 10-19 mg/kg, mean, 95% confidence interval), induced analgesia and hypothermia, but did not cause catalepsy. Moreover, a dose of oleamide without effect on motor function was anxiolytic in the social interaction test and elevated plus-maze. These actions of a single dose of oleamide lasted for 30 to 60 min. While rats became tolerant to oleamide following 8 days of repeated administration, oleamide is a poor inducer of physical dependence. Pretreatment with antagonists of the serotonin (5HT)1A, 5HT2C, and vanilloid receptors did not modify oleamide's effects. However, the cannabinoid receptor antagonist SR 141716A inhibited oleamide-induced analgesia in the tail-flick assay, the gamma-aminobutyric acid (GABA)A receptor antagonist bicuculline reversed the analgesia and hypothermia, and the dopamine D2 receptor antagonist L 741626 blocked oleamide's locomotor and analgesic actions. Interestingly, oleamide analogs resistant to hydrolysis by fatty acid amide hydrolase (FAAH) maintained but did not show increased behavioral potency or duration of action, whereas two FAAH inhibitors produced analogous behavioral effects. Thus, oleamide induces behaviors reminiscent of the actions of endogenous cannabinoids, but the involvement of GABAergic and dopaminergic systems, either directly or indirectly, in the actions of oleamide cannot be ruled out.

Amidohydrolases↗

PubMed2001

Studies of tolerance and dependence with the delta-opioid agonist SNC80 in rhesus monkeys responding under a schedule of food presentation.

Tolerance and dependence after acute or chronic administration of the selective delta-opioid agonist SNC80 were assessed in rhesus monkeys (Macaca mulatta) responding under a schedule of food presentation. SNC80 dose dependently decreased response rates. These effects waned after 5 h. When administered as an acute 24-h pretreatment, SNC80 (1.0-10.0 mg/kg) produced tolerance as evidenced by dose-dependent rightward shifts in the SNC80 dose-effect curve. Pretreatments of 3.2 or 10.0 mg/kg SNC80 increased the SNC80 ED50 by 4- or 25-fold, respectively. Tolerance to acute SNC80 was also time-dependent as evidenced by increased ED50 values when administered as a 5-h (14-fold), 24-h (25-fold), or 3-day (11-fold) pretreatment. The SNC80 dose-effect curve was similar to control after a 7-day pretreatment. The selective delta-antagonist naltrindole (1.0 mg/kg) partially blocked tolerance to acute SNC80. Chronic SNC80 (1.0-10.0 mg/kg/day) also produced dose-dependent rightward shifts in the SNC80 dose-effect curve. Chronic SNC80 was more effective than acute SNC80 in producing tolerance. Moreover, tolerance to chronic SNC80 waned more slowly than to acute SNC80. Acute or chronic SNC80 (10.0 mg/kg/day) also produced cross-tolerance to the rate-decreasing effects of other delta-agonists (SNC162 and SNC243A) but not to mu- (morphine) or kappa (U-50,488)-agonists. Changes in response rates or behavioral signs of withdrawal were not observed after the administration of opioid antagonists (i.e., naltrindole or naltrexone) in monkeys treated with SNC80. These data suggest that a pharmacologically selective tolerance develops to delta-agonists after both acute and chronic administration of SNC80 with little or no dependence.

Animals↗

PubMed2000

Synthesis and transporter binding properties of bridged piperazine analogues of 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine (GBR 12909).

