Different expression of adrenoceptors and GRKs in the human myocardium depends on heart failure etiology and correlates to clinical variables.

Downregulation of ß(1)- adrenergic receptors (ß(1)-ARs) and increased expression/function of G-protein-coupled receptor kinase 2 (GRK2) have been observed in human heart failure, but changes in expression of other ARs and GRKs have not been established. Another unresolved question is the incidence of these compensatory mechanisms depending on heart failure etiology and treatment. To analyze these questions, we quantified the mRNA/protein expressions of six ARs (α(1A), α(1B), α(1D), ß(1), ß(2), and ß(3)) and three GRKs (GRK2, GRK3, and GRK5) in left (LV) and right ventricle (RV) from four donors, 10 patients with ischemic cardiomyopathy (IC), 14 patients with dilated cardiomyopathy (DC), and 10 patients with nonischemic, nondilated cardiopathies (NINDC). We correlated the changes in the expressions of ARs and GRKs with clinical variables such as left ventricular ejection fraction (LVEF) and left ventricular end-systolic and left ventricular end-diastolic diameter (LVESD and LVEDD, respectively). The main findings were 1) the expression of the α(1A)-AR in the LV positively correlates with LVEF; 2) the expression of GRK3 and GRK5 inversely correlates with LVESD and LVEDD, supporting previous observations about a protective role for both kinases in failing hearts; and 3) ß(1)-AR expression is downregulated in the LV and RV of IC, in the LV of DC, and in the RV of NINDC. This difference, better than an increased expression of GRK2 (not observed in IC), determines the lower LVEF in IC and DC vs. NINDC.

A single conserved leucine residue on the first intracellular loop regulates ER export of G protein-coupled receptors.

The intrinsic structural determinants for export trafficking of G protein-coupled receptors (GPCRs) have been mainly identified in the termini of the receptors. In this report, we determined the role of the first intracellular loop (ICL1) in the transport from the endoplasmic reticulum (ER) to the cell surface of GPCRs. The alpha(2B)-adrenergic receptor (AR) mutant lacking the ICL1 is unable to traffic to the cell surface and to initiate signaling measured as ERK1/2 activation. Mutagenesis studies identify a single Leu48 residue in the ICL1 modulates alpha(2B)-AR export from the ER. The ER export function of the Leu48 residue can be substituted by Phe, but not Ile, Val, Tyr and Trp, and is unlikely involved in correct folding or dimerization of alpha(2B)-AR in the ER. Importantly, the isolated Leu residue is remarkably conserved in the center of the ICL1s among the family A GPCRs and is also required for the export to the cell surface of beta(2)-AR, alpha(1B)-AR and angiotensin II type 1 receptor. These data indicate a crucial role for a single Leu residue within the ICL1 in ER export of GPCRs.

Distribution and co-expression of adrenergic receptor-encoding mRNA in the mouse inferior colliculus.

Adrenergic receptors are mediators of adrenergic and noradrenergic modulation throughout the brain. Previous studies have provided evidence for the expression of adrenergic receptors in the midbrain auditory nucleus, the inferior colliculus (IC), but have not examined the cellular patterns of expression in detail. Here, we utilize multichannel fluorescent in situ hybridization to detect the expression of adrenergic receptor-encoding mRNA in the inferior colliculus of male and female mice. We found expression of α1 , α2A , and ß2 receptor-encoding mRNA throughout all areas of the IC. While we observed similar levels of expression of α1 receptor-encoding mRNA across the subregions of the IC, α2A and ß2 receptor-encoding mRNA was expressed differentially. To account for developmental changes in noradrenergic receptor expression, we measured expression levels in mice aged P15, P20, and P60. We observed little change in levels of expression across these ages. To ascertain the modulatory potential of multiple adrenergic receptor subtypes in a single IC cell, we measured co-expression of α1 , α2A , and ß2 receptor-encoding mRNA. We found greater proportions of cells in the IC that expressed no adrenergic receptor-encoding mRNA, α1 and α2A adrenergic receptor-encoding mRNA, and α1, α2A, and ß2 receptor-encoding mRNA than would be predicted by independent expression of each receptor subtype. These data suggest a coordinated pattern of adrenergic receptor expression in the IC and provide the first evidence for adrenergic receptor expression and co-expression in the subregions of the mouse auditory midbrain.

Beta-adrenergic-receptor localization by light microscopic autoradiography.

beta-Receptors were identified in rat brain by a light microscopic autoradiographic technique. The procedure involved binding 3H-labeled dihydroalprenolol to beta-receptors in intact slide-mounted tissue sections and generating autoradiograms by the apposition of emulsion-coated cover slips, Biochemical analysis of the binding indicated that these conditions provided a high degree of selective labeling of beta-receptors. High densities of receptors were found in superficial layers of the cerebral cortex, throughout the caudate-putamen, in the periventricular nucleus of the thalamus, in the molecular layer of the cerebellum, and in other areas. These results are in agreement with other electrophysiological and histochemical data. This radiohistochemical approach should be an important addition to other methods for mapping functional catecholamine neuronal pathways and sites of hormonal action.

Innervation and receptor profiles of the human apocrine (epitrichial) sweat gland: routes for intervention in bromhidrosis.

BACKGROUND: Human apocrine (epitrichial) sweat glands secrete in response to local or systemic administration of catecholamines and cholinergic agonists. As the process of secretion in human apocrine glands is not fully understood and no literature detailing the expression of adrenergic, cholinergic and purinergic receptors is available, there is a need to know the receptor types. Such data could provide new approaches for the treatment of axillary bromhidrosis. OBJECTIVES: To investigate the localization of nerve fibres, adrenergic, cholinergic and purinergic receptors in human axillary apocrine sweat glands by immunohistochemistry. METHODS: Human axillary apocrine sweat glands were investigated by serial sectioning of paraffin wax-embedded skin samples from volunteers. Sections were examined by light microscopy and immunohistochemistry, using antibodies against neurofilament, alpha- and beta-adrenoceptors, P2Y(1), P2Y(2) and P2Y(4) purinoceptors, and M(3) cholinoceptors. RESULTS: Neurofilaments were found near the eccrine but not the apocrine gland. Apocrine glands demonstrated the presence of beta-2 and beta-3 adrenoceptors in the secretory coil of the gland, but not alpha-1, beta-1 or M(3) receptors. Glandular purinergic staining (P2Y(1), P2Y(2) and P2Y(4)) was found in what looked like myoepithelial cells, while P2Y(1) and P2Y(2) staining was found on apical membranes and diffusely throughout secretory cells. Eccrine gland staining acted as internal positive controls. CONCLUSIONS: No nerve fibres were found near the apocrine gland, suggesting that any catecholamine influence is through humoral effects and that glands could be influenced by beta-adrenoceptor subtypes and purinoceptors. Blockage of both these types of receptors offers a route to controlling apocrine secretion from axillary glands and reducing the opportunity for the development of bromhidrosis.

Atrioventricular ring reentry in embryonic mouse hearts.