A series of analogues related to 1-[2-(diphenylmethoxy)ethyl]-4-(3-phenylpropyl)piperazine (2) and 1-¿2-[bis(4-fluorophenyl)methoxy]ethyl¿-4-(3-phenylpropyl)piperazine (3) (GBR 12935 and GBR 12909, respectively), in which the piperazine moiety was replaced by bridged piperazines for structural rigidity, has been designed, synthesized, and evaluated for their ability to bind to the dopamine transporter (DAT) and to inhibit the uptake of (3)H-labeled dopamine (DA). The binding data indicated that compounds 7 and 11, the N-methyl- and N-propylphenyl-3,8-diaza[3.2. 1]bicyclooctane analogues of 3, showed high affinity for the DAT (IC(50) = 8.0 and 8.2 nM, respectively), and 7 had high selectivity at the DAT relative to the serotonin transporter (SERT) (88- and 93-fold for binding and reuptake, respectively). They also displayed linear activity in DA uptake inhibition, possessing a similar binding and reuptake inhibition profile to 3. The N-indolylmethyl analogue 16 showed the highest affinity (IC(50) = 1.4 nM) of the series, with a 6-fold increase over its corresponding N-phenypropyl derivative 11. Interestingly, this compound exhibited a high ratio (29-fold) of IC(50) for the inhibition of DA reuptake versus binding to the DAT. Replacing the piperazine moiety of 2 and 3 with (1S, 4S)-2,5-diazabicyclo[2.2.1]heptane resulted in compounds 23-26, which showed moderate to poor affinity (IC(50) = 127-1170 nM) for the DAT. Substitution of the homopiperazine moiety of 4 with a more rigid 3,9-diazabicyclo[4.2.1]nonane gave compounds 28-33. However, the binding data showed that compound 32 displayed a 10-fold decrease in affinity at the DAT and a 100-fold decrease in selectivity at the DAT relative to the SERT compared to its corresponding homopiperazine compound 4.

Animals↗

PubMed2000

Design, synthesis, and monoamine transporter binding site affinities of methoxy derivatives of indatraline.

A series of methoxy-containing derivatives of indatraline 13a-f and 17 were synthesized, and their binding affinities for the dopamine, serotonin, and norepinephrine transporter binding sites were determined. Introduction of a methoxy group to indatraline affected its affinity and selectivity greatly. Except for the 4-methoxy derivative 13a,which had the same high affinity at the dopamine transporter binding site as indatraline, the other methoxy-containing analogues (13b-f and 17) exhibited lower affinity than indatraline for the three transporter binding sites. However, some of the analogues were more selective than indatraline, and the 6-methoxy derivative 13c displayed the highest affinity for both the serotonin and norepinephrine transporters. This compound retained reasonable affinity for the dopamine transporter and is a promising template for the development of a long-acting inhibitor of monoamine transporters. Such inhibitors have potential as medications for treatment, as a substitution medication, or for prevention of the abuse of methamphetamine-like stimulants.

Animals↗

PubMed2000

N-Cyclohexylethyl-N-noroxymorphindole: a mu-opioid preferring analogue of naltrindole.

The position of the indole in the indolomorphinans, which includes the delta opioid antagonist naltrindole, is considered to be responsible for the delta opioid selectivity for this class of ligands. Herein is described the N-cyclohexylethyl substituted N-nor-derivative, which is shown to be mu preferring. Thus, the nature of the N-substituent is equally important to the receptor selectivity for this class of ligands.

Analgesics↗

PubMed2000

Antalarmin blockade of corticotropin releasing hormone-induced hypertension in rats.

Central administration of CRH results in endocrinological, cardiovascular, and behavioral effects that suggest stress or anxiety. Among these is a marked pressor response. Parenteral administration of CRH, however, results in hypotension. We used parenteral administration of antalarmin, a novel, small molecule CRH1 receptor antagonist, and alpha-helical CRH(9-41), a peptidic CRHR1/CRHR2 antagonist to attempt to determine the receptor mechanisms through which CRH is acting in both of these situations. Our results suggest that the hypertension produced by central CRH administration is mediated through central CRHR1 receptors, whereas the hypotension produced by parenteral CRH administration is mediated through peripheral CRHR2 receptors.

Animals↗

PubMed2000

Probes for narcotic receptor-mediated phenomena. 27. Synthesis and pharmacological evaluation of selective delta-opioid receptor agonists from 4-[(alphaR)-alpha-(2S,5R)-4-substituted-2, 5-dimethyl-1-piperazinyl-3-methoxybenzyl]-N,N-diethylbenzamides and their enantiomers.