BACKGROUND: During development, AV conduction switches from base-to-apex to apex-to-base conduction after emergence of the conduction system. We hypothesize that after this transition, the bulk of the AV ring, although no longer required for AV conduction, remains transiently able to conduct, providing a potential arrhythmia substrate. We studied AV conduction during this transition and its sensitivity to autonomic modulation. METHODS AND RESULTS: Simultaneous voltage and Ca2+ mapping with RH-237 and Rhod-2 was performed with 2 CCD cameras in embryonic mouse hearts (n = 43). Additionally, isolated calcium mapping was performed in 309 hearts with fluo-3AM. Propagation patterns in voltage and Ca2+ mapping coincided. Arrhythmias were uncommon under basal conditions, with AV block in 14 (4%) and junctional rhythms in 4 (1%). Arrhythmias increased after stimulation with isoproterenol-junctional rhythm in 9 (3%) and ventricular rhythms in 22 (6%)-although AV block decreased (3 hearts, 1%). Adding carbachol after isoproterenol caused dissociated antegrade and retrograde AV ring conduction in 30 (8.6%) of E10.5 and E11.5 hearts, occurring preferentially in the right and left sides of the ring, respectively. In 2 cases, reentry occurred circumferentially around the AV ring, perpendicular to normal propagation. Reentry persisted for multiple beats, lasting from 3 to 22 minutes. No episodes of AV ring reentry occurred in E9.5 hearts. CONCLUSIONS: AV ring reentry can occur by spatial dissociation of antegrade and retrograde conduction during combined adrenergic and muscarinic receptor stimulation. Critical maturation (> E9.5) seems to be required to sustain reentry.

Studies on the importance of sympathetic innervation, adrenergic receptors, and a possible local catecholamine production in the development of patellar tendinopathy (tendinosis) in man.

Changes in the patterns of production and in the effects of signal substances may be involved in the development of tendinosis, a chronic condition of pain in human tendons. There is no previous information concerning the patterns of sympathetic innervation in the human patellar tendon. In this study, biopsies of normal and tendinosis patellar tendons were investigated with immunohistochemical methods, including the use of antibodies against tyrosine hydroxylase (TH) and neuropeptide Y, and against alpha1-, alpha2A-, and beta1-adrenoreceptors. It was noticed that most of the sympathetic innervation was detected in the walls of the blood vessels entering the tendon through the paratendinous tissue, and that the tendon tissue proper of the normal and tendinosis tendons was very scarcely innervated. Immunoreactions for adrenergic receptors were noticed in nerve fascicles containing both sensory and sympathetic nerve fibers. High levels of these receptors were also detected in the blood vessel walls; alpha1-adrenoreceptor immunoreactions being clearly more pronounced in the tendinosis tendons than in the tendons of controls. Interestingly, immunoreactions for adrenergic receptors and TH were noted for the tendon cells (tenocytes), especially in tendinosis tendons. The findings give a morphological correlate for the occurrence of sympathetically mediated effects in the patellar tendon and autocrine/paracrine catecholamine mechanisms for the tenocytes, particularly, in tendinosis. The observation of adrenergic receptors on tenocytes is interesting, as stimulation of these receptors can lead to cell proliferation, degeneration, and apoptosis, events which are all known to occur in tendinosis. Furthermore, the results imply that a possible source of catecholamine production might be the tenocytes themselves

A carbene-generating photoaffinity probe for beta-adrenergic receptors.

A new radioiodinated (2.2 Ci/mumol) iodocyanopindolol derivative carrying a 4-(3-trifluoromethyldiazirino)benzoyl residue has been synthesized. The long-wavelength absorption of the diazirine permits formation of the carbene by photolysis under very mild conditions. [125I]ICYP-diazirine binds with high affinity (Kd = 60 pM) to beta-receptors from turkey erythrocyte membranes. Upon irradiation, [125I]ICYP-diazirine is covalently incorporated in a Mr 40 000 protein. Stereoselective inhibition of photolabeling by the (-)enantiomers of alprenolol and isoproterenol indicated that the Mr 40 000 protein contains a beta-adrenergic binding site. The yield of specific labeling was up to 8.2% of total beta-receptor binding sites. The Mr 40 000 protein photolabeled in the membrane could be solubilized at comparable yield with either digitonin or Triton X-100. Irradiation of digitonin-solubilized turkey erythrocyte membranes with [125I]ICYP-diazirine resulted in specific labeling of two proteins with Mr 40 000 and 50 000. In guinea-pig lung membranes, at least five proteins were photolabeled, of which one (with approximately Mr 67 000) was labeled specifically.

Molecular characterization of alpha 1- and alpha 2-adrenoceptors.

Three 'alpha 1-adrenoceptors' and three 'alpha 2-adrenoceptors' have now been cloned. How closely do these receptors match the native receptors that have been identified pharmacologically? What are the properties of these receptors, and how do they relate to other members of the cationic amine receptor family? Kevin Lynch and his colleagues discuss these questions in this review.

Preponderance of beta-adrenergic binding sites in pancreatic islet cells of the rat.

Although the alpha- and beta-adrenergic receptors have opposing effects on insulin secretion, the inhibitory influence of alpha-receptors appears to predominate. To determine if this was due to differences in number and affinity of receptors, isolated rat pancreatic islet cells were incubated with [3H]-dihydroalprenolol and [3H]-dihydroergocryptine as ligands for beta- and alpha-adrenergic binding sites. It was found that the number of beta-adrenergic binding sites was 143 fmol/mg islet protein with a Kd = 0.57 nM. The number of alpha-adrenergic binding sites was 53 fmol/mg protein with a Kd = 0.26 nM. Thus, there are 2.7 times as many beta-adrenergic binding sites as alpha-binding sites, and neither binding site number nor affinity is responsible for the predominant influence of the alpha-adrenergic receptors.

Evidence for reduction of norepinephrine uptake sites in the failing human heart.

OBJECTIVES: This study investigated the role of neuronal uptake of norepinephrine (uptake-1) in human heart failure as a local factor for altering concentrations of norepinephrine at the cardiac myocyte membranes. BACKGROUND: Several beta-adrenergic neuroeffector defects occur in heart failure. Whether an alteration in norepinephrine uptake-1 occurs is still unresolved. METHODS: The role of norepinephrine uptake-1 was studied in electrically stimulated (1 Hz, 37 degrees C) human ventricular cardiac preparations and isolated myocardial membranes. RESULTS: The effectiveness of norepinephrine in increasing the force of contraction was decreased in relation to the degree of heart failure. In contrast, the potency of norepinephrine was increased in failing hearts (New York Heart Association functional class IV) in relation to the concentrations producing 50% of the maximal effect (EC50). The EC50 values for isoproterenol, which is not a substrate for norepinephrine uptake-1, were reduced in myocardium in functional classes II to III and IV compared with those in nonfailing myocardium. The uptake inhibitors cocaine and desipramine (3 mumol/liter) potentiated the positive inotropic effects of norepinephrine in nonfailing myocardium (p < 0.05) but not in functional class IV myocardium. Radioligand binding experiments using the uptake inhibitor hydrogen-3 mazindol revealed a significant decrease by approximately 30% in norepinephrine uptake-1 carrier density in functional classes II to III and IV myocardium versus nonfailing myocardium (p < 0.05). CONCLUSIONS: In human heart failure, there is a presynaptic defect in the sympathetic nervous system, leading to reduced uptake-1 activity. This defect in the failing heart can be mimicked by the effects of uptake blocking agents, such as cocaine and desipramine, in the nonfailing heart only. Compromised norepinephrine uptake-1 in functional class IV cannot be further increased by cocaine and desipramine. The pathophysiologic consequences could be an increased synaptic concentration of norepinephrine predisposing to adenylyl cyclase desensitization.

Beta-adrenergic receptors in chronic alcoholic rat hearts.