Potent, selective, and efficacious delta-opioid receptor agonists such as (+)-4-[(alphaR)-alpha-(2S,5R)-4-allyl-2, 5-dimethyl-1-piperazinyl-3-methoxybenzyl]-N,N-diethylbenzamide [SNC80, (+)-2] have been found to be useful tools for exploring the structural requirements which are necessary for ligands which interact with the delta-receptor. To determine the necessity for the 4-allyl moiety in (+)-2, this substituent was replaced with a variety of 4-alkyl, 4-arylalkyl, and 4-alkenyl substituents. The corresponding enantiomers of these compounds were also synthesized. The binding affinities for the mu-, delta-, and kappa-opioid receptors and efficacies in the functional GTPgammaS binding assay were determined for the (+)-2 related compounds and their enantiomers. The 4-crotyl analogue was found to have similar delta-receptor affinity and efficacy as (+)-2, but the 4-cyclopropylmethyl analogue, in the functional assay, appeared to be a partial agonist with little antagonist activity.

Animals↗

PubMed2000

Oral administration of a corticotropin-releasing hormone receptor antagonist significantly attenuates behavioral, neuroendocrine, and autonomic responses to stress in primates.

We evaluated the effects of the lipophilic nonpeptide corticotropin-releasing hormone (CRH) type 1 receptor antagonist antalarmin on the behavioral, neuroendocrine, and autonomic components of the stress response in adult male rhesus macaques. After oral administration, significant antalarmin concentrations were detected in the systemic circulation and the cerebrospinal fluid by a mass spectrometry-gas chromatography assay developed specifically for this purpose. Pharmacokinetic and dose-response studies suggested that an oral dose of 20 mg/kg was optimal for behavioral and endocrine effects. We then administered this dose in a double-blind, placebo-controlled fashion to monkeys exposed to an intense social stressor: namely, placement of two unfamiliar males in adjacent cages separated only by a transparent Plexiglas screen. Antalarmin significantly inhibited a repertoire of behaviors associated with anxiety and fear such as body tremors, grimacing, teeth gnashing, urination, and defecation. In contrast, antalarmin increased exploratory and sexual behaviors that are normally suppressed during stress. Moreover, antalarmin significantly diminished the increases in cerebrospinal fluid CRH as well as the pituitary-adrenal, sympathetic, and adrenal medullary responses to stress. We conclude that CRH plays a broad role in the physiological responses to psychological stress in primates and that a CRH type 1 receptor antagonist may be of therapeutic value in human psychiatric, reproductive, and cardiovascular disorders associated with CRH system hyperactivity.

Administration, Oral↗

PubMed2000

Synthesis and biological activity of fluoro-substituted pyrrolo[2,3-d]pyrimidines: the development of potential positron emission tomography imaging agents for the corticotropin-releasing hormone type 1 receptor.

A series of fluoro-substituted 4-(dialkylamino)pyrrolo[2,3-d]pyrimidines was synthesized and their binding affinity for corticotropin-releasing hormone type 1 receptor (CRHR1) was investigated. Compounds 11a and 11b possessed very high CRHR1 affinity (Ki=3.5, 0.91 nM, respectively). They are promising candidates for the development of 18F-containing nonpeptide PET radioligands for CRHR1.

Animals↗

PubMed2000

Neurochemical neutralization of methamphetamine with high-affinity nonselective inhibitors of biogenic amine transporters: a pharmacological strategy for treating stimulant abuse.