Properties of cardiac beta-adrenergic receptors from chronic alcoholic and control rats were studied to determine whether alterations in the receptor contribute to the decreased responsiveness of isolated working alcoholic rat hearts to beta-adrenergic stimulation. The receptors, assessed in crude membrane fractions by the binding of (-)[3H]dihydroalprenolol, did not differ significantly in either number or affinity in alcoholic rats (22.5 +/- 1.9 fmol . mg protein-1; Kd = 0.49 +/- 0.03 nmol . litre-1; n = 7) compared with control rats (25.9 +/- 1.3 fmol . mg protein-1; Kd = 0.55 +/-0.04 nmol . litre-1; n = 7). Competition experiments indicated that there was no difference in the binding affinity of (-)isoprenaline for the alcoholic and control rat heart receptors, nor in the affinity of (-)propranolol for he alcoholic and control rat heart receptors. In the presence of 5' -guanylylimidodiphosphate, the affinity of (-)isoprenaline for the receptors was decreased the same amount in the alcoholic and control rat hearts. These results suggest that the beta-adrenergic subsensitivity of chronic alcoholic rat hearts is mediated by a biochemical mechanism other than a direct alteration of the beta-adrenergic receptor or coupling between the receptor and adenylate cyclase.

Localization of α-adrenoceptors: JR Vane Medal Lecture.

UNLABELLED: This review is based on the JR Vane Medal Lecture presented at the BPS Winter Meeting in December 2011 by J.C. McGrath. A recording of the lecture is included as supporting information. It covers his laboratory's work from 1990 to 2010 on the localization of vascular α1 -adrenoceptors in native tissues, mainly arteries. MAIN POINTS: (i) α1 -adrenoceptors are present on several cell types in arteries, not only on medial smooth muscle, but also on adventitial, endothelial and nerve cells; (ii) all three receptor subtypes (α1 A , α1 B , α1 D ) are capable of binding ligands at the cell surface, strongly indicating that they are capable of function and not merely expressed. (iii) all of these cell types can take up an antagonist ligand into the intracellular compartments to which endocytosing receptors move; (iv) each individual subtype can exist at the cell surface and intracellularly in the absence of the other subtypes. As functional pharmacological experiments show variations in the involvement of the different subtypes in contractions of different arteries, it is concluded that the presence and disposition of α1 -adrenoceptors in arteries is not a simple guide to their involvement in function. Similar locations of the subtypes, even in different cell types, suggest that differences between the distribution of subtypes in model systems do not directly correlate with those in native tissues. This review includes a historical summary of the alternative terms used for adrenoceptors (adrenergic receptors, adrenoreceptors) and the author's views on the use of colours to illustrate different items, given his partial colour-blindness.

The beta-adrenergic receptor of newborn mouse skin.

Binding of the potent beta-adrenergic antagonist [125I]iodohydroxybenzylpindolol ([125I]IHYP) to particulate preparations from newborn mouse skin was characterized. A number of criteria were used to establish that binding occurred to specific, high affinity beta-adrenergic receptors in the skin preparations. Thus specific binding (that displaced by 10 micrometer concentrations of the beta-adrenergic antagonist (-)propranolol) reached equilibrium in 15--20 min, was saturable (ligand concentration for half-maximal saturation, 0.25 nM) and freely reversible. Stereoselectivity of binding was demonstrated by the observation that displacement of [125I]IHYP by (-)propranolol occurred at concentrations at least 100 times lower than with (+)isoproterenol. Displacement was also observed with the beta-adrenergic agonists (-)isoproterenol, (-)epinephrine and (-)norepinephrine, but not with the alpha-adrenergic antagonist phentolamine.

Adrenergic receptors. Models for regulation of signal transduction processes.

Adrenergic receptors are prototypic models for the study of the relations between structure and function of G protein-coupled receptors. Each receptor is encoded by a distinct gene. These receptors are integral membrane proteins with several striking structural features. They consist of a single subunit containing seven stretches of 20-28 hydrophobic amino acids that represent potential membrane-spanning alpha-helixes. Many of these receptors share considerable amino acid sequence homology, particularly in the transmembrane domains. All of these macromolecules share other similarities that include one or more potential sites of extracellular N-linked glycosylation near the amino terminus and several potential sites of regulatory phosphorylation that are located intracellularly. By using a variety of techniques, it has been demonstrated that various regions of the receptor molecules are critical for different receptor functions. The seven transmembrane regions of the receptors appear to form a ligand-binding pocket. Cysteine residues in the extracellular domains may stabilize the ligand-binding pocket by participating in disulfide bonds. The cytoplasmic domains contain regions capable of interacting with G proteins and various kinases and are therefore important in such processes as signal transduction, receptor-G protein coupling, receptor sequestration, and down-regulation. Finally, regions of these macromolecules may undergo posttranslational modifications important in the regulation of receptor function. Our understanding of these complex relations is constantly evolving and much work remains to be done. Greater understanding of the basic mechanisms involved in G protein-coupled, receptor-mediated signal transduction may provide leads into the nature of certain pathophysiological states.

Changes in tissue alpha- and beta-adrenergic receptors in renal hypertension in the rat.

Myocardial membranes prepared from renal hypertensive rats contained reduced concentrations of both alpha- and beta-adrenergic receptors. The decrease in alpha-receptor concentration measured by [3H]-dihydroergocryptine binding was from 80 +/- 6 (SEM) to 52 +/- 2 fmol/mg. Beta-receptor concentration measured by 125I-iodohydroxybenzylpindolol binding also decreased by about half from 80 +/- 16 to 41 +/- 9 fmol/mg. The affinities of the receptors were unchanged. There was no change in either concentration or affinity of beta receptors in membranes prepared from the lungs or kidneys of these hypertensive rats. There results demonstrate that the observed receptor changes are tissue-specific. Cardiac adrenergic receptor alterations are therefore not part of a generalized adrenergic receptor decrease associated with elevated circulating plasma catecholamine concentrations, but probably reflect a specific increase in cardiac sympathetic drive.

Sympathetic activity and cardiac adrenergic receptors in one-kidney, one clip hypertension in rats.

The activity of the sympathetic nervous system, as measured by levels of plasma and cardiac catecholamines and catecholamine metabolites and the function of cardiac alpha- and beta-adrenergic receptors, was evaluated at 3 days and 4 weeks after induction of one-kidney, one clip hypertension (1K1C) in the rat. At 3 days, the plasma level of norepinephrine (NE) was lower in the 1K1C group than the control group (p less than 0.01), whereas epinephrine (E) and the metabolites dihydroxymandelic acid (DOMA), dihydroxyphenylglycol (DOPEG), and normetanephrine (NMN) were similar in both groups. In addition, cardiac content of catecholamines, their metabolites, and adrenergic receptors were similar in both groups. At 4 weeks, plasma levels of NE and DOPEG were lower (p less than 0.01), whereas levels of DOMA and NMN were higher (p less than 0.02 and p less than 0.001, respectively) in the 1K1C group than the control group. Cardiac content of NE (p less than 0.01), and DOPEG (p less than 0.05) was significantly lower, whereas DOMA and NMN were significantly higher (p less than 0.01) in the 1K1C group as compared to controls. In addition, cardiac density of both alpha- and beta-adrenergic receptors was reduced in the 1K1C group, whereas receptor affinities were unchanged.(ABSTRACT TRUNCATED AT 250 WORDS)

Trophoblastic cells of the hydatidiform mole contain a beta 1-subtype adrenergic receptor.