The abuse of methamphetamine (METH) and other amphetamine-like stimulants is a growing problem in the United States. METH is a substrate for the 12-transmembrane proteins which function as transporters for the biogenic amines dopamine (DA), serotonin (5-HT), and norepinephrine (NE). Increased release of CNS DA is thought to mediate the addictive effects of METH, whereas increased release of NE in both the peripheral and CNS is thought to mediate its cardiovascular effects. The neurotoxic effects of METH on both dopaminergic and serotonergic nerves requires the transport of METH into the nerve terminals. Thus, transport of METH into nerve terminals is the crucial first step in the production of METH-associated pharmacological and toxicological effects. A single molecular entity which would block the transport of METH at all three biogenic amine transporters might function to neurochemically neutralize METH. This agent would ideally be a high-affinity slowly dissociating agent at all three transporters, and also be amenable to formulation as a long-acting depot medication, such as has been accomplished with an analog of GBR12909. As a first step towards developing such an agent, we established an in vitro assay which selectively detects transporter substrates and used this assay to profile the ability of a lead compound, indatraline, to block the releasing effects of METH and MDMA at the DA, 5-HT, and NE transporters. The major finding reported here is that indatraline blocks the ability of METH and MDMA to release these neurotransmitters. Synapse 35:222-227, 2000. Published 2000 Wiley-Liss, Inc.

Adrenergic Uptake Inhibitors↗

PubMed2000

delta-Opioid receptor agonists produce antinociception and [35S]GTPgammaS binding in mu receptor knockout mice.

We examined the effects of [D-Pen(2),D-Pen(5)]enkephalin (DPDPE), [D-Ala(2),Glu(4)]deltorphin (DELT), and (+)-4-[(alphaR)-alpha((2S, 5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N, N-diethylbenzamide (SNC80) on [35S]GTPgammaS binding in brain membranes prepared from micro-opioid receptor knockout (-/-) mice. The potency and maximal response (E(max)) of these agonists were unchanged compared to control mice. In contrast, while the potency of [D-Pen(2),pCl-Phe(4),D-Pen(5)]enkephalin (pCl-DPDPE) was not significantly different, the E(max) was reduced as compared to controls. In the tail-flick test, intracerebroventricular (i.c.v.) or intrathecal (i.th.) DELT produced antinociceptive effects in -/- mice with potency that did not differ significantly from controls. In contrast, the antinociceptive potency of i.c.v. and i.th. DPDPE was displaced to the right by 4- and 9-fold in -/- compared to control mice, respectively. Reduced DPDPE antinociceptive potency in -/- mice, taken together with reduced DPDPE- and pCl-DPDPE- stimulated G protein activity in membranes prepared from -/- mice, demonstrate that these agonists require mu-opioid receptors for full activity. However, because DELT mediated G protein activation and antinociception were both comparable between -/- and wild type mice, we conclude that the mu-opioid receptor is not a critical component of delta-opioid receptor function.

Analgesics, Opioid↗

PubMed2000

Pronounced and sustained central hypernoradrenergic function in major depression with melancholic features: relation to hypercortisolism and corticotropin-releasing hormone.

Both stress-system activation and melancholic depression are characterized by fear, constricted affect, stereotyped thinking, and similar changes in autonomic and neuroendocrine function. Because norepinephrine (NE) and corticotropin-releasing hormone (CRH) can produce these physiological and behavioral changes, we measured the cerebrospinal fluid (CSF) levels each hour for 30 consecutive hours in controls and in patients with melancholic depression. Plasma adrenocorticotropic hormone (ACTH) and cortisol levels were obtained every 30 min. Depressed patients had significantly higher CSF NE and plasma cortisol levels that were increased around the clock. Diurnal variations in CSF NE and plasma cortisol levels were virtually superimposable and positively correlated with each other in both patients and controls. Despite their hypercortisolism, depressed patients had normal levels of plasma ACTH and CSF CRH. However, plasma ACTH and CSF CRH levels in depressed patients were inappropriately high, considering the degree of their hypercortisolism. In contrast to the significant negative correlation between plasma cortisol and CSF CRH levels seen in controls, patients with depression showed no statistical relationship between these parameters. These data indicate that persistent stress-system dysfunction in melancholic depression is independent of the conscious stress of the disorder. These data also suggest mutually reinforcing bidirectional links between a central hypernoradrenergic state and the hyperfunctioning of specific central CRH pathways that each are driven and sustained by hypercortisolism. We postulate that alpha-noradrenergic blockade, CRH antagonists, and treatment with antiglucocorticoids may act at different loci, alone or in combination, in the treatment of major depression with melancholic features.

Adrenocorticotropic Hormone↗