Both beta 1- and beta 2-adrenergic receptors have been previously described in normal human placental homogenates; the cells upon whose surface membranes these receptors reside have not been identified. In order to show that a beta 1-adrenergic receptor is present on trophoblastic cells, the cells which mediate maternal-fetal transport and produce placental hormones, beta-adrenergic receptors were demonstrated in membrane fractions of human hydatidiform mole. Microscopic sections of the mole samples used demonstrated edematous villi lined by trophoblastic cells with minimal nontrophoblastic (stromal or vascular) contamination compared with placenta. (--)-[3H]Dihydroalprenolol [(--)-[3H]DHA] binding to molar membranes was reversible and saturable to a single class of sites (Kd = 0.97 +/- 0.12 nM; n = 7; maximum binding capacity, 72.9 +/- 6.4 fmol/mg protein). (--)-[3H]DHA binding was associated with catecholamine-stimulated adenylate cyclase activity. Agonist competition for the molar beta-adrenergic receptor showed the order of potency to be (--)isoproterenol much greater than norepinephrine = epinephrine, characteristic of a beta 1-adrenergic receptor subtype. Competition for (--)-[3H]DHA binding to trophoblastic membranes by the beta-adrenergic receptor subtype-specific agents metoprolol (beta 1 selective) and zinterol (beta 2 selective) was also characteristic of a homogeneous subtype of beta 1-adrenergic receptors. Because beta 1-adrenergic receptors alone were seen on trophoblast cells, the beta 2-adrenergic receptor in placenta must reside on nontrophoblastic elements (stromal or vascular endothelium). No differences in beta-adrenergic receptor binding were seen related with ploidy (2 or 3 N), the presence or absence of a fetus, or the progression of the mole to choriocarcinoma. Two choriocarcinoma cell lines, BeWo and JEG-3, however, showed no specific (--)-[3H]DHA binding. Human trophoblast contains beta 1-adrenergic receptors coupled to catecholamine-sensitive adenylate cyclase, supporting a role for catecholamines in the regulation of placental metabolism.

Catecholamines and their receptors in blood: evidence for alterations in schizophrenia.

The simultaneous determination of serum catecholamine (CA) and their receptors in blood cells offers the possibility of evaluating disturbances of the dopamine (DA) and noradrenaline (NA) neuronal systems in man. High-affinity binding sites for 3H-yohimbine in platelets, 3H-DHA in granulocytes, and 3H-spiperone in lymphocytes from healthy control persons, unmedicated (n = 28), and medicated (n = 8) schizophrenics, and from an unmedicated psychiatric control group (n = 14) were investigated. Furthermore, the actual concentration of the circulating CA was determined with HPLC-ECD. In unmedicated schizophrenics, as compared with controls, specific binding of 3H-spiperone to lymphocytes was markedly elevated in capacity and less in affinity. For beta 2 receptors a significant decrease was found in capacity with no change in affinity. The changes in alpha 2 receptors, viz. a slight decrease in capacity, were less distinct. The concentrations of circulating CA ranged from normal values to a more than threefold increase in NA and DA, whereas adrenaline (A) concentrations were nearly unchanged. No overall change in these data was found in the medicated schizophrenic patients. 3H-Spiperone binding was characteristically increased only in schizophrenics, but did not rise above control data in the nonschizophrenic psychiatric control group. Preliminary family studies suggest that this model could be valuable as a vulnerability marker.

Alpha 2-adrenoceptors in the brain of suicide victims: increased receptor density associated with major depression.

To examine directly in the brain the status of the alpha 2-adrenoceptor in major depression, the specific binding of the agonists [3H]clonidine and [3H]UK 14304 was quantitated in various brain regions of suicide victims with a retrospective diagnosis of depression or other psychiatric disorders. In depressed suicides, the binding capacity of [3H]clonidine was found to be increased in the hypothalamus (Bmax 35%-55% greater), and to a lesser extent in the frontal cortex, as compared with that in matched controls, schizophrenic suicides, or suicides with various diagnosis. The binding capacity of [3H]UK 14304 also was found increased in the frontal cortex (Bmax 30% greater), and to a lesser extent in the hypothalamus, of depressed suicides. In other brain regions such as the amygdala, hippocampus, and cerebellum there also was a tendency for an increased receptor density associated with suicide. Moreover, in the frontal cortex of suicides, the potency of norepinephrine in displacing the binding of the antagonist [3H]idazoxan also was found increased (Ki decreased eight-fold). The results indicate that the density and affinity of alpha 2A-adrenoceptors in the high-affinity state are increased in the brain of depressed suicides.